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Abstract

The World Health Organization suggests that the cardiovascular diseases (CVDs) are the major cause of mortality and account for two-thirds of the deaths all over the world. These diseases kill about 17 million people every year and 3 in every 10 deaths are due to these diseases. The past decade has seen considerable improvements in diagnosis as well as treatment of various heart diseases. Various new therapeutic targets are being identified through in-depth knowledge of the disease mechanisms which has favored the testing of new strategies leading to newer treatment options. Opioid peptides and G-protein-coupled opioid receptors (ORs) have been previously studied widely in terms of central nervous system actions in mitigating the pain and drug abuse. The OR agonism or antagonism induces cytoprotective states in the myocardium, rendering these receptors as an attractive target for protection of heart from the fatal heart diseases. The opioids can provide an extended window of protection of the heart from various diseases. Although the mechanisms may not be fully understood, they seem to play a crucial role in various CVDs such as hypertension, hyperlipidemia, ischemic heart disease myocardial ischemia, and congestive heart failure. Since these compounds are already being used in acute and chronic pain, soon these compounds might be approved for use as cardioprotective agents. The following review focuses on the new information acquired on the role of the ORs in various CVDs.

Keywords

opioid receptors cardiovascular diseases opioid agonist opioid antagonist

Introduction

Cardiovascular diseases (CVDs) including coronary heart disease, hypertension, and stroke are the major causes of deaths all over the world. In 2013, there were more than 54 million deaths globally, 32% of which were due to CVDs. Each year 17.5 million people die from CVDs, which accounts for about 31% of deaths all over the world.¹ There are several pharmacological therapies that have been used currently to treat the CVDs, which include β-blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blocker, calcium channel blockers, nitrates, digoxin, and so on. But these drugs are associated with several side effects such as changes in blood pressure, hyperkalemia, arrhythmias, edema, to name a few. According to a study conducted in various hospitals, it was suggested that about 1.2% of patients are admitted to the hospitals due to the side effects of the cardiovascular drugs that are given to them. About 193 different types of side effects were reported which were majorly due to the pharmacological effects of the drugs and to a lesser extent the immunological character of the drug. Most of the side effects were due to coronary vasodilators (31.53%), followed by calcium channel blockers (18%) and cardiac glycosides (12.6%).² Not only the drugs but the various surgical interventions that are done to treat the patients, such as angioplasty and coronary artery bypass graft, may also cause cardiac hypertrophy, remodeling, and so on, in the long run and can increase the chance of mortality and morbidity in the patients. Hence, we need new safe and effective targets to treat these diseases.

Several new targets have been identified for CVDs such as netrin-1³, myocardin,⁴ mitochondrial calcium uniporter,⁵ small interfering RNA,⁶ opioids receptors, and so on. Opioid and opioid receptors (ORs) have been generally associated with the pain-modulating pathways and also with the treatment of various other disorders, which include diarrhea, cough, postoperative pain, and cancer, but recently they have been found to play a certain role in the cardiovascular system. Opioid receptors have been documented to be used in various diseases such as hypertension, arrhythmia, hyperlipidemia, ischemic heart disease (IHD), and congestive heart failure (CHF). Despite positive results, there are very few clinical trials of OR-mediated targeted cardioprotection.⁷ In view of the abovementioned facts, this review aims to highlight and understand the role of the different types of opioids and ORs in various CVDs. We hypothesize that OR/s could serve as a novel target for several CVDs and opioid agonist/antagonist could be developed for the treatment of the same.

Structure and Types of OR

Opioid receptors belong to class A, G-protein-coupled receptors (GPCRs)—the rhodopsin subfamily. The ORs have 7 transmembrane-spanning helix. These receptors consist of a single polypeptide chain with an extracellular N-terminus and 7 hydrophobic transmembrane segments that are interconnected. These extracellular loops end with a cytoplasmic C-terminal tail. The N-linked glycosylation sites are present in the N-terminus, while the cytoplasmic loops and the C-terminal contain multiple phosphorylation sites. The hydrogen bonding network connects the helices which changes by protonation leading to its activation. The intracellular side of the membrane contains the eighth shorter helix which has many structural elements for maintaining uniform signal transduction.⁸

Opioid compounds and receptors have been related to management of pain and abuse of drugs. The different ORs which are known are mu (μ), delta (δ), kappa (κ), and ORL1. Table 1 provides an overview of different types of ORs.⁹

Table 1.

Different Types of Opioid Receptor and Their Pharmacological Actions.

Receptor	Location	Response
μ	Cortex, thalamus, olfactory bulb, nucleus accumbens, amygdala, others periaqueductal gray, spinal cord, intestinal tract, heart (in the sarcolemma)	Analgesia, respiratory depression, miosis, relaxed euphoria, sedation, sense of tranquility, reduced apprehension and concern, cough suppression, and reduced GI motility
μ1	Brain, spinal cord, periphery	Cortical analgesia and also associated with physical dependence
μ2	Brain, spinal cord, periphery	Euphoria, respiratory depression, miosis, reduced GI motility, physical dependence
μ3	Immune cells, amygdala, peripheral neural, CV endothelial cells	Unknown what it does
κ	Hypothalamus, periaqueductal gray, claustrum, spinal cord, heart (in the sarcolemma)	Spinal analgesia, dysphoria, psychotomimetic effects, miosis, minimal respiratory depression, involved in ischemic conditioning, antiarrhythmic effect, and antihyperlipidemic effect
δ	Pontine nuclei, amygdala, olfactory bulbs, cortex, heart (in the sarcolemma)	Creates analgesia, has antidepressant properties associated with physical dependence, and involved in ischemic conditioning
ORL1	Cortex, amygdala, hippocampus, septum, habenula, hypothalamus, spinal cord	Anxiety, depression, appetite loss, and also causes tolerance to μ agonists

Abbreviation: CV, cardiovascular; GI, gastrointestinal.

Opioid receptors are present in the areas which are associated with modulation of pain. These receptors activate Gi-proteins, form complexes that signal various cascades, and modify a variety of proteins. Table 2 provides an overview of various agonist and antagonist at ORs.^10
–12

Table 2.

Agonist and Antagonist at Different Opioid Receptors.

Drug	μ	δ	κ
Enkephalins	Antagonist	Agonist	–
β-Endorphin	Agonist	Agonist	–
Morphine	Agonist	Weak agonist	–
Codeine	Weak agonist	Weak agonist	–
Etorphine	Agonist	Agonist	Agonist
Buprenorphine	Partial agonist	–	–
Pentazocine	Antagonist or partial agonist	–	Agonist
Naloxone	Antagonist	Antagonist	Antagonist
U50488H	–	–	Agonist
Dalargin	Agonist	–	–
Biphalin	Agonist	Agonist	–

Signal Transduction Mechanism of OR

Opioid receptor signaling involves the activation of G-protein through an opioid agonist. The OR modulates calcium and potassium ion channels. The inhibitory function is mediated by the α subunit. The α unit dissociates from the βγ unit and binds with the inward rectifying potassium channel, Kir3. Channel gets deactivated when guanosine triphosphate gets converted to guanosine diphosphate and by the removal of βγ subunit from interaction with the potassium channel, which then causes hyperpolarization and produces an inhibitory effect. When activated, all ORs cause a reduction in calcium currents that are sensitive to the various type of calcium channel blockers. The βγ subunit directly binds to the calcium channel and inhibits its conductance.

G-protein-coupled receptor kinase 2/3 causes phosphorylation of ORs, which leads to arrestin 2/3 recruitment. Opioid receptors are regulated by arrestin-2 and 3 binding. Arrestin are proteins that help in determining the fate of a receptor. The phosphorylated arrestin-bound GPCR complex initiates alternate signal transduction cascade including mitogen-activated protein kinases (MAPKs). Mitogen-activated protein kinase pathways are diverse signaling cassettes that govern cellular responses such as cell proliferation, differentiation, apoptosis, and so on. The various forms of the MAPK family include extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun NH2-terminal Kinase (JNK) 1 to 3, and p38 (α, β, γ, δ) stress kinase. The opioid-induced MAPK cascade ERK1/2 is most frequently studied. These pathways have different triggers that activate them, that is, the JNK pathway is triggered by stress, inflammation, cytokine activation, and neuropathic pain, while the p38 MAPK pathway which is activated by cytokine production plays an important role in environmental stress and inflammation. After the signal transduction through the MAPK pathway, a response is produced and finally recycling takes place.⁷ A schematic representation of the signal transduction mechanism of ORs is provided in Figure 1.

Figure 1.

Signal transduction mechanism of opioid receptors.

Opioid and ORs in CVDs

Opioids have functions in the cardiovascular system. Opioid receptor activity may modulate vascular tone and may protect the heart. The OR agonism exerts a protective action on the heart tissue, making them a new target for cardioprotection. The ORs are involved in several CVDs such as IHD, hyperlipidemia, CHF, and hypertension, which are discussed in the upcoming sections.¹³

Hypertension

Hypertension is a condition in which there is an elevation in blood pressure in the arteries over a long period of time. It affects about 1.13 billion people worldwide.¹⁴ Opioid pathways cause hypotensive response through serotonergic receptor stimulation and all the ORs participate in it.¹⁵

The cardiovascular effects of biphalin, an agonist of opioid μ and δ receptors, were studied. Biphalin was infused in hypertensive rats and normotensive Wistar-Kyoto rats. Along with mean atrial pressure (MAP) and heart rate, renal blood flow and iliac blood flow were measured using transonic probes on the renal and iliac artery, respectively. The effects of biphalin were compared with those of intravenous morphine and it suggested that biphalin decreased MAP, while there was no significant effect on the heart rate. The renal blood flow increased modestly and both renal and hind limb vascular resistance decreased significantly. The effects were blocked by inhibition of peripheral ORs with naloxone methiodide.¹⁶

A study was conducted to observe the hypotensive effect of β-endorphin on the blood pressure in healthy participants and in patients with hypertension. A randomized double-blind design involving 11 healthy volunteers and 12 patients with hypertension received a β-endorphin infusion followed by an infusion with the opioid antagonist naloxone. These effects were mediated through OR agonism, which was through the inhibition of vasoconstrictive substances such as norepinephrine and endothelin-1 and by the simultaneous stimulation of vasorelaxing peptides such as atrial natriuretic factor (ANF) and growth hormone (GH) levels/insulin-like growth factor-I (IGF-I). It was concluded that at higher doses β-endorphin induces a hypotensive effect which is mediated by ORs.¹⁷ The mechanisms through which the β-endorphin produces such hemodynamic effects in the participants have not been completely determined. It was suggested that the hypotensive response was due to the alterations in circulating vasoactive hormones. This view was supported by 2 main considerations, namely, a consistent β-endorphin-mediated reduction in the vasoconstrictive neurohormones such as nonepinephrine and endothelin 1 and β-endorphin-mediated increase in the plasma concentrations of vasorelaxing peptides.¹⁸ In an animal study, it has been documented that opioids inhibit endothelin release from the porcine aorta.¹⁹ It has been reported that opioids lead to presynaptic inhibition of release of noradrenaline.¹⁸ Additionally, sympathetic nervous system (SNS) activity is decreased by the stimulation of the mu ORs.²⁰

In another study, β-endorphin is reported to cause an increase in the plasma GH levels and IGF-I in fasted rats. It was also shown that activation of GH levels and IGF-I levels caused lowering of the blood pressure and peripheral vascular resistance through the nitric oxide (NO) pathway.²¹ Thus, from the abovementioned facts, we can say that β-endorphin produces a reduction in lowering the blood pressure.

In another study, when the endogenous opioid peptides were given through the lateral ventricle injections, it produced a significant pressor response,²² and when endorphin was given intracerebroventricularly, it produced an increase in blood pressure in obese rats.²³ On the other hand, β-endorphin, when given as a cerebroventricular injection, produces a significant fall in blood pressure,²⁴ and when it is given in the hypothalamic preoptic area, it abolishes the pressor response produced by hypertonic saline solution and causes hypotension and bradycardia.²⁵

In another study, OR antagonist, naloxone, and a placebo, which is dextrose 5% in water, were given to healthy male volunteers and to the male patients having essential hypertension. The study was single-blind, placebo-controlled, cross-over design. The plasma cortisol levels significantly increased in the patients with hypertension at low doses of naloxone. It was concluded that endogenous opioids do not play a significant role in regulating BP and HR. The authors suggested that this might be due to the endogenous opioid substances that produce a tonic inhibitory effect on the release of cortisol, which is greater in patients with hypertension than in normotensive patients, though the exact mechanism was not determined.²⁶

A study was conducted to understand the role of brain mu (µ), κ, and δ ORs and the effect of brain serotonergic (5-hydroxytryptamine-3 [5-HT3]) receptors on blood pressure for which the MAP was recorded in rats who received a 5-HT3 selective agonist m-chlorophenyl biguanide (m-CPBG). To understand whether the central serotonergic pathways were involved in regulating the blood pressure, the MAP was recorded in rats treated with 5-HT3 antagonist ondansetron which acted as controls in the study. To understand the role of central opiatergic pathways in the hypotensive response induced by central 5-HT3 receptor stimulation, rats received m-CPBG 30 minutes after the pretreatment with distinct opioid antagonists: naloxone binding to µ receptors, norbinaltorphimine (nor-BNI) binding to K receptors, and naltrindole binding to δ receptors. It was concluded that all the OR subtypes µ, κ, and δ need to be simultaneously activated for 5-HT3 receptor-dependent hypotension to occur since the blockade of each one of these receptors completely abolishes this effect.²⁷ This study confirms that the serotonergic receptor-dependent mechanism contributes to the regulation of the cardiovascular effects since the hypertensive response that is observed after the administration of ondansetron indicates that the serotonergic receptors have a tonic inhibitory effect on blood pressure.²⁸ The importance of serotonergic pathways in controlling the blood pressure has been previously demonstrated in nonstressed rats and also the selective agonist-induced 5-HT3 receptor activation blocks stress-induced hypertension.²⁹ Another study suggested that the 5-HT3 receptors located at medial septum/vertical limb of the diagonal band) through angiotensinnergic mechanisms tonically inhibit the sympathetic activity in that area.³⁰

The ongoing phase 3 trial conducted to observe the effects of blood pressure on elderly patients as reported in Table 4 also supports our hypothesis that opioids play a significant role in hypertension. Hence, μ and δ opioid agonists, such as β-endorphin, and nonspecific antagonist, such as naloxone, can be promising drug candidates in future for hypertension.

Arrhythmia

The abnormality in the sequence of normal activation of the myocardium leading to an abnormal heart rhythm is called an arrhythmia. Some common symptoms include dizziness, palpitations, and syncope, while sudden cardiac death remains one of the major health concerns.³¹ About 50% of patients have sudden death at first manifestation of arrhythmia.³²

A study was undertaken to understand the involvement of δ- and κ-ORs in both ischemia- and reperfusion-induced arrhythmias and to elucidate some of the plausible mechanisms conferring antidysrhythmic effects on opioid δ- and κ-receptor agonists and antagonists. Different models of arrhythmia (calcium chloride, adrenaline, and ischemia/reperfusion-induced arrhythmias) were employed. The following opioid agonists, antagonists, and blockers were used in the study:

[d-Ala(2), d-leu(5)]enkephalin (DADLE), a selective δ-receptor agonist;

trans-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl)benzeneacetamide (U-50488 H), a selective κ-receptor agonist;

naltriben methanesulfonate (NTB), a selective δ(2)-antagonist with κ-receptor agonist-like activity;

natrindole, a nonselective δ(1)- and δ(2)-receptor antagonist;

nor-BNI dihydrochloride, a selective κ-receptor antagonist;

chelerythrine, a selective protein kinase C (PKC) inhibitor; and

glibenclamide, a selective blocker of adenosine tri phosphate (ATP)-sensitive K channel.

The results of the studies suggested that both opioid, δ(1)- and κ-receptors are involved in the phenomenon of ischemic heart preconditioning, and the antidysrhythmic effects of the opioids seem to be mediated mainly via κ-receptors. The antidysrhythmic effect of U50488H was found to be a consequence of its β-blocking activity and its ability to prolong myocardial action potential. The antiarrhythmic effects of these compounds were almost completely abolished by pretreatment with glibenclamide.³³ These results were consistent with another reported study where κ receptor agonist U50488H reduced the effects of ischemia on arrhythmia and infarct.³⁴ In this study, 2 series of the experiment were performed on the isolated rat myocardium to determine the role of κ and δ ORs in mediating the effects of ischemic precondition in both infarct and arrhythmia

Through the experiments, it was found that nor-BNI, which is a selective κ receptor antagonist, attenuated the ameliorating effect of ischemic preconditioning (IP) and κ-receptor agonist U50488H or a δ OR selective agonist (DADLE) and reduced the infarct size in arrhythmia by mimicking the effects of IP.³⁵

Thus, this study suggests that κ-ORs mediate the IP effects in both infarct and arrhythmia, while the δ OR mediated the effects on infarcts only. The authors suggested that the cardioprotective effects were mediated through PKC and ATP-sensitive K⁺ (K⁺ATP) channels that worked by reducing the infarct size.^24,36,37 A study reported that κ receptor agonist U50488H produces cardioprotection that is similar to the metabolic inhibition preconditioning via PKC in the rat ventricular myocyte.³⁸

The present observations suggested that ORs may have a potential to protect the myocardium during cardiac ischemia at the early stages of myocardial infarction (when early arrhythmias are the most common causes of death).³⁹ These studies support our hypothesis that opioids play a significant role in arrhythmia. Hence, DADLE, a selective δ-receptor agonist; U-50488 H, a selective κ-receptor agonist; NTB, a selective δ(2)-antagonist with κ-receptor agonist-like activity; natrindole, a nonselective δ(1)- and δ(2)-receptor antagonist; and nor-BNI, a selective κ-receptor antagonist can be promising drug candidates in future for hypertension.

Hyperlipidemia

Hyperlipidemia refers to the disorder that results in an elevation in the serum lipid levels, that is, elevation of fats, cholesterol, and triglycerides. According to the World Health Organization (WHO), hyperlipidemia is a major risk factor for many CVDs accounting for more than 133 million people in the United States and Europe. ⁴⁰ It is commonly seen in developed countries where people have a high-fat diet. High serum lipid levels lead to deposition and oxidation of LDL-C in the vessel wall, causing endothelial dysfunction through inflammation, oxidation, and endothelial nitric oxide synthase (eNOS) uncoupling, which ultimately lead to atherosclerosis. These risk factors alter endothelial function and disturb the vascular homeostasis. Thus, it is very important to maintain the endothelium function in hyperlipidemia to prevent atherosclerosis at an early stage. The vascular integrity is maintained with endothelium-derived substances such as NO.⁴¹

A study was conducted to understand the role of the opioid system in stress-induced hypercholesterolemia. Stressful stimuli are known to cause an increase in the total plasma cholesterol levels and in turn activating the opioid systems. In this study, the female rats were fed with high-cholesterol diets consisting of cholic acid. For the next 5 days, they were subjected to immobilization stress paradigm which increased low- and very-low-density lipoprotein cholesterol level and reduced high-density lipoprotein cholesterol level. When these rats were pretreated with naltrexone, an opiate antagonist, it prevented the stress-induced changes, which suggested that endogenous opioid systems play a role in the treatment of stress-induced hypercholesterolemia.⁴²

A study was conducted to observe the effects of U50488H (a selective κ-OR agonist) on the hyperlipidemia-impaired endothelial function and also to determine the role of Akt-stimulated NO production in it. In this study, the rats were fed a high-fat diet for the period of 14 weeks. It was demonstrated that κ-OR stimulation with U50488H caused the dilation of the vessels in a NO-dependent manner. This effect is mediated through the preservation of eNOS phosphorylation by activation of phosphatidylinositide 3-kinases/protein kinase B (PI3K/Akt) signaling pathway and downregulation of inducible NO synthase (iNOS) expression/activity. It has also shown to attenuate the pulmonary arterial pressure in rats and protection of the pulmonary artery endothelium through preservation of eNOS activity and antiapoptotic effect, suggesting that κ-OR stimulation with U50488H can play an important role in protecting the endothelial function in hyperlipidemia.^43,44

A clinical trial was conducted to observe the effects of opioids on patients with coronary artery diseases as reported in Table 4, which also supports our hypothesis that opioids may have played a significant role in future for the treatment of hyperlipidemia. Hence, U50488H, a selective κ-OR agonist, and nonspecific antagonist such as naltrexone can be promising drug candidates in future for hyperlipidemia.

Ischemic Heart Disease

Ischemic heart disease occurs when the coronary arteries become narrow by a gradual buildup of fatty material within their walls. Normally, coronary arteries supply oxygen-rich blood to the heart muscles. Hence, when occluded, it leads to an imbalance between the demand and supply of oxygen in the heart. Ischemic heart disease is the major cause of death all over the world,^45

–48 which increases the economic and resource burden on the health-care systems. Although there is a decline in the mortality rates in the high-income countries from IHD,^49

–54 the mortality rates continue to increase in the low-income countries.⁵⁵

Conditioning is a procedure where the alternating period of ischemia and reperfusion is applied on long-standing ischemia. Cardiac ORs, μ, κ, and δ are involved in mediating “conditioning” responses through receptor ligation before or immediately after the ischemic insult. Opioid receptor subtypes are engaged in various pro-survival kinase cascades to produce a desirable effect. Pre- and postconditioning responses are widely studied.⁵⁶

In preconditioning, the heart is protected from the ischemic injury by subjecting the myocardium through a brief period of ischemia followed by reperfusion therapy. When the conditioning stimulus is applied during or after the event (reperfusion), it is called postconditioning. Preischemic OR agonism mimics IP and the antagonists of the OR counter the protection with preconditioning when applied prior to the IP stimulus, in an acute setting or in a delayed preconditioning model.⁵⁷

Opioid receptor–based preconditioning pretreatment with the µ receptor-selective agonist remifentanil reduced circulating troponin I and creatine kinase-MB levels following a coronary bypass and it was also suggested that the morphine pretreatment reduced the inflammatory response and improved myocardial performance following cardiopulmonary bypass.⁵⁶ Preconditioning-like effects of selective δ receptor agonists have been confirmed in a variety of models including neonatal and adult rat cardiomyocytes where ischemia and reperfusion were performed in an intact infarct rat model and it was concluded that mesenteric preconditioning releases endogenous opioids that protect the myocardium from ischemic injury.⁵⁸ A similar study was also performed in in situ and ex vivo rodent hearts, which suggested that PKC plays an important role in cardioprotection after δ receptor stimulation with TAN-67.⁵⁹ Cardioprotection via the δ-1 OR is through the pertussis toxin-sensitive mechanism with the involvement of Gi/o protein. This is in agreement with the fact that PKC is involved in IP-induced cardioprotection. The ATP-sensitive potassium ion channels are also said to be involved in the cardioprotective effects mediated by the ORs.^60

–65 Another study done on rabbit myocardium reported that late preconditioning was observed after δ receptor activation through an agonist BW-373U86 whose effect was counteracted by cyclooxygenase-2 (COX-2) inhibitor celecoxib.⁶⁶ This study suggests that the ischemia-induced late IP is mediated by increased expression and activity of iNOS^67,68 and COX-2. The NOS mediates its action in late preconditioning against infarction through the adenosine A1 receptor.^69

–72 Inducible NO synthase is known to mediate the δ-1 OR-induced late IP. Previous studies have also suggested that δ ORs induce both early and late postconditioning against myocardial infarction^{57,73

–78} and the protective phenomenon induced by the δ OR s is through the generation of free radicals,^79

–82 PKC,^65,83

–86 Gio proteins,^87,88 ATP-sensitive K-channels,^{75,79,88

–94} and MAPKs.^8,95,96 Mechanisms of protection via such a transferrable opioid may also involve ROS generation,⁹⁷ ERK1/2 and PKC signals,⁹⁸ CGRP signaling, and inhibition of the mitochondrial permeability transition pore (mPTP).⁹⁹

The OR subtypes mediating ischemic postconditioning is still being studied. In isolated myocardium, the role of the delta opioid receptor (DOR) appears to be really crucial¹⁰⁰ and its antagonism can also counteract ischemic postconditioning in vivo.¹⁰¹ In some studies, elevations in cardiac enkephalins during ischemic postconditioning in rats coupled with DOR- and μ OR (MOR)-dependent protection was reported.¹⁰²

The post-conditioning effects of agonists both in vitro and in vivo suggest that myocardial protection may be induced via selective κ OR (KOR) or DOR. The mechanisms activated by MOR selective agents are similar to those coupled to KOR and DOR responses, including PI3K/Akt signaling with an inhibition of glycogen synthase kinase 3β and modulation of bcl-2-like protein 4 (BAX) and B-cell lymphoma 2 expression,¹⁰³ PKC activity and attenuation of intercellular adhesion molecule 1 expression,¹⁰⁴ opening of mitochondrial ATP-sensitive K+ channels, and inhibition of the mPTP.¹⁰⁵

The ongoing phase 3 trial conducted to observe the effects of an opioid analgesic in the treatment of ischemic pain in patients as reported in Table 4 also supports our hypothesis that opioids may have played a significant role in future for the treatment of IHD . Hence, µ receptor-selective agonist remifentanil, δ receptor agonist TAN-67, and BW-373U86 can be promising drug candidates in future for IHD.

Congestive Heart Failure

Heart failure is a chronic condition that affects the ability of the heart muscles to pump blood which is caused by the fluid buildup around the heart which causes it to pump inefficiently, whereas “congestive heart failure occurs due to the blood backing up into or congesting the liver, abdomen, lower extremities, and lungs. About 26 million people have CHF worldwide.¹⁰⁶

A study was conducted to show the effect of opioids on CHF where 3 groups of dogs with CHF and 1 group of sham-operated dogs were taken. One group of dogs with CHF was given normal saline as pretreatment, whereas the other 2 groups were pretreated with either propranolol alone (β-blockade) or propranolol plus prazosin (α- plus β-blockade).¹⁰⁷ Congestive heart failure was observed in the animals with ascites, increased body weight, hepatomegaly, high right atrial pressure, increased heart rate, reductions in cardiac output, left ventricular failure, and a decrease in the regional blood flow. Compared to sham-operated animals, animals with CHF exhibited significantly higher baseline levels of plasma β-endorphin and cortisol. The study suggested that opiate antagonism inhibits the SNS and increase the norepinephrine and arterial pressure. The hemodynamic effects of endogenous opiates are probably mediated by a central nervous system action of the peptides to decrease SNS activity. There are a close interaction and interdependency of the opioid system and the SNS. They have been shown to inhibit the release of norepinephrine during nerve stimulation from adrenergically innervated peripheral tissues and to modulate peripheral adrenergic transmission. β-Endorphin is elevated in chronic CHF, and the endogenous opioids probably contribute significantly to the circulatory dysfunction observed in CHF. Opiate receptor antagonism is responsible for its role in heart failure. The improvement in systemic and regional hemodynamics in CHF after opiate receptor inhibition is probably mediated through inhibition of SNS.¹⁰⁸

In another study, DOR localization was determined by radioligand binding using naltrindole, and by double immunofluorescence, confocal analysis in the left ventricle (LV) of male Wistar rats with CHF was carried out.¹⁰⁹ After 28 days, the extent of CHF, adaptations in left ventricular δ OR, and precursor peptide proenkephalin (PENK) expression were examined. The results showed that severe CHF was accompanied by upregulation of δ OR and PENK on mRNA as well as receptor proteins.¹¹⁰ These studies indicate that the DOR system possesses the ability to regulate calcium homeostasis in cardiomyocytes, particularly in response to cardiac failure.¹¹¹

A similar study was done using male Wistar rats to show the effect of κ OR s (KOR) and its endogenous ligand precursor peptide prodynorphin in response to heart failure. It was suggested that after heart failure, they are upregulated on the mRNA and protein level in the LV. This suggests that the cardiac κ opioid system may play an important role in modulating the heart failure.112

In a study previously reported, β-endorphin is also stated to cause a positive response of ANF and produce potent vasodilation and diuretic effects,^113,114 in healthy people and patients with dilated cardiomyopathy during mental stress.¹¹⁵

These studies support our hypothesis that opioids play a significant role in CHF. Hence, μ and δ opioid agonists, such as β-endorphin and DOR antagonist naltrindole, can be promising drug candidates in future for CHF.

Table 3 contains the summary of various opioid agonist and antagonist being used in different heart diseases. Table 4 contains the list of various clinical trials being conducted on different heart diseases.¹¹⁶

Table 3.

Summary of the Opioid Agonist and Antagonist in Various Cardiac Diseases.

Disease	Name of Drug	Agonist/Antagonist and Receptor	Animal Model/Participant	Key Effect	Reference
Hypertension	Biphalin	Agonist of μ and δ receptors	Hypertensive Wistar-Kyoto rats	Decreased mean atrial pressure	¹⁶
Hypertension	β-Endorphin	Agonist of μ receptors	Hypertensive patients	Hypotensive effect was observed	^17,18
Hypertension	β-Endorphin	Agonist of μ receptors	Fasted rats	Through the activation of GH and IGF-I levels there was a reduction in blood pressure and peripheral vascular resistance through the nitric oxide pathway.	²¹
Hypotension	Opioid peptides	Agonist of μ, κ, and δ receptors, respectively	Obese rats	There was an elevation in blood pressure	²²
Hypotension	Endorphins	Agonist of μ, κ, and δ receptors, respectively	Obese rats	There was an elevation in blood pressure	²³
Hypertension	Beta-endorphin	Agonist of μ receptors	Obese rats	There was an fall in blood pressure	^24,25
Hypertension	Naloxone	Antagonist of μ, κ, and δ receptors	Patients with hypertension	Hypertensive patients responded to lower doses of naloxone with greater increases in plasma cortisol.	²⁶
Hypertension	Naloxone, norbinaltorphimine, and naltrindole	Antagonist of μ, κ, and δ receptors, respectively	Hypertensive Wistar-Kyoto rats	Simultaneous activation of µ, κ and δ opioid receptors appears to be necessary for 5-HT3 receptor-dependent hypotension to occur since the blockade of each one of these receptors completely abolishes this effect	^27,28
Arrhythmia	[d-Ala(2), d-leu(5)]enkephalin (DADLE), trans-3,4-dichloro-N-methyl-N-[2-(1- pyrrolidinyl)cyclohexyl]benzeneacetamide (U-50488 H), naltriben methanesulfonate (NTB), natrindole, norbinaltorphimine dihydrochloride (nor-BNI)	A selective δ-receptor agonist; a selective κ-receptor agonist; a selective δ(2)-antagonist with κ-receptor agonist-like activity; a nonselective δ(1)- and δ (2)-receptor antagonist; a selective κ-receptor antagonist	Arrhythmia-induced rats	It was suggested that both opioid δ (1)- and κ-receptors are involved in the phenomenon of ischemic heart preconditioning (IPC), the antidysrhythmic effects of the opioids seem to be mediated mainly via κ-receptors. The antidysrhythmic effect of U50488H was found to be a consequence of its β-blocking activity and its ability to prolong myocardial action potential	³³
Arrhythmia	Norbinaltorphimine (nor-BNI)	A selective κ-receptor antagonist	Arrhythmia-induced rats	Reduced the infarct size in arrhythmia	^34,35
Arrhythmia	U50488H d-Ala2-d-leu5-enkephalin (DADLE)	A selective κ-receptor agonist; a δ-opioid receptor selective agonist	Arrhythmia-induced rats	Reduced the infarct size in arrhythmia	^36,37,38
Hyperlipidemia	Naltrexone	Opiate antagonist	Cholesterol-cholic, acid-fed female rats	Pretreatment with the opiate antagonist, naltrexone prevented the stress-induced changes which suggested a possible role of endogenous opioid systems in stress-induced hypercholesterolemia	⁴²
Hyperlipidemia	U50488H	Selective κ-opioid receptor agonist	Hyperlipidemia-induced rats	κ-OR stimulation with U50488H protects endothelial function in hyperlipidemia	^43,44
Ischemic heart disease	Remifentanil	µ-selective agonist	Neonatal and adult rat cardiomyocyte, in situ and ex vivo rodent hearts, rabbit	Pretreatment with the agonist reduced the inflammatory response and improved myocardial performance following cardiopulmonary bypass	⁵⁶
Ischemic heart disease	TAN-67	δ receptor agonist	Rodent hearts	Provided cardioprotection through the protein kinase C activation	^59 –65
Ischemic heart disease	BW-373U86	δ receptor agonist	Rabbit myocardium	The activation of delta opioid receptor increased expression and activity of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) which mediated the late ischemic preconditioning and provided benefits in ischemic heart disease	^66 –72
Congestive heart failure	Naloxone	Antagonist of μ, κ, and δ receptors	Dogs induced with congestive heart failure	β-endorphin is elevated in chronic CHF, and the endogenous opioids probably contribute significantly to the circulatory dysfunction observed in CHF. Opiate-receptor antagonism is responsible for its role in heart failure	^107,108
Congestive heart failure	Naltrindole	δ receptors	Male Wistar rats induced with congestive heart failure	These studies indicate that the DOR system possesses the ability to regulate calcium homeostasis in cardiomyocytes particularly in response to cardiac failure	^109 –111
Congestive heart failure	Endogenous ligand precursor peptide prodynorphin (PDYN)	κ opioid receptor	Male Wistar rats with congestive heart failure	These findings suggest that the cardiac κ opioid system may play an important role in modulating the heart failure	¹¹²
Congestive heart failure	β-Endorphin	Agonist of μ receptors	In healthy people and in patients with dilated cardiomyopathy	β-Endorphin caused a positive response of ANF and produce potent vasodilation and diuretic effects in healthy people and patients with dilated cardiomyopathy	^113 –115

Abbreviations: CHF, congestive heart failure; DOR, delta opioid receptor; GH, growth hormone; IGF-I, insulin-like growth factor-I .

Table 4.

Clinical Trials Involving Study of Agonist/Antagonists of Opioid Receptors in Cardiac Diseases.

Title	Objective	Status	Key Results	Reference
Opioid compromise in hypertension-modulating factors	To confirm the preliminary findings of age, race, and hypertension chronicity effects on opioid and cardiovascular responses to stress and to determine the opioid mechanisms mediating these effects using an opioid receptor blockade strategy	Suspended	Reasons for suspending the trials were not disclosed	¹¹⁶
Opioid receptors influence ischemia–reperfusion injury	This study will increase our knowledge about the mechanism of ischemic preconditioning and may also provide leads to exploit this endogenous protective mechanism in a clinical setting by using annexin A5 scintigraphy	Suspended	Reasons for suspending the trials were not disclosed	¹¹⁶
Ischemic pain control with analgesic methods	To evaluate qualitative and quantitative pain control, incidence of adverse effects after treating with opioid analgesic	Ongoing, phase 3	No results reported	¹¹⁶
Fentanyl effect on blood pressure in elderly patients after induction of general anesthesia	This study examines the effect of fentanyl administration on blood pressure in elderly patients	Ongoing, phase 3	No results reported	¹¹⁶
The impact of opioids in coronary heart disease	In this study, the risk of opioid medications on coronary heart disease in adults is investigated	Completed	Results not posted	¹¹⁶

Conclusion

The OR appears to be an interesting candidate for clinical cardioprotection. They appear to target adaptive/protective responses to physiological and pathological stimuli. There are several studies which suggest that the use of OR-dependent analgesics and anesthetics may provide cardioprotection in patients, which is due to the ability of the opioids to reduce cardiac injury markers and inflammatory responses. The major drawbacks of these ORs have a potential to induce cardiorespiratory depression, and its prolonged agonism may also cause immunosuppressive or neuroendocrine changes along with addiction. However, such effects are receptor subtype-specific, and various studies show that cardioprotection can be effectively induced by brief and relatively low levels of subtype-specific OR agonism. As the technology is advancing, we are getting a better understanding of the various pathways through which the ORs function to produce a cardiovascular effect. Focused studies are required in the future with selective agonist and/or antagonist or to have specific pan agonistic activity. Thus, from the various preclinical and clinical studies conducted earlier, we can say that the ORs pose a great potential in being the targets for the treatments of various CVDs in future. Moreover, since these opioids are already approved for pain, the massive risk of withdrawal due to safety issues is alleviated. Additionally, newer agents can be designed such that the chemical moieties have specific pan agonistic properties which may serve as a boon for treating various CVDs in future.

Footnotes

Author Contributions

Bhoomika M. Patel contributed to conception and design, contributed to interpretation, critically revised the manuscript, gave final approval, and agrees to be accountable for all aspects of work ensuring integrity and accuracy. Hemangi Rawal contributed to acquisition and analysis, drafted the manuscript, and agrees to be accountable for all aspects of work ensuring integrity and accuracy.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Bhoomika M. Patel, BPharm, PhD

References

GBD Mortality and Causes of Death Collaborators. Global, regional, and national age–sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the global burden of disease study 2013. Lancet. 2015;385(9963):117–171.

Koleva

Madzharova

Baleva

Dragoicheva

Stoikova

Side effects of cardiovascular drugs. Vutur Boles. 1989;28(5):24–30.

Layne

Ferro

Passacquale

. Netrin-1 as a novel therapeutic target in cardiovascular disease: to activate or inhibit? Cardiovasc Res. 2015;107(4):410–419.

Alexander

Torrado

. In search of novel targets for heart disease: myocardin and myocardin-related transcriptional cofactors. Biochem Int. 2012;2012:973723.

Perricone

Richard

Vander

.Novel therapeutic strategies for ischemic heart disease. Pharmacol Res. 2014;89:36–45.

Raghunathan

Patel

, Therapeutic implications of small interfering RNA in cardiovascular diseases. Fundam Clin Pharmacol. 2013;27(1):1–20.

Headrick

See Hoe

Du Toit

Peart

. Opioid receptors and cardioprotection—“opioidergic conditioning” of the heart. Br J Pharmacol. 2015;172(8):2026–2050.

Al-Hasani

Bruchas

. Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology. 2011;115(6):1363–1381.

Dietis

Rowbotham

Lambert

. Opioid receptor subtypes: fact or artifact. Br J Anaesth. 2011;107(1):8–18.

10.

Way

Fields

Way

. Opioid analgesics and antagonists. In: Katzung

, ed. Basic and Clinical Pharmacology. United States: Appleton-Lange; 1998:496–515.

11.

Schuckit

Segal

. Opioid drug abuse and dependence. In: Isselbacher

Braunwald

Wilson

, eds. Harrison’s Principles of Internal Medicine. 14th ed, McGraw-Hill, Inc Health Professions Division; Pennsylvania, U.S; 1998:2508–2512.

12.

Coda

. Opioids. In: Barash

Cullen

Stoelting

, eds. Clinical Anesthesia. 3rd ed. Philadelphia, PA: Lippincott-Raven Publishers; 1997:329–358.

13.

Williams-Pritchard

. Myocardial opioid receptors in conditioning and cytoprotection. Pharmaceuticals. 2011;4(3):470–484.

14.

Global Health Observatory (GHO) data (2016). http://www.who.int/gho/ncd/risk_factors/blood_pressure_prevalence_ text/en/. Accessed February 19, 2018.

15.

Fregoneze

Oliveira

Ribeiro

Ferreira

De Castro

Silva

. Multiple opioid receptors mediate the hypotensive response induced by central 5-HT 3 receptor stimulation. Neuropeptides. 2011;45(3):219–227.

16.

Badzynska

Lipkowsi

Sadowski

. An antihypertensive opioid: biphalin, a synthetic non-addictive enkephalin analogue decreases blood pressure in spontaneous hypertensive rats. Pharmacol Rep. 2016;68(1):51–55.

17.

Cozzolino

. Acute pressor and hormonal effects of beta-endorphin at high doses in healthy and hypertensive subjects: role of opioid receptor agonism. J Clin Endocrinol Metab. 2005;90(9):5167–5174.

18.

Gaddis

Dixon

. Modulation of peripheral adrenergic neurotransmission by methionine-enkephalin. J Pharmacol Exp Ther. 1982;221(2):282–287.

19.

Arendt

Schmoeckel

Wilbert

Plasse

Heucke

Werdan

. Bidirectional effects of endogenous opioid peptides on endothelin release in porcine aortic endothelial cell culture: mediation by opioid receptor and opioid receptor antagonist-insensitive mechanisms. J Pharmacol Exp Ther. 1995;272(1):1–7.

20.

Kienbaum

Heuter

Michel

. Chronic delta-opioid receptor stimulation in humans decreases muscle sympathetic nerve activity. Circulation. 2001;103:850–855.

21.

Napoli

Guardasole

Angelini

. Acute effects of growth hormone on vascular function in human subjects. J Clin Endocrinol Metab. 2003;88(6):2817–2820

22.

Lang

Brückner

Kempf

. Opioid peptides and blood pressure regulation. Clin Exp Hypertens A. 1982;4(1-2):249–269.

23.

. Role of limbic peptidergic circuits in regulation of arterial pressure, relevant to development of essential hypertension. Neuropeptides. 2006;40(5):299–308.

24.

Laubie

Schmitt

Vincent

Remond

. Central cardiovascular effects of morphinomimetic peptides in dogs. Eur J Pharmacol. 1977;46(1):67–71.

25.

Caeiro

Vivas

. Beta-endorphin in the median preoptic nucleus modulates the pressor response induced by subcutaneous hypertonic sodium chloride. Exp Neurol. 2008;210(1):59–66.

26.

Fuenmayor

Cubeddu

. Cardiovascular and endocrine effects of naloxone compared in normotensive and hypertensive patients. Eur J Pharmacol. 1986;126(3):189–197.

27.

Fregoneze

Oliveira

Ribeiro

Ferreira

De Castro

Silva

. Multiple opioid receptors mediate the hypotensive response induced by central 5-HT3 receptor stimulation. Neuropeptides. 2011;45(3):219–227.

28.

Feuerstein

Sirén

. The opioid system in cardiac and vascular regulation of normal and hypertensive states. Circulation. 1987;75(1 pt 2):I125–I129.

29.

Ferreira

Silva

Cointeiro

Oliveira

Faustino

Fregoneze

. Role of central 5-HT3 receptors in the control of blood pressure in stressed and non-stressed rats. Brain Res. 2004;1028(1):48–58.

30.

Urzedo-Rodrigues

Ferreira

Almeida

. Blockade of 5-HT(3) receptors at septal area increase blood pressure in unanaesthetized rats. Auton Neurosci. 2011;159(1-2):51–61.

31.

Zheng

Croft

Giles

Mensah

. Sudden cardiac death in the United States, 1989 to 1998. Circulation. 2001;104(18):2158–2163.

32.

Benditt

Ferguson

Grubb

. Tilt testing for assessing syncope. J Am Coll Cardiol. 1996;28(1):263–275.

33.

Valtchanova-

M A

Missankov

Ojewole

. Evaluation of the antidysrhythmic effects of delta- and kappa-opioid receptor agonists and antagonists on calcium chloride-, adrenaline- and ischemia/reperfusion-induced arrhythmias in rats. Methods Find Exp Clin Pharmacol. 2004;26(1):31–38.

34.

Guan-Ying

Song

Jian-Ming

. k- but not d-opioid receptors mediate effects of ischemic preconditioning on both infarct and arrhythmia in rats. Am J Physiol Heart Circ Physiol. 2001;280(1):H384–H391.

35.

Xia

Zhang

Shen

. Decreased affinity of k-opioid receptor binding during reperfusion following ischemic preconditioning in the rat heart. Life Sci. 1996;58:1307–1317.

36.

Kloner

. Does protein kinase C play a role in ischemic preconditioning in rat hearts? Am J Physiol Heart Circ Physiol. 1995;268(1 pt 2):H426–H431.

37.

Liu

Ytrehus

Downey

. Evidence that translocation of protein kinase C is a key event during ischemic preconditioning of rabbit myocardium. J Mol Cell Cardiol. 1994;26(5):661–668.

38.

Wong

. Cardioprotection of preconditioning by metabolic inhibition in the rat ventricular myocyte: involvement of k-opioid receptor. Circ Res. 1999;84(12):1388–1395.

39.

Liu

Downey

. Ischemic preconditioning protects against infarction in rat heart. Am J Physiol Heart Circ Physiol. 1992; 263(4 pt 2):H1107–H1112.

40.

Published on Euractive Infographics. 2015. https://www.euractiv.com/section/health-consumers/infographic/infographic--the-highest-prevalence-of-high-cholesterol-in-the-world/. Accessed February 18, 2018.

41.

Tian

Zheng

. κ-opioid receptor stimulation improves endothelial function via akt-stimulated no production in hyperlipidemic rats. Sci Rep. 2016;6:26807.

42.

Bryant

Story

Yim

. Assessment of endogenous opioid mediation in stress-induced hypercholesterolemia in the rat. Psychosom Med. 1988;50(6):576–585.

43.

Maslov

Lishmanov

IuB

Barzakh

. Clinical response to agonists of mu and beta opiate receptors in patients with ischemic heart disease: effects of D-Ala2-Leu5-Arg6-enkephalin on hemodynamics, oxygen balance and lipid spectrum of blood. Eksp Klin Farmakol. 2008;71(2):21–28.

44.

Shi

Fan

. Vasculoprotective effect of U50,488H in rats exposed to chronic hypoxia: role of Akt-stimulated NO production. J Appl Physiol. 1985;14(2):238–244.

45.

World Health Statistics 2015. http://www.who.int/whosis/whotat/2015/en/index.html. Updated December, 2016. Accessed February 19, 2018.

46.

Kochanek

Murphy

. Deaths: Final data for 2007. Nat Vital Stat Rep. 2010;58(19):135.

47.

Scarborough

Wickramasinghe

Bhatnagar

. London: Trends In Coronary Heart Disease 1961–2011. 2011 Published on British Heart Foundation. https://www.bhf.org.uk/∼/media/files/research/heart-statistics/bhf-trends-in-coronary-heart-disease01.pdf. Accessed January 25, 2018.

48.

Rosamond

Flegal

Furie

. Heart disease and stroke statistics—2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008;117(4):e25–e146.

49.

Scarborough

Bhatnagar

Wickramasinghe

. British Heart Foundation. Coronary heart disease statistics. http://heart.bmj.com/content/early/2015/05/06/eartjnl-2015-307516. 2010. Updated July 2016. Accessed February 19, 2018.

50.

Allender

Scarborough

Peto

European Heart Network; Brussels: 2008. European cardiovascular disease statistics 2008. http://www.ehnheart.org/cvd-statistics.html. Updated August, 2016. Accessed February 19, 2018.

51.

Uemura

Pisa

. Trends in cardiovascular disease mortality in industrialized countries since 1950. World Health Stat Q. 1988;41(3-4):155–178.

52.

Ragland

Selvin

Merrill

. The onset of decline in ischemic heart disease mortality in the United States. Am J Epidemiol. 1988;127(3):516–531.

53.

Tunstall-Pedoe

Kuulasmaa

Mähönen

. Contribution of trends in survival and coronary-event rates to changes in coronary heart disease mortality: 10-year results from 37 WHO MONICA project populations. Monitoring trends and determinants in cardiovascular disease. Lancet. 1999;353(9164):1547–1557.

54.

Rodríguez

Malvezzi

Chatenoud

. Trends in mortality from coronary heart and cerebrovascular diseases in the Americas: 1970-2000. Heart. 2006;92(4):453–460.

55.

Levi

Chatenoud

Bertuccio

. Mortality from cardiovascular and cerebrovascular diseases in Europe and other areas of the world: an update. Eur J Cardiovasc Prev Rehabil. 2009;16(3):333–350.

56.

Jin

. Remifentanil preconditioning lowers cardiac troponin 1 level in patients undergoing off-pump coronary artery bypass graft surgery. Nan Fang Yi Ke Da Xue Xue Bao. 2009;29(8):1554–1556.

57.

Schultz

Rose

Yao

Gross

. Evidence for involvement of opioid receptors in ischemic preconditioning in rat hearts. Am J Physiol. 1995;268(5 pt 2):H2157–H2161.

58.

Patel

Moore

Hsu

Gross

. Cardioprotection at a distance: mesenteric artery occlusion protects the myocardium via an opioid sensitive mechanism. J Mol Cell Cardiol. 2002;34(10):1317–1323.

59.

Fryer

Wang

Hsu

Gross

. Essential activation of PKCδ in opioid-initiated cardioprotection. Am J Physiol Heart Circ Physiol. 2001;280(3):H1346–H1353.

60.

Fryer

Schultz

Hsu

Gross

. Importance of PKC and tyrosine kinase in single or multiple cycles of preconditioning in rat hearts. Am J Physiol Heart Circ Physiol. 1999;276(4 pt 2):H1229–H1235.

61.

Ping

Zhang

Qiu

. Ischemic preconditioning induces selective translocation of protein kinase C isoforms e and h in the heart of conscious rabbits without subcellular redistribution of total protein kinase C activity. Circ Res. 1997;81:404–414.

62.

Schultz

Hsu

Nagase

. TAN-67, a d-opioid receptor agonist, reduces infarct size via activation of Gi/o proteins and KATP channels. Am J Physiol Heart Circ Physiol. 1998;274(3 pt 2):H909–H914.

63.

Speechly-Dick

Mocanu

Yellon

. Protein kinase C: its role in ischemic preconditioning in the rat. Circ Res. 1994;75(3):586–590.

64.

Tosaki

Maulik

Engelman

Das

. The role of protein kinase C in ischemic/reperfused preconditioned isolated rat hearts. J Cardiovasc Pharmacol. 1996;28(5):723–731.

65.

Ytrehus

Liu

Downey

. Preconditioning protects ischemic rabbit heart by protein kinase C activation. Am J Physiol Heart Circ Physiol. 1994;266(36 pt 2):H1145–H1152.

66.

Kodani

Xuan

Shinmura

Takano

Tang

Bolli

. Delta-opioid receptor-induced late preconditioning is mediated by cyclooxygenase-2 in conscious rabbits. Am J Physiol Heart Circ Physiol. 2002;283(5):H1943–H1957.

67.

Bolli

Manchikalapudi

Tang

. The protective effect of late preconditioning against myocardial stunning in conscious rabbits is mediated by nitric oxide synthase. Evidence that nitric oxide acts both as a trigger and as a mediator of the late phase of ischemic preconditioning. Circ Res. 1997;81(6):1094–1107.

68.

Takano

Manchikalapudi

Tang

. Nitric oxide synthase is the mediator of late preconditioning against myocardial infarction in conscious rabbits. Circulation. 1998;98(5):441–449.

69.

Guo

Bao

Tang

. Pharmacological preconditioning (PC) with adenosine A1 and opioid delta 1 receptor agonists in iNOS-dependent (Abstract). Circulation. 2000;102(5):II–121.

70.

Kodani

Shinmura

Xuan

. Cyclooxygenase-2 does not mediate late preconditioning induced by activation of adenosine A1 or A3 receptors. Am J Physiol Heart Circ Physiol. 2001,281(2):H959–H968.

71.

Takano

Bolli

Black

Jr . A1 or A3 adenosine receptors induce late preconditioning against infarction in conscious rabbits by different mechanisms. Circ Res. 2001;88(5):520–528.

72.

Zhao

Chelliah

Levasseur

Kukreja

. Inducible nitric oxide synthase mediates delayed myocardial protection induced by activation of adenosine A1 receptors: evidence from gene-knockout mice. Circulation. 2000;102(8):902–907.

73.

Fryer

Hsu

Eells

Nagase

Gross

. Opioid-induced second window of cardioprotection: potential role of mitochondrial KATP channels. Circ Res. 1999;84(7):846–851.

74.

Fryer

Hsu

Gross

. ERK And P38 MAP kinase activation are components of opioid-induced delayed cardioprotection. Basic Res Cardiol. 2001;96(2):136–142

75.

Fryer

Hsu

Nagase

Gross

. Opioid-induced cardioprotection against myocardial infarction and arrhythmias: mitochondrial versus sarcolemmal ATP-sensitive potassium channels. J Pharmacol Exp Ther. 2000;294(2):451–457.

76.

Fryer

Pratt

Hsu

Gross

. Differential activation of extracellular signal regulated kinase isoforms in preconditioning and opioid-induced cardioprotection. J Pharmacol Exp Ther. 2001;296(2):642–649.

77.

Huh

Gross

Nagase

. Protection of cardiac myocytes via delta-1-opioid receptors, protein kinase C, and mitochondrial KATP channels. Am J Physiol Heart Circ Physiol. 2001;280(1):H377–H383.

78.

Schultz

J el-J

Hsu

Nagase

. TAN-67, a delta_1-opioid receptor agonist, reduces infarct size via activation of Gi/o proteins and KATP channels. Am J Physiol Heart Circ Physiol. 1998;274(3 pt 2):H909–H914.

79.

Cohen

Yang

Liu

Heusch

Downey

. Acetylcholine, bradykinin, opioids, and phenylephrine, but not adenosine, trigger preconditioning by generating free radicals and opening mitochondrial K(ATP) channels. Circ Res. 2001;89(3):273–278.

80.

McPherson

Yao

. Morphine mimics preconditioning via free radical signals and mitochondrial K(ATP) channels in myocytes. Circulation. 2001;103(2):290–295.

81.

McPherson

Yao

. Signal transduction of opioid induced cardioprotection in ischemia- reperfusion. Anesthesiology. 2001;94(6):1082–1088.

82.

Patel

Hsu

Moore

Gross

. BW373U86, a delta opioid agonist, partially mediates delayed cardioprotection via a free radical mechanism that is independent of opioid receptor stimulation. J Mol Cell Cardiol. 2001;33(8):1455–1465.

83.

Miki

Cohen

Downey

. Opioid receptor contributes to ischemic preconditioning through protein kinase C activation in rabbits. Mol Cell Biochem. 1998;186(1-2):3–12.

84.

Wang

Ashraf

. Role of protein kinase C in mitochondrial KATP channel-mediated protection against Ca2+ overload injury in rat myocardium. Circ Res. 1999;84(10):1156–1165.

85.

Lou

Pei

. Modulation of protein kinase C and cAMP dependent protein kinase by delta-opioid. Biochem Biophys Res Commun. 1997;236(3):626–629.

86.

Murry

Jennings

Reimer

. Preconditioning with ischemia, a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74(5):1124–1136.

87.

Schultz

Hsu

Gross

. Ischemic preconditioning in the intact rat heart is mediated by delta-1but not mu- or kappa–opioid receptors. Circulation. 1998;97(13):1282–1289.

88.

Schultz

Jel-J

Hsu

Nagase

Gross

. TAN-67, a delta-1-opioid receptor agonist, reduces infarct size via activation of Gi/o proteins and KATP channels. Am J Physiol Heart Circ Physiol. 1998;274(3 pt 2):H909–H914.

89.

Ockaili

Emani

Okubo

Brown

Krottapalli

Kukreja

. Opening of mitochondrial KATP channel induces early and delayed cardioprotective effect: role of nitric oxide. Am J Physiol. 1999;277(6 Pt 2):H2425–H2434.

90.

Huh

Gross

Nagase

Liang

. Protection of cardiac myocytes via delta -1-opioid receptors, protein kinase C, and mitochondrial KATP channels. Am J Physiol Heart Circ Physiol. 2001;280(1):H377–H383.

91.

Liang

Gross

. Direct preconditioning of cardiac myocytes via opioid receptors and KATP channels. Circ Res. 1999;84(12):1396–1400

92.

Michael

Baines

Downey

. Ischemia preconditioning: from adenosine receptor to KATP channel. Annu Rev Physiol. 2000;62:79–109.

93.

Ambrosio

Tritto

Chiariello

. The role of oxygen free radicals in preconditioning. J Mol Cell Cardiol. 1995;27(4):1035–1039.

94.

Schultz

Hsu

Gross

. Morphine mimics the cardioprotective effect of ischemic preconditioning via a glibenclamide-sensitive mechanism in the rat heart. Circ Res. 1996;78(6):1100–1104.

95.

Garlid

Paucek

Yarov-Yarovoy

Sun

Schindler

. The mitochondrial KATP channel as a receptor for potassium channel openers. J Biol Chem. 1996;271(15):8796–8799.

96.

Gutstein

Rubie

Mansour

Akil

Woodgett

. Opioid effects on mitogen-activated protein kinase signalling cascades. Anesthesiology.1997;87(5):1118–1126.

97.

Weinbrenner

Schulze

Sárváry

Strasser

. Remote preconditioning by infrarenal aortic occlusion is operative via delta1-opioid receptors and free radicals in vivo in the rat heart. Cardiovasc Res. 2004;61(3):591–599.

98.

Shimizu

Tropak

Diaz

. Transient limb ischaemia remotely preconditions through a humoral mechanism acting directly on the myocardium: evidence suggesting cross-species protection. Clin Sci (Lond). 2009;117(5):191–200.

99.

Zhang

Wang

. Kappa-opioid receptors mediate cardioprotection by remote preconditioning. Anesthesiology. 2006;105(3):550–556.

100.

Wang

Gao

Sun

. Delta-opioid receptor mediates the cardioprotective effect of ischemic postconditioning. Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2008;24(2):184–189.

101.

Jang

Wang

Zhou

Xia

. Postconditioning prevents reperfusion injury by activating delta-opioid receptors. Anesthesiology. 2008;108(2):243–250.

102.

Zatta

Kin

Yoshishige

Mueller

Norfleet

. Evidence that cardioprotection by postconditioning involves preservation of myocardial opioid content and selective opioid receptor activation. Am J Physiol Heart Circ Physiol. 2008;294(3):H1444–H1451.

103.

Wang

Yang

. Kappa-opioid receptor stimulation inhibits augmentation of Ca2+transient and hypertrophy induced by isoprenaline in neonatal rat ventricular myocytes—role of CaMKIIdelta(B). Eur J Pharmacol. 2008;595:52–57.

104.

Min

Kim

. Morphine postconditioning attenuates ICAM-1 expression on endothelial cells. J Korean Med Sci. 2011;26(2):290–296.

105.

Kim

Chun

Park

. Morphine-induced postconditioning modulates mitochondrial permeability transition pore opening via δ-1 opioid receptors activation in isolated rat hearts. Korean J Anesthesiol. 2011;61(1):69–74.

106.

Ambrosy

. The global health and economic burden of hospitalizations for heart failure. lessons learned from hospitalized heart failure registries. J Am Coll Cardiol. 2014;63(12):1123–1133.

107.

Cleaveland

Rangno

Shand

. Standardized isoproterenol sensitivity test: effects of sinus arrhythmias, atropine and propranolol. Arch Intern Med. 1972;130(1):47.

108.

Liang

. The role of endogenous opioids in congestive heart failure: effects of nalmefene on systemic and regional hemodynamics in dogs. Circulation. 1987;75(2):443–451.

109.

Van den Brink

Delbridge

Rosenfeldt

. Endogenous cardiac opioids: enkephalins in adaptation and protection of the heart. Heart Lung Circ. 2003;12(3):178–187.

110.

Headrick

Pepe

Peart

. Non-analgesic effects of opioids: cardiovascular effects of opioids and their receptor systems. Curr Pharm Des. 2012;18(37):6090–6100.

111.

Treskatsch

Feldheiser

Shaqura

. Cellular localization and adaptive changes of the cardiac delta opioid receptor system in an experimental model of heart failure in rats. Heart Vessels. 2016;31(2):241–50.

112.

Treskatsch

Feldheiser

Shaqura

. Upregulation of the kappa opioidergic system in left ventricular rat myocardium in response to volume overload: adaptive changes of the cardiac kappa opioid system in heart failure. Pharmacol Res. 2015;102:33–41.

113.

Roy

Ogilvie

Larochelle

Hamet

Leenen

. Cardiac and vascular effects of atrial natriuretic factor and sodium nitroprusside in healthy men. Circulation. 1989;79(2):383–392.

114.

Fontana

Bernardi

Merlo Pich

. Opioid peptide modulation of circulatory and endocrine response to mental stress in humans. Peptides. 1997;18(2):169–175.

115.

Fontana

Bernardi

Merlo Pich

. Opioid peptides in response to mental stress in asymptomatic dilated cardiomyopathy. Peptides. 1998;19(7):1147–1153.

116.

Clinical trials.gov Database. https://clinicaltrials.gov/. Updated December 2017. Accessed February 19, 2018.

Opioids in Cardiovascular Disease: Therapeutic Options

Abstract

Keywords

Introduction

Structure and Types of OR

Signal Transduction Mechanism of OR

Opioid and ORs in CVDs

Hypertension

Arrhythmia

Hyperlipidemia

Ischemic Heart Disease

Congestive Heart Failure

Conclusion

Footnotes

Author Contributions

Declaration of Conflicting Interests

Funding

ORCID iD

References