Vascular and cardiac benefits of angiotensin receptor blockers

doi:10.1016/S0002-9343(02)01241-X

The American Journal of Medicine

Volume 113, Issue 5, 1 October 2002, Pages 409-418

https://doi.org/10.1016/S0002-9343(02)01241-X Get rights and content

Abstract

Angiotensin II not only is a vasoconstrictor, but it also affects cell growth and apoptosis, inflammation, fibrosis, and coagulation. Blockade of the renin-angiotensin system, either with inhibitors of the generation of angiotensin (angiotensin-converting enzyme [ACE] inhibitors) or with blockers of angiotensin receptors, reduces blood pressure and inhibits other pathophysiological actions. These other effects provide benefits in coronary heart disease, heart failure, diabetic nephropathy, and stroke beyond blood pressure reduction. These benefits were first demonstrated with ACE inhibitors. However, the mechanism of action of angiotensin receptor blockers, which block angiotensin II stimulation at the angiotensin type 1 receptor but not at the type 2 receptor, may have advantages, particularly for endothelial dysfunction and vascular remodeling, as well as cardiac and renal protection. Recent multicenter trials suggest that ACE inhibitors and angiotensin receptor blockers may reduce morbidity and mortality associated with cardiovascular and renal disease beyond blood pressure reduction. Several studies with different angiotensin receptor blockers, including comparisons with ACE inhibitors, are under way, and should provide further guidance for their clinical use.

Section snippets

Vascular effects of angiotensin II

The renin-angiotensin system, specifically its main effector, angiotensin II, has many effects on blood pressure 3, 4. Angiotensin II is generated from angiotensin I by ACE, mainly in the pulmonary circulation and in tissues. Angiotensin I is formed from angiotensinogen by the action of renin, which is of renal origin. Other enzyme systems, such as the serine protease chymase, which are distributed widely in human tissues including the heart and the vasculature, also promote the formation of

Functions of angiotensin type 1 and type 2 receptors

Angiotensin II acts via type 1 and type 2 receptors. The type 1 receptors mediate the known effects of angiotensin II 2, 3, 17, 24, 25 (Table 1), including smooth muscle cell proliferation and growth, enhancement of inflammation via macrophage activation and cell migration, and generation of oxygen free radicals 26, 27. These processes contribute to atherosclerotic disease and acute ischemic events (23). Blockade of the renin-angiotensin system with ACE inhibitors or angiotensin receptor

Endothelial dysfunction and vascular remodeling

Structural and functional changes in resistance vessels may raise peripheral resistance and increase the complications of hypertension 33, 34. Remodeling of small (resistance) arteries may be one of the first manifestations of target organ damage in mild essential hypertension (35), before development of left ventricular hypertrophy, carotid artery intima-media thickening, or appearance of microalbuminuria. Small resistance arteries from patients with hypertension have a smaller lumen and

Angiotensin-converting enzyme inhibitor–based evidence

Studies in patients with hypertension have demonstrated that the effects of ACE inhibitors resemble the favorable effects of these agents on vascular structure and function in experimental models of hypertension in rats 48, 49, 50, 51, 52, 53, 54, 55. In patients with coronary heart disease who did not have hypertension, severe hyperlipidemia, or heart failure, treatment with the ACE inhibitor quinapril led to improved endothelial function (56). In contrast, the beta-blocker atenolol, which

Conclusion

Several clinical trials have demonstrated that ACE inhibitors prevent cardiovascular events in patients with vascular disease and with hypertension. Whether angiotensin receptor blockers will have similar benefits is less certain, but findings from recent and ongoing studies should further define their role in the treatment and prevention of the morbidity and mortality associated with cardiovascular disease (26).

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Citation Excerpt :
Being shorter than Ang II by one amino acid, Ang-(1-7) opposes the deleterious actions of Ang II through activation of the Mas receptor,1 which also belongs to the GPCR family. While AT1 signaling is involved in vasoconstriction, fibrosis, and inflammation,3 Mas signaling is associated with vasodilation, reduction of oxidative stress, antiproliferative, antifibrotic, and anti-inflammatory effects.1 Pieces of evidence suggest that chronic imbalance between these 2 branches may contribute to the development of different pathologies.1
The renin-angiotensin system (RAS) plays an important role in erectile function. The RAS contains 2 major axes: one deleterious, composed of ACE-Ang II-AT1 receptor, and another protective, composed of ACE2-Ang-(1-7)-Mas receptor. While aging is a well-known cause for development of male sexual disorders, little is known about local regulation of the RAS in age-related erectile dysfunction (ED).
The present study aimed to assess regulation of the RAS in aging-associated ED rat model and evaluate possible options for disease management through pharmacological modulation of the RAS.
Penile tissues were harvested from 3-, 12-, and 24-month-old Wistar rats. Local expression of major RAS components and ED markers was measured by RT-PCR. Protein expression of RAS components was assessed by western blot. Collagen deposition was measured by Sirius Red and immunohistochemical staining. Evaluation of collagen content was also performed in penile sections of Mas-knockout mice by Sirius Red and Masson’s trichrome stainings. Finally, the effect of Ang-(1-7) pretreatment on TGF-β–induced myofibroblast activation was studied in primary cavernosal and immortalized fibroblasts.
Experimental results highlighted the essential role of the RAS in modulation of cavernosal fibrosis.
The present study demonstrates local expression of angiotensinogen mRNA alongside with major RAS components, which suggests local autonomous functioning of the RAS within penile tissue. Gene expression analysis revealed strong positive correlation between ACE-Ang II-AT1 axis with markers for inflammation and fibrosis. While corpus cavernosum from 24-month-old rats was characterized by increased collagen deposition, protein expression of ACE, AT1, and Mas was shown to be upregulated in the penile tissue of this group. At the same time, penile sections from Mas-knockout mice (FVB/N background) were also shown to have increased collagen deposition. Finally, it was demonstrated that Ang-(1-7) treatment of primary cavernosal and immortalized fibroblasts was able to alleviate TGF-β–induced fibroblast-to-myofibroblast transition.
The present study suggests Ang-(1-7) treatment as a possible strategy for pharmacological management of fibrosis-associated ED in aging.
The link between the RAS and penile fibrosis, indicated by a holistic screening of different ED markers, was confirmed by in vivo and in vitro data. However, results, presented in the manuscript, need to be further reinforced by human data. Important to note, the main goal of the study was to characterize RAS regulation in aging condition rather than state any causal relationships.
Present study characterizes RAS regulation in aging-associated ED and indicates its important role in cavernosal fibrosis.
Bragina ME, Costa-Fraga F, Sturny M, et al. Characterization of the Renin-Angiotensin System in Aged Cavernosal Tissue and its Role in Penile Fibrosis. J Sex Med 2020;17:2129–2140.
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The identification of the Mas receptor as molecular target for angiotensin-(1-7) represented a landmark in the understanding of the renin–angiotensin system (RAS). Besides its cardiovascular actions, Mas stimulation seems to exert protective effects in several systems and organs, opposing the detrimental effects of the overactivation of the Ang II/AT₁ axis. This chapter will focus on the current knowledge on Mas receptor agonists, which opened up an entirely new direction for promising drugs and therapeutics.
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Here, we examined the expression of ACE2 in erectile tissues and its actions against hypercholesterolemia‐induced corpus cavernosum (CC) injury.
Hypercholesterolemic apolipoprotein E knockout (ApoE^−/−) mice, a well‐known model of ED, were treated with diminazene aceturate (DIZE), an ACE2 activator compound, or vehicle for 3 weeks. Reactive oxygen species (ROS), collagen content, and protein expression of ACE2, neuronal nitric oxide synthase (nNOS), endothelial nitric oxide synthase (eNOS), nicotinamide adenine dinucleotide phosphate‐oxidase (NADPH) subunits were evaluated in the penis of DIZE‐treated and untreated ApoE^−/− mice. Functional studies were performed in CC strips.
ACE2 expression and its role in modulating nitric oxide (NO)/ROS production and fibrosis within the CC of hypercholesterolemic mice were the main outcome measures.
ACE2 was expressed in smooth muscle and endothelial cells of mouse CC. Interestingly, ACE2 was downregulated in penis of hypercholesterolemic mice with ED, suggesting a protective role of ACE2 on the CC homeostasis. In accordance with that, pharmacological ACE2 activation by DIZE treatment reduced ROS production and NADPH oxidase expression, and elevated nNOS and eNOS expression and NO bioavailability in the penis of ApoE^−/− mice. Additionally, DIZE decreased collagen content within the CC. These beneficial actions of DIZE on the CC were not accompanied by improvements in atherosclerotic plaque size or serum lipid profile.
ACE2 is expressed in erectile tissue and its reduction is associated with hypercholesterolemia‐induced ED. Additionally, treatment with DIZE improved hypercholesterolemia‐induced CC injury, suggesting ACE2 as a potential target for treating ED. Fraga‐Silva RA, Costa‐Fraga FP, Montecucco F, Sturny M, Faye Y, Mach F, Pelli G, Shenoy V, da Silva RF, Raizada MK, Santos RAS, and Stergiopulos N. Diminazene protects corpus cavernosum against hypercholesterolemia‐induced injury. J Sex Med 2015;12:289–302.
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¹: The work by Dr. Schiffrin mentioned in this article has been supported by grants 13570 and 37917, and by a group grant to the Multidisciplinary Research Group on Hypertension, from the Canadian Institutes of Health Research, and by research grants from Merck-Frosst Canada, Bristol-Myers Squibb Canada, and Sanofi-Synthélabo Canada. Dr. Schiffrin has received research grant support or been a consultant for Astra-Zeneca, Aventis, Bayer, Bristol-Myers Squibb, Hoffmann-LaRoche, Merck, Novartis, Pfizer, and Sankyo.

View full text

ReviewVascular and cardiac benefits of angiotensin receptor blockers

Abstract

Section snippets

Vascular effects of angiotensin II

Functions of angiotensin type 1 and type 2 receptors

Endothelial dysfunction and vascular remodeling

Angiotensin-converting enzyme inhibitor–based evidence

Conclusion

Am J Kidney Dis

J Biol Chem

J Am Coll Cardiol

Am J Med

Regul Pept

Am J Hypertens

Lancet

Lancet

Lancet

Lancet

Am J Hypertens

Lancet

J Card Fail

Am J Cardiol

Lancet

J Am Coll Cardiol

Achieving blood pressure targets in the management of hypertension

Blood Press

Recent progress in angiotensin II type 2 receptor research in the cardiovascular system

Hypertension

Tissue angiotensin and pathobiology of vascular disease. A unifying hypothesis

Hypertension

Angiotensin II-forming pathways in normal and failing hearts

Circ Res

Widespread tissue distribution of human chymase

J Hypertens

A novel vascular smooth muscle chymase is upregulated in hypertensive rats

J Clin Invest

Conditional and targeted overexpression of vascular chymase causes hypertension in transgenic mice

Proc Natl Acad Sci USA

Dual pathway for angiotensin II formation in human internal mammary arteries

Br J Pharmacol

Functional evidence for a role of vascular chymase in the production of angiotensin II in isolated human arteries

Circulation

Regulation of local angiotensin II formation in the human heart in the presence of interstitial fluid. Inhibition of chymase by protease inhibitors of interstitial fluid and of angiotensin-converting enzyme by Ang-(1-9) formed by heart carboxypeptidase A-like activity

Circulation

Significance of chymase-dependent angiotensin-II forming pathway in the development of vascular proliferation

Circulation

Vasoconstrictor effect of the angiotensin-converting enzyme–resistant, chymase-specific substrate [Pro11D-Ala12] angiotensin I in human dorsal hand veinsin vivo demonstration of non-ACE production of angiotensin II in humans

Circulation

Signal transduction mechanisms mediating the physiological and pathophysiological actions of angiotensin II in vascular smooth muscle cells

Pharmacol Rev

Tissue angiotensin system in cardiovascular medicine. A paradigm shift?

Circulation

Prothrombotic effects of angiotensin

Adv Intern Med

Role of NADH/NADPH oxidase–derived H2O2 in angiotensin II–induced vascular hypertrophy

Hypertension

Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone

J Clin Invest

Current concepts of the pathogenesis of the acute coronary syndromes

Circulation

Angiotensin II type 1 receptor blockers

Circulation

Angiotensin type 2 receptors: potential importance in the regulation of blood pressure

Curr Opin Nephrol Hypertens

Angiotensin II-induced hypertension accelerates the development of atherosclerosis in apoE-deficient mice

Circulation

Roles of angiotensin II type 2 receptor stimulation associated with selective angiotensin II type 1 receptor blockade with valsartan in the improvement of inflammation-induced vascular injury

Circulation

Can antihypertensive drugs reduce atherosclerosis and its clinical complications?

Am J Hypertens

Comparative effect of ACE inhibition and angiotensin II type I receptor antagonism on bioavailability of nitric oxide in patients with coronary artery diseaserole of superoxide dismutase

Circulation

Role of the angiotensin AT2 receptor in blood pressure regulation and therapeutic implications

Am J Hypertens

Differential roles of AT1 and AT2 receptor subtypes in vascular trophic and phenotypic changes in response to stimulation with angiotensin II

Arterioscler Thromb Vasc Biol

Angiotensin II type 2 receptor mediates programmed cell death

Proc Natl Acad Sci USA

Reactivity of small blood vessels in hypertensionrelation with structural changes. State of the art lecture

Hypertension

Review
Vascular and cardiac benefits of angiotensin receptor blockers

Vasoconstrictor effect of the angiotensin-converting enzyme–resistant, chymase-specific substrate [Pro¹¹_D-Ala¹²] angiotensin I in human dorsal hand veinsin vivo demonstration of non-ACE production of angiotensin II in humans

Role of NADH/NADPH oxidase–derived H₂O₂ in angiotensin II–induced vascular hypertrophy

Role of the angiotensin AT₂ receptor in blood pressure regulation and therapeutic implications

Differential roles of AT₁ and AT₂ receptor subtypes in vascular trophic and phenotypic changes in response to stimulation with angiotensin II