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Combined Use of Calcium Channel Blockers and Inhibitors of the Renin–Angiotensin System for Treating Hypertension

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Combined Use of Calcium Channel Blockers and Inhibitors of the Renin–Angiotensin System for Treating Hypertension Review Combined use of calcium channel blockers and inhibitors of the renin–angiotensin system for treating hypertension Reduced cardiovascular events and mortality have been reported for hypertensive subjects treated with dihydropyridine-type calcium channel blockers (CCBs) and inhibitors of the renin–angiotensin system (RAS) in clinical trials. Recent evidence suggests that these agents may have vascular benefits that cannot be attributed to the reduction of blood pressure alone. Dihydropyridine-type CCBs and RAS blockers have been shown to improve endothelial activity while reducing inflammation. These changes in vascular activity have been confirmed by pulse wave analyses, which show a reduced impact of pressure wave reflections on central systolic blood pressure. In this article, we examine the separate and combined effects of CCB and RAS inhibition in reducing cardiovascular risk through enhanced vascular function. 1 KEYWORDS: aliskiren n angiotensin n calcium channel blockers n endothelial Yoshiko Mizuno , dysfunction n hypertension n inflammation n oxidative stress n renin Robert F Jacob2 & R Preston Mason† A number of structural and functional mecha- production through enzymatic mechanisms 1Department of Cardiovascular nisms have been identified in the pathogen- or by stimulating direct release by its redox Medicine, The University of Toyko, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan esis of hypertensive vascular disease, includ- congeners in a spontaneous fashion. While all 2Elucida Research LLC, PO Box 7100, ing endothelial dysfunction, oxidative stress antihypertensive medications lower BP, certain 100 Cummings Center, Suite 135L, Beverly, MA 01915, USA and inflammation. The vascular endothelium drug classes have pleiotropic effects that may †Author for correspondence: controls vasomotor tone through the release of contribute to cardiovascular risk reduction. The Cardiovascular Division, Department of Medicine, Brigham & Women’s signaling molecules such as nitric oxide (NO). relative importance of BP reduction versus the Hospital, Harvard Medical School, Hypertension, together with other cardiovascu- mechanisms associated with vascular protection PO Box 7100, 100 Cummings Center, Suite 135L, Beverly, MA 01915, USA lar risk factors, impairs the endothelium and its remains a subject of considerable debate [2]. The Tel.: +1 978 867 2125 responsiveness to normal stimuli. In addition, primary purpose of antihypertensive therapy is Fax: +1 978 921 4195 the mechanical forces inherent in hypertension BP reduction, which continues to be the accepted [email protected] activate compensatory neurohormonal mecha- basis for their clinical benefit [3]. Developing a nisms, including the renin–angiotensin system better understanding of the mechanisms under- (RAS), which negatively impact the structure of lying hypertensive vascular disease, as well as the the vascular wall. Antihypertensive drugs may pleiotropic actions of antihypertensive agents, have class-specific hemodynamic and endothe- offers the potential for more targeted therapy lial effects that mitigate these disease processes that reduces global cardiovascular risk. when used separately or in specific combinations. Measurements of endothelial function include In this article, we focus on dihydro pyridine changes in central circulation indices of pressure. (DHP)-type calcium channel blockers (CCBs) Indeed, measures of central arterial pressure to and RAS inhibitors as a combination treatment vital organs are powerful predictors of cardio- for hypertension; however, there are other phar- vascular events and are closely associated with macologic approaches to blood pressure (BP) vascular function [4,5]. Central aortic pressure is reduction that are supported by outcome stud- determined by cardiac output and peripheral vas- ies. As with any therapeutic approach, there are cular resistance – factors that, along with arterial studies that may provide both positive and nega- stiffness, determine the timing and magnitude tive findings for any particular agent, depend- of pressure wave reflections. A portion of each ing on various design aspects such as patient stroke volume is delivered distally during systole, characteristics and predefined end points. with the remainder delivered by elastic recoil of Pharmacological approaches that reduce cen- the aorta during diastole in a manner influenced tral aortic pressure and vascular resistance asso- by the relative elasticity of the central arteries [5]. ciated with hypertension have also been shown Increases in central arterial stiffness result in the to reduce clinical events [1]. These agents may delivery of greater portions of each stroke volume improve vasodilation through enhanced NO during systole. The velocities of both forward bioavailability by either increasing endogenous and reflected waves increase, thus the reflected 10.2217/THY.11.17 © 2011 Future Medicine Ltd Therapy (2011) 8(3), 247–260 ISSN 1475-0708 247 Review Mizuno, Jacob & Mason Calcium channel blockers & inhibitors of the renin–angiotensin system for treating hypertension Review wave returns earlier to the aorta and raises central The eNOS enzyme has multiple functional aortic pressure. Central aortic stiffness contrib- regions, including a reductase domain that utes directly to the generation of a wide pulse contains binding sites for FAD, FMN and pressure with higher systolic BP (SBP) and lower NAD(P)H, and that is linked by a calcium/cal- diastolic BP. Antihypertensive agents produce modulin binding site to an oxygenase domain different effects on central aortic pressure and that contains the binding sites for heme, BH4 hemodynamics despite similar effects on BP and l-arginine. In the presence of calcium, cal- measured over the brachial artery, as e videnced modulin and adequate l-arginine levels, elec- by the results of recent clinical trials. trons are transferred from NAD(P)H to the FAD and FMN redox carriers in the reductase Hypertension & domain to the heme moiety in the oxygenase endothelial dysfunction domain, where they ultimately oxidize the Endothelial dysfunction, a hallmark feature of guanidino group of l-arginine to liberate NO hypertension, is characterized by attenuated and l-citrulline. The BH4 cofactor functions as NO bioavailability, resulting in elevated vas- both an allosteric and redox cofactor for eNOS. cular resistance and reduced sensitivity to nor- As a result, the presence of BH4 improves the mal stimuli of vasodilation, such as shear stress binding affinity of eNOS for l-arginine and and acetylcholine. This abnormality is an early the heme ligand. Reduced levels of BH4 lead event in atherogenesis and is causally related to to eNOS uncoupling and disruption of its enhanced oxidative stress. Aging, vascular injury, homodimeric configuration. In the uncoupled metabolic disorders and deficiencies in essential state, eNOS does not produce adequate levels - substrate (l-arginine) and enzyme cofactors of NO but instead generates O2 from molecular (e.g., tetrahydrobiopterin) also contribute to oxygen, which in turn reacts rapidly with avail- - reduced NO bioavailability [6,7]. In the kidney, able NO to form ONOO (Figure 1). Generally, NO induces renal arterial vasodilation, inhib- reduced NO bioavailability is the result of its sodium reabsorption and reduces mesangial either reduced eNOS activity or increased - cell proliferation and extracellular matrix syn- eNOS uncoupling with O2 production and - thesis in response to injury [8,9]. Under disease ONOO formation. - conditions, excessive superoxide (O2 ) genera- In spontaneously hypertensive rats, for exam- tion reduces NO bioavailability in glomerular ple, a pronounced loss in NO bioavailability was endothelial cells to form a toxic p roduct known observed despite an increase in levels of eNOS - as peroxynitrite (ONOO ) [9]. as compared with normotensive animals [13]. Nitric oxide is generated from the conversion This effect was even more pronounced in these of l-arginine to l-citrulline by endothelial nitric animals following the induction of diabetes, oxide synthase (eNOS), which requires calcium/ as measured in both arterial and glomerular calmodulin, flavin adenine dinucleotide (FAD), endothelial cells [9]. The basis for this paradoxi- flavin mononucleotide (FMN) and tetrahydrobi- cal loss of NO despite increased enzyme levels - opterin (BH4) as cofactors. Under conditions of is the production of O2 by uncoupled eNOS. A cardiovascular risk, such as hyperlipidemia and similar change in eNOS expression, as well as - - hypertension, there is abnormal eNOS activity an increase in O2 and ONOO generation, was despite normal or even enhanced expression of observed in normal rats that were made hyper- the enzyme. Indeed, overexpression of eNOS in tensive by surgical procedures such as aortic apoE knockout mice caused significantly larger banding [14]. Glucose intolerance, as occurs in atherosclerotic lesions as compared with control diabetes, is also believed to impair eNOS activity mice in a manner that was ameliorated with BH4 through enhanced oxidative stress. supplementation [10]. Under conditions in which Rates of hypertension are disproportionately vascular tissue levels of BH4 are deficient or lack- higher in African–Americans, which leads to ing, eNOS becomes dysfunctional. This results increased rates of cardiovascular disease as com- in the enzymatic reduction of molecular oxygen pared with other populations [15]. Under controlled by eNOS in a manner that is no longer
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