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Abstract

Background:

Statins, a class of lipid lowering drugs, decrease mortality associated with cardiovascular events. As hypercholesterolemia is often accompanied by hypertension, a large number of patients receive therapy with statins and antihypertensive drugs which act via the renin–angiotensin–aldosterone system (RAAS). New guidelines published by the American Heart Association and American College of Cardiology on the treatment of dyslipidaemia and the reduction of atherosclerotic cardiovascular risk, which use a risk prediction algorithm based on risk factors such as hypertension but not low-density lipoprotein (LDL) level, may even further increase the number of patients receiving such concomitant therapy.

Method:

In this paper we review studies on an interaction between statins, the RAAS and antihypertensive drugs acting via the RAAS.

Result:

Accumulating evidence suggests that the combination of statins and drugs affecting the RAAS exerts a synergistic effect on the circulatory system. For example, statins may lower arterial blood pressure and augment the effect of antihypertensive drugs acting via the RAAS. Statins may interact with the RAAS in a number of ways i.e. to decrease the expression of receptors for angiotensin II (Ang II), inhibit the Ang II-dependent intracellular signalling, reduce the RAAS-dependent oxidative stress and inflammation as well as inhibit the synthesis of Ang II and aldosterone.

Conclusion:

Although statins given either alone or together with antihypertensive drugs acting via the RAAS may lower arterial blood pressure, further research is needed to evaluate the mechanisms and their therapeutic significance.

Keywords

Statins renin–angiotensin–aldosterone system cardiovascular disease hypertension angiotensin hypercholesterolaemia aldosterone

Introduction

The renin–angiotensin–aldosterone system (RAAS) is an enzymatic cascade which has been vigorously studied for more than a century. First, Tiegerstedt and Bergman identified a pressor substance, named renin, produced by the kidneys.¹ Further studies have showed that the RAAS comprises a number of enzymes, peptides and their receptors, these have been reviewed elsewhere.^2–7

Accumulating evidence suggests that disturbances in the RAAS play a key role in the development of cardiovascular diseases such as hypertension, atherosclerosis and heart failure.^2,8–10 Over the last three decades drugs interfering with the RAAS have been used as the first-line treatment in the majority of cardiovascular diseases: however, the mechanisms behind their beneficial effects have not been fully elucidated. For instance, it has been reported that after prolonged treatment with angiotensin converting enzyme inhibitors (ACE-Is), the plasma level of angiotensin II (Ang II) returns to that before the onset of the treatment, which may be associated with action of the chymase.^11,12 Drugs that are currently used in the treatment of cardiovascular diseases and act via the RAAS include renin inhibitors, ACE-Is, angiotensin type 1 receptor blockers (ARBs) and aldosterone antagonists. Other components of the RAAS, which may become therapeutic targets include the AT2 receptor (ATR2) and ACE2/Ang(1–7)/Mas receptors.¹³

Statins, a class of lipid-lowering compounds, have become some of the most studied drugs and have been proved to decrease mortality and morbidity associated with cardiovascular events^14–19 and stroke.²⁰ In addition to the reduction in cardiovascular risk, statins have been suggested to exert beneficial effects in other diseases such as Alzheimer’s dementia.²¹ The major therapeutic effects of statins are associated with their lipid-lowering properties,^22,23 however, there is evidence that even patients with normal blood low-density lipoprotein (LDL) level may benefit from statin treatment.²⁴

Recently, the American Heart Association and American College of Cardiology published new prevention guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk²⁵ which do not identify target cholesterol levels as the goal when treating dyslipidaemia and use a newly developed risk prediction algorithm based on risk factors such hypertension but not LDL level.²⁶ Arguably, such an approach will substantially increase the number of patients treated with statins.

Statins

Short characteristic of the drug class

The first statin, mevastatin, was isolated in 1976.^27,28 A decade later, lovastatin, as the first out of the statins was registered in the USA. To date, the group of statins include over 10 representatives but only six of them are clinically used i.e. atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin. It appears that at comparable doses there is no superiority of one statin over the other in reducing LDL level and cardiovascular risk.^29,30

Pharmacokinetic and pharmacodynamic properties of statins have been extensively reviewed elsewhere.^31–34 In short, lovastatin and simvastatin are pro-drugs which require activation in the hepatocyte by esterases, while other statins are administered in active β-hydroxy acid form. The lipophilic statins i.e. atorvastatin, fluvastatin, lovastatin and simvastatin enter hepatocytes mainly via passive diffusion. Hydrophilic statins such as pravastatin and rosuvastatin cross the cell membrane via an active transport system such as the organic anion polypeptide 1B1. These differences result in higher liver selectivity for hydrophilic statins. In this context, Koga et al. showed that pravastatin inhibits synthesis of cholesterol in hepatocytes only, while lovastatin and simvastatin also inhibit cholesterol synthesis in other tissues.³⁵ There are also significant differences between statins in penetration through the blood-brain barrier (BBB). Tsuji et al. showed that lovastatin and simvastatin in lactone form cross the BBB by passive diffusion while their acid forms are carried by an active transport system.³⁶

Lipid-lowering and non-lipid-dependent effects of statins

Cholesterol is the basic sterol synthesised by animals. It is an essential component of cell membranes and is required for the biosynthesis of bile acids, vitamin D and steroid hormones such as aldosterone. In humans two-thirds of cholesterol is produced endogenously in hepatocytes.³⁷ Statins decrease synthesis of cholesterol in hepatocytes by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA), a rate-limiting enzyme in the synthesis of cholesterol.³⁸ Lowering of intracellular cholesterol increases the expression of LDL-receptors which in turn increases uptake of LDL from the blood. These result in the reduction of total cholesterol and LDL plasma levels. In addition, statins increase high-density lipoprotein (HDL) and lower triglyceride blood levels.^39,40 Statins have been found to reduce blood cholesterol more effectively than other lipid-lowering agents.⁴¹

Statins exert a broad spectrum of biological effects which may be of therapeutic importance.^42–45 Statins have been found to exert anti-inflammatory effects,⁴⁶ reduce oxidative stress^47,48 and increase bioavailability of nitric oxide (NO)^49,50 which improves the function of endothelium in arteriosclerosis.⁵¹ Additionally, statins decrease the synthesis of thromboxane A2, a strong vasoconstrictor, and improve vasodilation.⁴⁹ These effects of statins may depend on their intracellular effects as well as on interaction with biological mediators such as NO, Ang II and aldosterone.

The anti-inflammatory effects of statins result from a number of mechanisms. First, it has been found that statins decrease expression of adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1),⁵² vascular cell adhesion molecule-1 (VCAM-1)⁵³ and others,^54–56 which inhibit the adhesion of leucocytes to the endothelium. Second, statins affect cell migration by reducing the activity of chemokines (monocyte chemoattractant protein-1 (MCP-1), interleukin 8 (IL-8), regulated on activation, normal T-cell expressed and secreted (RANTES)^57,58 as well as the synthesis of proinflammatory cytokines such as IL-1β,⁵⁹ IL-6,⁶⁰ tumor necrosis factor alpha (TNF-α)⁶¹ and C-reactive protein.⁶² Furthermore, statins have been found to decrease the activity of nuclear factor kappa B(NF-κB) activated by inflammatory stimuli^61,63 as well as up-regulate IκBα, an nuclear factor kappa B(NF-κB) inhibitor.^64,65

Antioxidant properties of statins are associated with inhibition of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and increase in the activity of catalase, which results in the reduction of reactive oxygen species (ROS) activity.^47,66 A number of studies showed that statins reduce oxidation of LDL,^48,67 which diminishes oxidative stress and attenuates development of atherosclerosis.⁶⁸

The increase in bioavailability of NO is another example of non-lipid dependent effects of statins. It has been reported that statins increase the synthesis of NO^49,50,69,70 and, in addition, may prolong NO half-life by reducing the activity of ROS which easily react with NO.⁷¹

Finally, HMG-CoA inhibitors, by decreasing cholesterol synthesis, reduce other mevalonic intermediates such as isoprenoids (farnesyl pyrophosphate, geranyl pyrophosphate) which play a pivotal role in prenylation, a posttranslational modification of proteins, including regulatory proteins such as small G proteins.⁷² In this line of evidence, it was found that atorvastatin stimulates the unprenylation of γ subunit of β-adrenoreceptor, which impairs an intracellular signalling and decreases responsiveness to noradrenaline.⁷³

Interactions between statins and the RAAS in cardiovascular diseases

Cardiovascular diseases (CVDs) such as hypertension, arteriosclerosis and heart failure are accompanied by changes in RAAS activity. Although these changes vary in nature, and may be both primary as well as secondary, treatment with drugs affecting the RAAS has been proved to reduce cardiovascular events.^74–77 Since CVDs are often accompanied by hypercholesterolaemia, a large number of patients receive statins and drugs acting via the RAAS. Interestingly, it has been suggested that such concomitant treatment may exert a synergistic effect on the circulatory system.^78,79

Arteriosclerosis which is often associated with hypertension is thought to result from hypercholesterolaemia,¹⁷ inflammation,⁸⁰ oxidative stress,⁶⁸ as well as disturbances in the RAAS.⁸¹ In this context, statins lower blood cholesterol as well as reduce oxidative stress, inflammation and macrophage-related production of metalloproteinases.^82–85 Several lines of data show that mechanisms behind beneficial, non-lipid dependent effects of statins in arteriosclerosis are dependent on inhibition of the RAAS.^47,66,86 By the same token, statins may improve cardiac performance in heart failure^86–88 as inhibition of the RAAS reduces retention of salt and water, lowers peripheral resistance and exerts beneficial effects on cardiovascular remodelling.^8,89,90 However, the use of statins in patients with heart failure remains controversial.^91,92 An extensive review on the effects of statins in arteriosclerosis and heart failure may be found elsewhere.^93–95

Statins, the RAAS and hypertension

Hypertension is a major risk factor for CVDs and death. Statins as well as drugs affecting the RAAS play a pivotal role in primary and secondary prevention of cardiovascular events.^74,76,77,96 Drugs affecting the RAAS have served as a mainstay of antihypertensive therapy for over three decades. Interestingly, several lines of evidence suggest that statins lower arterial blood pressure (BP)^97–103 as well as boost the efficacy of antihypertensive drugs.^79,104 However, studies on the hypotensive effect of statins provide conflicting results.^105–109

In this context, it has been suggested that statins reduce the hypertensive effect of Ang II.^110,111 Straznicky and collaborators showed that pravastatin decreases the pressor response to intravenous infusion of Ang II in mildly hypertensive patients.¹¹¹ Similarly, reduction in pressor response to intravenously administered Ang II, likely due to the inhibition of Ang II–dependent production of free radicals, has been reported in normotensive Sprague-Dawley rats treated with simvastatin.¹¹⁰ Furthermore, atorvastatin and simvastatin but not pravastatin have been shown to decrease the responsiveness of vascular smooth muscle cells to Ang II.¹¹² In contrast, Sim et al. found that treatment with statins increases vascular sensitivity to Ang II in hypercholesterolaemic patients. The authors imply that this phenomenon may be explained by altered balance between ATR1 and ATR2 in hypercholesterolaemia.¹¹³ Besides, it has been reported that pravastatin given to patients after myocardial infarction does not affect BP and the risk of developing new hypertension over a follow-up period of five years.¹⁰⁶

Statins have also been found to affect the brain control of BP.^114–116 For example, in our studies we have found that Sprague-Dawley rats treated with simvastatin exhibit a smaller hypertensive response to intracerebroventricularly infused Ang II than controls.^114,115 In addition, there is some evidence that hypercholesterolaemia may affect the brain RAAS,^116,117 and the integrity of the BBB,¹¹⁸ which may change the effect of blood-borne hormones such as Ang II and aldosterone on the brain mechanism controlling BP.

Further evidence for an interaction between statins and the RAAS is provided by studies which show that statins enhance the hypotensive effect of ACE-I and ARBs.^79,119 Spósito and collaborators reported that hypercholesterolaemic patients receiving concomitant treatment with statins and ACE-I show a greater fall in BP than patients receiving ACE-I alone.⁷⁹ Similarly, in an animal model of hypertension, simvastatin given together with either valsartan or enalapril was reported to cause a synergistic drop in BP.¹¹⁹ In contrast, Mancia at al. reported that treatment with pravastatin does not enhance the hypotensive effect of fosinopril in hypertensive patients.¹⁰⁵ Furthermore, in hypertensive, hypercholesterolaemic patients the concomitant treatment with losartan and simvastatin failed to reduce BP more than treatment with losartan alone, however, the combined therapy improved endothelial function and reduced inflammatory markers to a greater extent than monotherapy with either drug.⁷⁸ Likewise, simvastatin and ramipril given together improved endothelium-dependent vasodilation as well as reduced oxidative stress and inflammation more than ramipril alone.¹²⁰ In this line, concomitant therapy with statins and ARBs or ACE-Is has repeatedly been found to improve vascular reactivity to vasodilator substances.^78,120,121

Hypotensive effects of statins, likely due to an interaction with the RAAS, are also supported by the results of meta-analyses of clinical data. The meta-analysis by Strazzullo et al. found that statins have a small but significant hypotensive effect: however, the hypotensive effect of statins as well as possible synergetic effect of statins and hypotensive drugs may depend on a selection of drugs and patients.¹⁰⁹

The synergistic effect of statins and drugs affecting the RAAS may involve the inhibition of vascular remodelling, proliferation, hypertrophy of vascular smooth muscle cells, fibrosis, apoptosis and activity of matrix metalloproteinases.^82,122–126 All of these may reduce peripheral resistance and lower BP.

Mechanisms of an interaction between statins and the RAAS in BP regulation

HMG-CoA reductase inhibitors may interact with the RAAS in a number of ways (Figure 1). For example, it has been found that statins decrease expression of AT1Rs,^116,127,128 inhibit Ang II-dependent intracellular signalling,^86,126,129 reduce RAAS-dependent oxidative stress^47,66 and inflammation,⁸⁶ as well as inhibit the synthesis of Ang II and aldosterone.^121,130

Figure 1.

Interactions between statins and the renin–angiotensin–aldosterone system (RAAS) in the circulatory system. ANG II: angiotensin II (ATR: angiotensin receptor).

The reduction of expression of AT1R by statins has been reported in vascular smooth muscle cells in rats^127,131 and in the brain of rabbits with heart failure.¹¹⁵ The reduction of AT1R expression may be due to lowering cholesterol level as well as due to cholesterol-independent effects of statins.^116,127,131 In this line, it has been shown that pravastatin and atorvastatin act as Peroxisome proliferator-activated receptor gamma (PPARγ) activators^132,133 and that the activation of PPARγ results in decreased AT1R mRNA and protein expression.¹³⁴ Reduction in AT1R expression may be a particularly important in hypercholesterolaemia which is associated with the increased expression of AT1R in vascular smooth muscle cells,^135–138 formation of ROS and increase in Ang II-dependent vasoconstriction.^136–139 Furthermore, it has been found that statins inhibit the prenylation of Rac1 and expression of the Nox1 subunit of NADPH oxidase thus reducing ROS production dependent on stimulation of AT1R.⁴⁷ In contrast, the withdrawal of treatment with statins has been found to increase mRNA and protein expression of AT1R in rat aortic vascular smooth muscle.¹⁴⁰

In addition, the interactions between statins and the RAAS may involve the Ang II-dependent intracellular pathways. For example, it has been found that statins downregulate RhoA/Rho kinase, mitogen-activated protein kinase (MAPK) pathways, redox processes and Ang II-mediated production of superoxide radicals.^116,126,129

Finally, statins may affect the synthesis of aldosterone in the adrenal glands by reducing endogenous cholesterol, an essential substrate for steroid hormones production,^121,130 or by inhibiting the action of Ang II, a major stimulus for aldosterone synthesis. These effects, however, depend on the properties of statins, especially their water solubility.^35,141 In this connection, Ide et al. reported that hypercholesterolaemic patients receiving lipophilic simvastatin, but not hydrophilic pravastatin, show reduced aldosterone synthesis sensitivity to Ang II.¹⁴² Experimental studies in Dahl salt-sensitive rats maintained on high sodium diet showed that simvastatin and losartan given together reduced aldosterone level in renal and cardiac tissue while the statin given alone reduced plasma aldosterone.¹²¹ On the other hand, a short-term treatment with atorvastatin has been found to not affect aldosterone plasma level.¹⁴³

Perspectives

Accumulating evidence suggests that the concomitant treatment with statins and drugs affecting the RAAS may exert a synergistic effect on BP: however, the mechanisms as well as the therapeutic potential of such an interaction have not yet been clarified. Experimental studies show that the two groups of drugs share common pathways and mediators, which may explain some of the unexpected effects of statins, such as a hypotensive effect.

The new guidelines on the treatment of dyslipidaemia and the reduction of atherosclerotic cardiovascular risk,^25,26 if enthusiastically implemented by physicians, will substantially increase the number of hypertensive patients receiving statins as well as increase the average length of statin treatment. This will provide more data to address the effect of statins and their interaction with antihypertensive drugs on BP. It needs to be stressed however, that the population of patients treated with statins according to new guidelines will differ from present statin users, and may display some unexpected effects of statins on BP. Moreover, although currently used, statins have relatively excellent safety,^144–146 and there is no evidence of adverse events due to statins and antihypertensive drug interactions, excluding certain calcium-channel blockers, it is likely that a number of reported adverse events will increase along with the number of patients receiving such treatment.

Conclusions

Statins as well as drugs acting via the RAAS substantially reduce cardiovascular risk. Several lines of evidence suggest that statins given either alone or together with antihypertensive drugs acting via the RAAS lower BP. However, it is too early to judge whether potential hypotensive effect of satins should be considered by a physician who sees a hypertensive patient. Further research is needed to evaluate the mechanisms of interaction between statins and the RAAS, and their therapeutic significance.

Footnotes

Acknowledgements

The authors are in debt to T Zera for his critical comments on the manuscript.

Conflicts of interest

None declared.

Funding

This paper and associated studies were supported by the Ministry of Science and Higher Education Republic of Poland, Juventus Plus grant IP2011 057571.

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Statins,the renin–angiotensin–aldosterone system and hypertension – a tale of another beneficial effect of statins

Abstract

Background:

Method:

Result:

Conclusion:

Keywords

Introduction

Statins

Short characteristic of the drug class

Lipid-lowering and non-lipid-dependent effects of statins

Interactions between statins and the RAAS in cardiovascular diseases

Statins, the RAAS and hypertension

Mechanisms of an interaction between statins and the RAAS in BP regulation

Perspectives

Conclusions

Footnotes

Acknowledgements

Conflicts of interest

Funding

References