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Abstract

High incidences of myocardial infarction associated with high morbidity and mortality, are a major concern and economic burden on industrialized nations. Persistent β-adrenergic receptor stimulation with isoproterenol leads to the development of oxidative stress, myocardial inflammation, thrombosis, platelet aggregation and calcium overload, which ultimately cause myocardial infarction. Therapeutic agents that are presently employed for the prevention and management of myocardial infarction are beta-blockers, antithrombotics, thrombolytics, statins, angiotensin converting enzyme inhibitors, angiotensin II type 1 receptor blockers, calcium channel blockers and nitrovasodilators. In spite of effective available interventions, the mortality rate of myocardial infarction is progressively increasing. Thus, there has been a regular need to develop effective therapies for the prevention and management of this insidious disease. In this review, the authors give an overview of the consequences of isoproterenol in the pathogenesis of cardiac disorders and various therapeutic possibilities to prevent these disorders.

Keywords

atherosclerosis calcium overload inflammation isoproterenol oxidative stress reactive oxygen species

Introduction

Cardiovascular diseases are the most common cause of death in the world. Myocardial infarction (MI), an insidious condition, plays a major role in this mortality [Yusuf et al. 2004; Iakovlev, 2010; Gerczuk and Kloner, 2012]. MI is characterized by intense chest pain, which may radiate into the neck, jaw and arms, and can cause shortness of breath. Patients suffering from cardiovascular and metabolic disorders such as hypertension, atherosclerosis and diabetes mellitus are at a higher risk of MI [Bianchi et al. 2008; Erbel and Budoff, 2012; Ma et al. 2012]. The growing list of pathophysiological changes seen during MI is due to the development of oxidative stress, myocardial inflammation, thrombosis and calcium overload, and altered signalling pathways. Recent studies have suggested that increased β-adrenergic receptors play a role in the generation of myocardial oxidative stress, inflammation, calcium overload and coronary spasm, followed by loss of myocytes [Communal et al. 1998; Frangogiannis et al. 2002]. β-adrenergic mediated oxidative stress generates reactive oxygen species (ROS), which lead to the formation of a macrophage-rich atheroma and, as a consequence, the risk of unstable angina, thrombosis and acute MI develops [Stanger and Weger, 2003; Libby and Aikawa, 2002, 2003]. β-adrenergic receptor activation induces the expression of interleukin (IL)-18, a proinflammatory cytokine, in the myocardium and in cardiac-derived endothelial cells via activation of nuclear factor (NF)-κB [Chandrasekar et al. 2004]. Further, β-adrenergic over-activation increases the concentration of cyclic adenosine monophosphate (cAMP) through activation of adenyl cyclase, resulting in activation of protein kinase A and phosphorylation of L-type calcium channels. This cellular signalling cascade increases intracellular calcium concentration in the heart, followed by the induction of a series of myocardial events such as abnormal gene transcription and loss of myocytes in terms of incidence of apoptosis and necrosis [Mann et al. 1992; Iwase et al. 1996; Communal et al. 1998; Geng et al. 1999]. Isoproterenol (ISO) is a synthetic nonselective β-adrenergic agonist [Ma et al. 2009; Nichtova et al. 2012]. ISO is commonly administered in high doses to induce experimental acute MI in rats [Hussain et al. 2012; Patel et al. 2012; Nagoor Meeran and Stanely Mainzen Prince, 2012] and this action is mediated by inducing myocardial oxidative stress, inflammation and calcium overload, through activation of β1-adrenergic receptors in the heart [Mohan and Bloom, 1999; Izem-Meziane et al. 2012; Vijayan et al. 2012]. Persistent β-adrenergic receptor activation with ISO is associated with deleterious myocardial effects, including left ventricular hypertrophy [Rona et al. 1959; Taylor and Tang, 1984; Ni et al. 2011; Song et al. 2011], increased ventricular collagen content and a reduced inotropic response to ISO [Vassallo et al. 1988; Chang et al. 1982; Kenakin and Ferris, 1983]. ISO treatment directly increases cardiac expression and activity of angiotensin converting enzymes (ACE); thus activation of the circulatory as well as the cardiac angiotensin system could be expected under sympathoexcitatory heart failure [Oliveira and Krieger, 2005]. Clinical and experimental studies have tried out a number of therapeutic agents such as beta-blockers, antithrombotics, statins, ACE inhibitors, calcium channel blockers (CCBs) and nitrovasodilators; these are being employed for the prevention, management and mitigation of MI [Ott and Fenster, 1991; Held and Yusuf, 1993; Spinarová et al. 2011; Burchill et al. 2012; Bhatt, 2012; Carey et al. 2012]. Exploring pharmacological interventions to ameliorate ISO-induced cardiac abnormalities is of potential therapeutic value in preventing the initiation and progression of MI. This article reviews the ISO-induced consequences and various explored pharmacological interventions which ameliorate ISO-induced cardiac abnormalities

Consequences of ISO administration

ISO mediated oxidative stress

Oxidative stress plays a critical role in the development of structural and functional changes in the heart. Oxidative stress is generated due to ROS and imbalanced antioxidant defence mechanisms [Bagatini et al. 2011]. ROS are generated by an activated nicotinamide adenine dinucleotide phosphate oxidase, xanthine oxidase, autooxidized catecholamines, increased angiotensin-II and aldosterone levels as well as released proinflammatory cytokines [Di Filippo et al. 2006; Landmesser et al. 2002]. Further, the other cause of ROS generation is signalling alterations. ROS-dependent apoptosis [Remondino et al. 2003], extracellular matrix biosynthesis [Zhang et al. 2005] and cardiac hypertrophy [Zhang et al. 2007] following ISO-induced β-adrenergic receptor (AR) activation have been described. The catecholamine-induced cardiotoxicity was explained by direct and indirect formation of free radicals and sulphydryl reactivity through a variety of its oxidation products which inactivates cell functions [Singal et al. 1981]. Chronic as well as acute treatment with a renowned β-agonist catecholamine, ISO enhances cardiac oxidative stress in rats [Zhang et al. 2005]. The occurrence of oxidative stress in ISO-injected rats was indicated by the increase in cardiac malondialdehyde content and formation of conjugated dienes as well as by the low Reduced Glutathione/Oxidized Glutathione (GSH/GSSG) ratio, and by reducing the level of superoxide dismutase (SOD), catalase, glutathione peroxidise [Tappia et al. 2001; Dhalla et al. 2000]. Excessive stimulation of cardiac β-adrenergic receptors and angiotensin II type 1 receptors by ISO increases oxidative stress and reduces cAMP formation in the ventricle membranes thus causing MI [Zhang et al. 2005; Singal et al. 1982; Remondino et al. 2003; Zhang et al. 2007; Singh et al. 2000, Tappia et al. 2001]. ISO increases the release of cytochrome-c and activation of c-Jun NH2-terminal kinase (JNK), and extracellular signal-regulated kinase activities which further generate ROS and induces apoptosis [Remondino et al. 2003; Saadane et al. 1999] (Figure 1). ISO-mediated accumulation of collagen and phosphorylation of p38 Mitogen activated protein kinase (MAPK) kinase and their upstream elements, Ras-related C3 botulinum toxin substrate 1 (Rac-1), proto-oncogene serine/threonine-protein kinase (Raf-1), Apoptosis signal-regulating kinase 1 (ASK-1), which promote lipid peroxidation. Lipid peroxidation increases membrane permeability and causes cardiac injury [Singal et al. 1983; Singal et al. 1982; Zhang et al. 2007] (Figure 1). ISO decreases coronary blood flow [Somani et al. 1970] and produces a complete shutdown of myocardial perfusion in the crucial early period of ISO cardiotoxicity. Overall these findings suggest that myocardial cells are injured with ROS generated by ISO.

Figure 1.

Beta adrenergic receptor over activation mediated cardiac toxicity through oxidative stress, Calcium overload and inflammatory cascades.

ISO mediated calcium overload

Calcium maintains the vitality of organs by contraction and relaxation in smooth muscles and endothelial tissues [Orallo, 1996]. Fluctuations in the intracellular free calcium ion concentration control a number of diverse cellular processes (vasa vasorum flow, endothelial contraction, collagen, elastins, proteoglycans synthesis and platelet activity) affecting various proteases and calcium dependent phospholipase enzymes [Henry, 1990]. Studies suggest that early alteration of sarcolemma due to calcium overload results from exaggerated direct β-receptor stimulation. Several studies also reported that an increased concentration of cAMP by the over-activation of β-adrenergic receptors results in an altered cellular signalling cascade, which increases intracellular calcium concentration in the heart [Mann et al. 1992; Iwase et al. 1996; Geng et al. 1999]. ISO administration releases endogenous myocardial norepinephrine, increases calcium influx into myocardial cells and this increase in calcium influx results in cell necrosis and the breakdown of membrane permeability barriers [Mallov, 1984] (Figure 1). Increase of myocardial Ca²⁺ content will result in myofilament over-stimulation, increase of contractile force and oxygen requirement as well as excessive adenosine triphosphate (ATP) breakdown; each of these factors contribute to cardiac muscle cell injury [Tokgözoğlu, 2009].

Ca²⁺ influx followed by its deposition in mitochondria occurs as early as 2 minutes following ISO administration [Ishikawa et al. 2004; Cohen and Fuster, 1990]. ISO-induced intracellular calcium overload affects the membrane by activating calcium-dependent phospholipases and protease enzymes and depletion of high energy phosphates [Nirdlinger and Bramante, 1974; Titus, 1983; Fleckenstein et al. 1974; Kondo et al. 1987]. Activation of these calcium dependent enzymes further, inhibits membrane-bound enzymes such as Na⁺/K⁺-ATPase and as a result there is an increase in Na⁺ levels and a loss of cytoplasmic K⁺ ions. This increased Na⁺ concentration leads to calcium accumulation through the Na⁺- Ca²⁺ exchange system (Figure 1). The summation of these alterations leads to cellular dysfunction and cardiotoxicity [Ramos et al. 1984].

ISO mediated inflammation

Inflammation associated metabolic disorders, namely hypertension, hypercholesterolemia, hyperhomocysteinemia, lipid deposition and diabetes, are the major risk factors responsible for the development of cardiovascular diseases [Niessen et al. 2003]. ISO induces IL-18 expression both in vivo and in vitro via activation of NF-κB (Figure 1). This induction mediates progressive left ventricular remodelling in heart failure [Chandrasekar et al. 2004]. NF-κB activation is β-2AR dependent and requires signalling through a cascade involving heteromeric G protein subunit (Gi), Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3Kc), Protein kinase B (Akt) and IKK (Figure 1). Further, these signalling cascades are critical for cardiac cells [Chandrasekar et al. 2004]. IL-18 promotes and activates the migration of inflammatory cells [McInnes et al. 2005]. In addition, ISO induces cardiotoxic effects via other inflammatory cytokines such as tumour necrosis factor (TNF)-α, IL-1β, and IL-6 through cAMP [Mann, 1996, 1998; McInnes et al. 2005; Murray et al. 2000].

ISO mediated lipid peroxidation

ISO causes oxidative stress in the myocardium resulting in infarct-like necrosis of the heart muscle and an increase in the levels of lipids in the myocardium. The levels of mitochondrial calcium, cholesterol, free fatty acids, and triglycerides were considerably increased and ATP and phospholipids were considerably decreased in ISO-induced rats [Kumaran and Prince, 2010]. The mitochondrial membrane is rich in polyunsaturated fatty acids (PUFAs) which are present in its phospholipids form and highly susceptible to lipid peroxidation [Halliwell and Gutteridge 1990]. Activated lipid peroxidation is an important pathogenic event in MI and the levels of lipid peroxide reflect the major stages of disease and its complications.

Administration of ISO induces lipid peroxidation in the mitochondrial membrane [Tappel 1973]. The process of lipid peroxidation is one of oxidative conversion of PUFAs to products known as malondialdehydes, which are measurable as thiobarbituric acid reactive substances or lipid peroxides [Bakan et al. 2002]. Kumaran and Prince showed in the results of their study that mitochondrial lipid peroxidation products (thiobarbituric acid reactive substances and plasma lipid hydro peroxides) were increased during ISO administration [Kumaran and Prince, 2010]. An increase in mitochondrial lipid peroxide level indicates enhanced lipid peroxidation by free radicals generated on ISO administration. Increased levels of lipid peroxides injure blood vessels, causing increasing adherence and aggregation of platelets to the injured sites [Grylewski, 1980].

ISO mediated renin–angiotensin release

Activation of the renin–angiotensin system plays a crucial role in the progression of hemodynamic alterations and cardiac remodelling. ISO significantly elevates plasma cAMP, plasma renin activity, plasma aldosterone, and cardiac ACE activity with long-term administration [Grimm et al. 1998]. It has also been suggested that ISO increases left ventricular and right ventricular weight with activation of the circulatory renin–angiotensin system [Nagano and Ogihara, 1994]. Increased plasma levels of atrial natriuretic peptide found a close correlation of infarct size and right atrial and left-ventricular end-diastolic pressures. ACE activity also increases in the heart after infarction [Hirsch et al. 1991], mainly in the scar tissue [Hokimoto et al. 1995; Busatto et al. 1997].

Pharmacological interventions to attenuate ISO-induced MIs

As stated in the previous section, the consequences of ISO induction is myocardial injury due to high myocardial oxidative stress, lipid deposition, release of angiotensin and aldosterone, calcium overload and exaggerated myocardial inflammatory events, which are followed by induction of apoptosis and necrosis with loss of myocardial cells. This section of the review updates numerous pharmacological interventions, which halt the progression of myocardial injury and could be utilised to ameliorate the toxicity in ISO treated animals.

Lipid-lowering agents

Fibrates are lipid-lowering agents, which on long treatment significantly ameliorate myocardial injury. Fenofibrate confers its benefits on endothelial function, inflammatory cytokines, cardiac hypertrophy and vascular dysfunction by showing increased expression of peroxisome proliferator-activated receptor-α in ISO-induced acute MI with reduction of cardiac marker enzymes [lactate dehydrogenase (LDH) and creatine phosphokinase isoenzyme (CK-MB)] (Table 1) [Devchand et al. 1996; Yuan et al. 2008]. The protective effect of clofibrate in ISO-induced MI is due to its ability to change corticosterone and serum lipid levels in the circulation [Wexler and Greenberg, 1978]. Statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors)exhibit cardioprevention by their lipid lowering action and by increasing the level of deprived enzymes in myocardial-infarct rats. Specifically, rosuvastatin reduces inflammatory cytokines, tissue TNF-α and upregulates vascular endothelial growth factor level (Table 1). Further, fluvastatin and atorvastatin also attenuate acute MI by maintaining the antioxidant defence system and ATP activity [Zaitone and Abo-Gresha, 2012; Akila et al. 2007; Trivedi et al. 2006]. Moreover, combined therapy of atorvastatin and coenzyme Q10 improves the left ventricular function in ISO-induced heart failure in rats [Garjani et al. 2011].

Table 1.

Mechanisms of action exhibited by isoproterenol in the pathogenesis of cardiac disorders and the role of therapeutic drugs in myocardial protection.

S. no	Drug	Mechanism of action of isoproterenol	Preventive mechanism of drug	Reference
1	Mibefradil (CCBs)	β-adrenergic stimulation with ISO enhanced contractility and Ca²⁺ availability by increasing calcium overload, contractile dysfunction, and arrhythmias in failing hearts	Protects myocardium against ischaemia-induced Ca²⁺-overload and increases β-adrenergic response in chronically failing rat hearts, Potent vasodilating effect, improved chronic inotropic response	Sandmann et al. [1999], Min et al. [1999]
2	Metoprolol (betablocker)	ISO increases negative inotropic/chronotropic effect and lipid peroxidation effect	Negative inotropic/chronotropic effects, reduces lipid peroxidation and also reduces the myocardial energy demand by decreasing the heart rate	Kalaycioglu et al. [1999]
3	Carvedilol (vasodilator and beta-blocker)	Alters oxidative stress and lipid levels	Inhibited Fe(++)-initiated lipid peroxidation by scavenging free radicals	Yue et al. [1992]
4	Amiodarone	Oxidative stress after ISO-induced myocardial injury, decrease in GSH levels and activities of SOD and an increase in MDA level	Protective effects against oxygen radical-mediated injury in cardiac myocytes and maintains the level of biochemical marker enzymes	Ide et al. [1999], Albayrak et al. [2009]
5	Fenofibrate (PPAR α)	Utilization of free fatty acids was reduced in ISO, i.e. increases the level of fatty acids resulting in myocardial injury	Activates lipoprotein lipase and reduces apoproteins thus increasing lipolysis and eliminating triglyceride-rich particles from plasma	Yuan et al. [2008]
6	Magnesium chloride	ISO administration revealed significant reduction of CK (C Max) activity	Maintains ionic balance and cellular enzymes	Naik et al. [1999]
7	Verapamil (CCB)	Increase in calcium level and overexpression of β- adrenergic receptors	Reduces calcium overload and reduces overexpression of β-adrenergic receptors	Min et al. [1999], Hanafy et al. [2010]
8	Amlodipine (CCB)	Pathological changes and oxidative stress and calcium overload after ISO administration	Reduces lipid peroxidation and reduces calcium level	Min et al. [1999], Sathish et al. [2003]
9	Nicorandil K(ATP) channel opener	ISO showed significant changes in antioxidant defence system and lipid profile levels	Maintains lipid profile and antioxidant defence system	Sathish et al. [2003]
10	Enalapril (ACE inhibitor)	β-receptor sensitization and increase in negative inotropic effect	Sympatho inhibition and prevention of β-adrenergic desensitization and also improves ionotropic response	Igawa et al. [2002]
11	Quinidine (class I antiarrhythmic agent)	Administration of ISO induced lipid per oxidation in cardiac tissue and exhibited a significantly elevated serum glutamate oxaloacetate transaminase levels. Increased SOD with a concomitant decrease in catalase activity	Reduction of lipid peroxidation reaction, exerts an ‘indirect antioxidant’ effect, scavenge superoxide anion and hydrogen peroxide	Chattopadhyay et al. [2003]
12	DITPA (Thyroid hormone analogue)	ISO alters endothelial function after myocardial infarction	Improves endothelial nitric oxide and β-adrenergic receptor mediated vasorelaxation by increasing nitric oxide in the vasculature	Spooner et al. [2004]
13	Propranolol and labetalol (beta-blocker)	ISO can cause ischaemic myocardial alterations, lipid peroxide generation and procoagulant activity, including areas of myocardial necrosis, contraction band necrosis, increased plasma levels of cardiac necrosis markers (c-troponin I and myoglobin)	Prevents myocardial necrosis damage and the associated risk factors.	Pinelli et al. [2004]
14	Imidapril (ACE inhibitor)	Alterations in cardiac function, positive inotropic effect of ISO, β1-adrenergic density and ISO stimulated AC activity in the failing heart	Prevents changes in β- adrenergic signal transduction in CHF, decreases calcium level and reduces AC activity	Sethi et al. [2004]
15	Atorvastatin	ISO administration produced severe myocardial damage and oxidative stress in rats	Reduces cholesterol formation by reducing the synthesis of mevalonate acid by inhibiting HMG-CoA reductase	Trivedi et al. [2006]
16	Nimesulide (cyclooxygenase-2 inhibitor)	Administration of ISO increases inflammatory markers such as CK isozyme and troponin-I in serum	Anti-ischaemic effects	Saeed and Ahmed [2005, 2006]
17	Fluvastatin	ISO-treated rats showed significant rise in ST-segment and increase in content of LDH, glutamic oxalacetic transaminase, CK and MDA, as well as a fall in the activities of glutathione peroxidase, SOD and catalase were observed.	Cardioprotective effect by inhibiting HMG-CoA reductase inhibitor via maintaining activities of endogenous antioxidant enzymes	Zhou et al. [2008]
18	Lacidipine, ramipril and valsartan	Oxidative stress has been increased after ISO administration with alterations in biochemical levels	Improves nitric oxide stress and DNA damage by maintaining serum enzymes	Keles et al. [2009]
19	Telmisartan (PPAR-δ)	ISO-induced cardiotoxicity with a significant reduction in activities of myocardial CK-MB isoenzyme, LDH, SOD, catalase, and reduced GSH level along with increase in MDA content	Attenuates the development of acute myocardial infarction by restoring hemodynamic, biochemical, histopathological and ultrastructural changes along with increases in MDA content	Goyal et al. [2009, 2010]
20	Captopril (ACE inhibitor)	ISO-induced myocardial damage by biochemical enzymatic alterations	Potent vasodilating effect	Asdaq and Inamdar [2010]
21	Fasudil hydrochloride hydrate	ISO-induced heart failure in relationship with RhoA/ROCK to the ERK and the JNK pathways	ρ-kinase inhibitor suppresses ISO-induced heart failure in rats via JNK and ERK1/2 pathways	Wang et al. [2011]
22	Rosuvastatin	ISO induced myocardial injury by increasing serum cardiac biomarker, inflammatory markers such as TNF-α	Promotes angiogenesis and reduces cholesterol level by suppressing the synthesis of mevalonic acid, also reduces tissue, TNF-α and upregulated vascular endothelial growth factor levels	Zaitone and Abo-Gresha [2012]
23	Dexrazoxane (DEX)	ISO increases myocardial calcium overload and influence in fenton reaction that alters iron-chelating property	Exerts iron-chelating properties in reducing catecholamine toxicity and also inhibits myocardial calcium overload	Zatloukalová et al. [2012]
24	SMP-300	ISO-induced ST segment depression and increases Na+/H+ exchange	Selective Na+/H+ exchange inhibitor that targets in the prevention of angina	Yamamoto et al. [2002]
25	Aspirin	ISO marked increases in cholesterol, free fatty acids, triglycerides and lipid peroxides in heart mitochondria, activity of Na+ K(+)-ATPase decreases, activity of Ca²⁺-ATPase increases	Decreases the level of cholesterol, free fatty acids, triglycerides and lipid peroxides	Manjula and Devi [1993]
26	Cromakalim	ISO administration alters biochemical markers and decreases blood clotting time	Increase in blood clotting time and also depleted intracytoplasmic glycogen	Aghi et al. [1992]

ISO, isoproterenol; CK, creatine kinase; PPAR, peroxisome proliferator-activated receptors; CCB, calcium channel blocker; K(ATP), ATP-sensitive potassium; ACE, angiotensin 1converting enzyme; AR, adrenergic receptor; AC, adenylyl cyclise; CHF, congestive heart failure; HMG-CoA, 3-hydroxy-3-methyl-glutaryl-CoA; CK-MB, creatine phosphokinase; LDH, lactate dehydrogenase; MDA, malondialdehyde; SOD, superoxide dismutase; GSH, glutathione; ERK, extracellular signal-regulated kinases; JNK, c-jun NH 2-terminal kinase; TNF-α, tumour necrosis factor-α.

Antioxidative agents

Quinidine, a Na+ channel blocker with free radical scavenging effects, strengthens the antioxidant defence system by elevating SOD and catalase activity (Table 1) [Chattopadhyay et al. 2003]. Dhalla and colleagues [Dhalla et al. 2000] experimentally demonstrated that free radical scavenging enzymes are the first-line cellular defence against oxidative stress by decomposing O₂ and H₂O₂ before interacting to form more reactive hydroxyl radicals. In addition to this, Akila and colleagues [Akila et al. 2007] showed significant increases in catalase activity after reperfusion, suggesting that the antioxidant defence system protects the cells against reactive species. Administration of telmisartan and olmesartan reduces this increased level of malondialdehyde (Table 1) [Goyal et al. 2009; Zhang et al. 2007]. The occurrence of oxidative stress in the ISO-injected rats was indicated by the increase of cardiac malondialdehyde content. Pretreatment with monoamine oxidase inhibitors significantly ameliorates the severity of myocardial injury produced by ISO treatment. This action was reflected by improved biochemical events [Stanton et al. 1970; Singh et al. 1980]. Aspirin treatment decreases the biochemical lesions which occur due to the activation of lipid peroxidation and also normalizes the antioxidant defence enzymes such as α-glycerophosphate dehydrogenase (GDP), glutathione S-transferase, SOD, and catalase (Table 1) [Manjula et al. 1994].

ACE inhibitors and AT1 receptor blockers

Angiotensin receptor blockers treatment was found to be more effective for reducing cardiac mass enlargement, oxidative stress and collagen accumulation in ISO-infused mice [Brown et al. 2005; Kass et al. 2004]. ACE inhibitors directly prevent the inappropriate growth and hypertrophy stimulated by angiotensin II and other growth factors in rat myocardial tissue [Weber, 1997; Lindpaintner et al. 1993]. Asdaq and Inamdar [Asdaq and Inamdar, 2010] showed that long-term use of captopril (an ACE inhibitor) effectively reduces the size of myocardial infarcts (Table 1). Captopril dislodges the effect of ISO by retaining back the activity of superoxide dismutase, catalase, LDH and CK-MB [Asdaq and Inamdar, 2010]. Further, long term captopril treatment resulted in a significant reduction in left ventricular end-systolic volume index, and increase in stroke volume index and ejection fraction [French et al. 1999]. The protective role of carvedilol (α- and β-adrenoreceptor blocker) in preventing MI was associated with attenuation by scavenging free radicals and inhibiting lipid peroxidation [Yue et al. 1992] (Table 1).

β-adrenoreceptor antagonist

Beta-blockers are more beneficial than ACE inhibitors in cardioprotection. Metoprolol exerts a cardioprotective effect by showing a significant reduction in ventricular fibrillation, the event causing myocardial ischaemia and infarction [Coram et al. 1987, Kalaycioglu et al. 1999] (Table 1). Propanolol shows myocardial protective action mediated through hormonal (corticosterone, aldosterone) and metabolic changes (blood pressure). Further, it brings biochemical changes such as reduction of blood serum creatine phosphokinase, LDH and triglyceride levels [Wexler, 1985].

Calcium antagonists

The rational use of combination treatment provides more powerful results in preclinical studies as suggested by the use of verapamil (a calcium antagonist) and magnesium chloride. The two drugs reveal significant cardioprotective potential by reducing CK-MB activity in ISO-induced MI [Naik et al. 1999] (Table 1). Further, Sathish and colleagues [Sathish et al. 2003] found that the combined dose of nicorandil and amlodipine, proved to be more protective in experimentally-induced MI in rats. The extent of lysosomal membrane damage was reduced and lysosomal membrane integrity was preserved by these drugs. Calcium antagonists have a variety of actions to overcome excitation contractions, tending to produce vasodilatation and reduce myocardial contractility. On the other hand, it also limits the calcium entry into cardiac and smooth muscle cells, thereby reducing the splitting of adenosine triphosphate and myocardial oxygen demand. Dexrazoxane probably decreases the mortality rate in ISO-treated animals by reducing myocardial calcium overload and improving histological impairment as well as peripheral hemodynamic changes [Zatloukalová et al. 2012] (Table 1). Moreover, verapamil exerts protection against myocardial lesions, electrocardiographic alterations, high plasma cardiac necrosis marker c-troponin I levels, and prevents the hemodynamic and procoagulation changes. Therefore verapamil seems to be suitable for preventing myocardial ischaemic lesions induced by ISO and vasopressin [Pinelli et al. 2004]. Nimodipine is used in the management of patients with stroke or subarachnoid haemorrhage [Towart and Kazda, 1979]. Diltiazem has potent coronary vasodilator activity, which proves to be beneficial in the treatment of stable and unstable angina, ultimately reducing intracellular Ca2 + accumulation and MI [Strauss et al. 1982; Hossack et al. 1984; Boden et al. 1985; Clozel et al. 1983]. The cardioprotective action of CCB (verapamil, amlodipine and diltiazem) therapies on ISO-treated animals have been augmented and determined by diagnostic enzymes such as LDH and CK-MB in serum and heart tissue homogenate [Kumar et al. 2009]. Mibefradil protects the myocardium against ischaemia-induced Ca²⁺-overload and improves the cardiac function by increasing β-adrenergic responsiveness in chronically failing rat hearts [Sandmann et al. 1999]. Oxodipine and nitrenidipine, both by exhibiting CCB properties, reduce the infarct size lesions located in the subendocardial areas of the left ventricle intramural at the apex and ventricular septum [Pérez-Cao et al. 1994]. CCBs provoke spasm and are useful in improving the prognosis in patients with acute myocardial infarction (AMI) after stent implantation by suppressing coronary spasms [Katoh et al. 2012].

Other synthetic treatments

Spironolactone treatment in ISO-treated rats reduces elevated mRNA levels of transforming growth factor β, connective tissue growth factor, matrix metalloprotease 2, matrix metalloprotease inhibitor 2, TNF-α, IL-1β, p22phox (subunit of NADPH oxidase) and xanthine dehydrogenase [Martín-Fernández et al. 2012]. Propanolol and its combination therapy with nifedipine and guggulsterone exhibit cardiac protection against an ISO-induced marked increase of lipid peroxides, xanthine oxidase, creatine phosphokinase, phospholipase and superoxide dismutase enzymes [Kaul and Kapoor, 1989]. Together, lacidipine (a CCB), ramipril (an ACE inhibitor) and valsartan (an AT1 receptor blocker) reduce the severity of MI as indicated by routine biochemistry indicators, alanine aminotransferase, aspartate aminotransferase, LDH, creatine kinase (CK), CK-MB, troponin I (TnI) and nitric oxide. 7, 8-Dihydro-8-oxo-guanine, which is an indicator of DNA damage, was decreased by lacidipine, ramipril and valsartan. [Bayir et al. 2012; Keles et al. 2009]. Cromakalim, a potassium channel opener seems to be beneficial on serum LDH, serum glutamic oxaloacetic transaminase and depleted intracytoplasmic glycogen in ISO-treated animals [Aghi et al. 1992] (Table 1). The thyroid hormone analogue, 3, 5 diiodothyropropionic acid, improves the endothelial function by enhancing endothelial nitric oxide and β- adrenergic-mediated vasorelaxation. Thus, this analogue shows a protective effect against inflammatory reactions induced in MI [Spooner et al. 2004] (Table 1).

Nutraceuticals treatment

The beneficial effects of nutraceuticals represent a great impact on nutritional therapy. Recently reported nutritional therapy seems beneficial in dislodging the effect of ISO-induced myocardial injuries. Myocardial injuries have occurred following mechanisms such as mitochondrial dysfunction, calcium overload, lipid peroxidation, alteration in membrane bound enzymes, apoptosis and cell necrosis. Mitochondria play a central role in the energy-generating process within the cell. Apart from this important function, mitochondria are involved in complex processes such as apoptosis. The cardioprotective actions of potassium channel openers have revealed that cardiac mitochondria are more important as the primary targets of these drugs than the plasma membrane. Murugesan and Manju reported that luteolin ameliorates mitochondrial damage in ISO- induced MI by maintaining lipid peroxidation metabolism due to its free radical scavenging properties [Murugesan and Manju, 2013].

The mechanism for the protective effect of p-coumaric acid is attributed to antilipid peroxidative, antioxidant and antiapoptotic properties. p-Coumaric acid pretreatment showed protective effects on apoptosis by inhibiting oxidative stress [Prince and Jyoti, 2013]. The cardioprotective effect of Crocus sativus L. (saffron) aqueous extract and safranal in ISO-induced MI was through modulation of oxidative stress in such a way that they maintain the redox status of the cell, by maintaining functional and structural damage through reduction of lipid peroxidation [Mehdizadeh et al. 2013]. Korean red ginseng extract significantly protects against cardiac injury and ISO-induced cardiac infarction by bolstering the antioxidant action in myocardial tissues. Moreover, Korean red ginseng extract also protects the secretion of inflammatory cells by suppressing caspase-3 activity and TNF-α protein production [Lsim et al. 2013].

In the context of the aforementioned studies, it is apparent that any given synthetic and natural products extend their protective effects through assorted mechanisms. It has been found that most of the products act through one or other of their antioxidant potential and many among them give protection from lipid peroxidation to the myocardium. Moreover, natural and synthetic drugs have also been able to reduce or even prevent the inflammation that arises due to myocardial necrosis produced by ISO intoxication. Synthetic drugs are the preferable treatment to overcome the above problems as treatment with natural products requires high doses, long treatment, the characterization of chemical constituents and the difficulty in extrapolating the findings to clinical research. Natural products still hold great potential among them as a first-line therapy for myocardial injuries because the chances of occurrence of adverse events in natural products were much less compared with synthetic products. So, a future prospective could be the exploration of nutraceutical products, their activity and the targeting of the mechanisms involved in prevention against ISO-induced toxicity.

Conclusion

In summary, it has been concluded that ISO, a synthetic non-selective β-adrenergic agonist induced pathophysiological changes, which were seen during MI. ISO develops oxidative stress, myocardial inflammation, thrombosis, calcium overload and also alters signalling pathways. The rational use of certain pharmacological interventions alone or in combination with a few nutraceuticals helps in attenuating these ISO-induced changes. These interventions halt the progression of myocardial injury and could be utilised to ameliorate ISO- induced toxicity.

Footnotes

Acknowledgements

We express our thanks to Dr Rajendar Singh, Chairman, Shri Om Parkash, Director and Mr Sanjeev Kalra, Administrator, Rajendra Institute of Technology and Sciences, Sirsa, India, for their inspiration and constant support. Gratitude is also extended to Dr Pitchai Balakumar for his expert suggestions.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors have no conflicts of interest to declare.

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Exploration of pharmacological interventions to prevent isoproterenol-induced myocardial infarction in experimental models

Abstract

Keywords

Introduction

Consequences of ISO administration

ISO mediated oxidative stress

ISO mediated calcium overload

ISO mediated inflammation

ISO mediated lipid peroxidation

ISO mediated renin–angiotensin release

Pharmacological interventions to attenuate ISO-induced MIs

Lipid-lowering agents

Antioxidative agents

ACE inhibitors and AT1 receptor blockers

β-adrenoreceptor antagonist

Calcium antagonists

Other synthetic treatments

Nutraceuticals treatment

Conclusion

Footnotes

Acknowledgements

Funding

Conflict of interest statement

References