Comparison of the cardiovascular protection by omapatrilat and lisinopril treatments in DOCA-salt hypertension

Millette, Esther; Demeilliers, Bénédicte; Wu, Rong; Laplante, Marc-André; Midaoui, Adil El; Moreau, Pierre; Lamontagne, Daniel; Champlain, Jacques de

doi:10.1097/00004872-200301000-00022

Cited by 14 publications

(12 citation statements)

References 24 publications

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“…Indeed, in general, endothelium-mediated (drug-and shear stress-stimulated) dilation of isolated coronary arteries is reduced in hypertensive humans 11,[53][54][55][56][57] and animals, 19,21,32,36,45,51,52,[58][59][60][61][62] while the endothelium-independent vasodilatory responses to sodium nitroprusside and adenosine are often unaltered. 21,32,45,55,63 There are exceptions to these general observations 18,33,50,[63][64][65][66] and the vessel type (conduit vs resistance artery), 45,57 the mode of precontraction, 33 and the vasodilator protocol 45,56,61,67 or eliminated 58,68,69 by inhibitors of eNOS in isolated coronary vessels from hypertensive animals, suggesting that NO remains an important component of vascular function even when its bioavailability is reduced in hypertension.…”

Section: Nitric Oxide-mediated Vasomotor Function Of Isolated Coronarmentioning

confidence: 99%

“…29,30 A number of genetic, neurohumoral, and local factors contribute. 9,11,19,[29][30][31][32][33][34][35][36] to these adaptations which result in increases in resistance, as well as reduced flow and increased diffusion distances, all of which impair oxygen delivery and organ function. Although nitric oxide (NO) likely contributes to the structural remodeling accompanying hypertension, the focus of this review does not include description of structural adaptations, and the reader is referred to other works dealing with these topics.…”

Section: Introduction To Coronary Hemodynamics In Hypertensionmentioning

confidence: 99%

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Nitric oxide and coronary vascular endothelium adaptations in hypertension

Levy

Chung²,

Kroetsch

et al. 2009

VHRM

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This review highlights a number of nitric oxide (NO)-related mechanisms that contribute to coronary vascular function and that are likely affected by hypertension and thus become important clinically as potential considerations in prevention, diagnosis, and treatment of coronary complications of hypertension. Coronary vascular resistance is elevated in hypertension in part due to impaired endothelium-dependent function of coronary arteries. Several lines of evidence suggest that other NO synthase isoforms and dilators other than NO may compensate for impairments in endothelial NO synthase (eNOS) to protect coronary artery function, and that NO-dependent function of coronary blood vessels depends on the position of the vessel in the vascular tree. Adaptations in NOS isoforms in the coronary circulation to hypertension are not well described so the compensatory relationship between these and eNOS in hypertensive vessels is not clear. It is important to understand potential functional consequences of these adaptations as they will impact the efficacy of treatments designed to control hypertension and coronary vascular disease. Polymorphisms of the eNOS gene result in significant associations with incidence of hypertension, although mechanistic details linking the polymorphisms with alterations in coronary vasomotor responses and adaptations to hypertension are not established. This understanding should be developed in order to better predict those individuals at the highest risk for coronary vascular complications of hypertension. Greater endothelium-dependent dilation observed in female coronary arteries is likely related to endothelial Ca 2+ control and eNOS expression and activity. In hypertension models, the coronary vasculature has not been studied extensively to establish mechanisms for sex differences in NO-dependent function. Genomic and nongenomic effects of estrogen on eNOS and direct and indirect antioxidant activities of estrogen are discussed as potential mechanisms of interest in coronary circulation that could have implications for sex-and estrogen status-dependent therapy for hypertension and coronary dysfunction. The current review identifies some important basic knowledge gaps and speculates on the potential clinical relevance of hypertension adaptations in factors regulating coronary NO function.

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Section: Nitric Oxide-mediated Vasomotor Function Of Isolated Coronarmentioning

confidence: 99%

Section: Introduction To Coronary Hemodynamics In Hypertensionmentioning

confidence: 99%

Nitric oxide and coronary vascular endothelium adaptations in hypertension

Levy

Chung²,

Kroetsch

et al. 2009

VHRM

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“…Similar results were obtained in Dahl-sensitive and deoxycorticosterone acetate (DOCA)-salt-treated rats [10][11][12]. In this latter model, Millette et al [12] recently reported that omapatrilat increases the animals' survival.…”

Section: Preclinical and Preliminary Clinical Studiesmentioning

confidence: 52%

“…In hypertensive animal models, omapatrilat has also been found to improve the structure and the endothelial function of resistant arteries and to improve cardiac and vascular fibrosis in stroke-prone spontaneously hypertensive rats [8,9]. Similar results were obtained in Dahl-sensitive and deoxycorticosterone acetate (DOCA)-salt-treated rats [10][11][12]. In this latter model, Millette et al [12] recently reported that omapatrilat increases the animals' survival.…”

Section: Preclinical and Preliminary Clinical Studiesmentioning

confidence: 67%

Recent clinical trials with omapatrilat: New developments

Zanchi

Maillard²,

Burnier³

2003

Current Science Inc

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Omapatrilat belongs to the vasopeptidase inhibitors, ie, drugs that possess the ability to inhibit simultaneously the membrane-bound zinc metalloproteases, angiotensin-converting enzyme (ACE), and the neutral endopeptidase EC 3.4.24.11 (NEP). Omapatrilat was targeted to treat patients with hypertension and congestive heart failure. The preclinical and early clinical studies conducted with omapatrilat were very promising. Indeed, omapatrilat appeared to be a very potent antihypertensive agent with very favorable effects on cardiac function in heart failure patients. In contrast to these early studies, the large clinical trials were more disappointing. The results of the OCTAVE trial confirmed the antihypertensive efficacy of omapatrilat, but at the price of an angioedema rate more than threefold higher than that of an ACE inhibitor in the overall population (2.17% vs 0.68%), and close to fourfold higher in the black population. In OVERTURE, a large randomized control trial in heart failure, angioedema was also more common with omapatrilat, but the incidence was much lower (0.8% with omapatrilat vs 0.5% with enalapril). However, omapatrilat was not convincingly superior to the ACE inhibitor. Because angioedema is probably a class side effect of vasopeptidase inhibitors, the higher incidence of this potentially life-threatening complication with omapatrilat has likely stopped the development of this new class of agents. The future of vasopeptidase inhibitors will depend on the ability to improve the risk/benefit ratio either by developing agents that produce less angioedema, or by defining more precisely a high-risk population that could take advantage of dual ACE/NEP inhibition.

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“…effects of omapatrilat have recently been demonstrated, including effects on endothelial-dependent coronary artery dilatation [24] and on macrophage infiltration and oxidative stress status [13].…”

Section: Discussionmentioning

confidence: 99%

Anti-atherosclerotic and renoprotective effects of combined angiotensin-converting enzyme and neutral endopeptidase inhibition in diabetic apolipoprotein E-knockout mice

Jandeleit‐Dahm

Lassila

Davis

et al. 2005

Journal of Hypertension

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These studies demonstrate the anti-atherosclerotic and renoprotective effects of omapatrilat in diabetic apo E-KO mice, a model of accelerated atherosclerosis and renal injury. These effects were observed in association with the local inhibition of ACE and NEP at the tissue level in the aorta and kidney. These results suggest that the anti-atherosclerotic effect conferred by omapatrilat treatment in the diabetic apo E-KO mouse is predominantly mediated by its capacity to inhibit local vascular ACE. By contrast, in the kidney, local renal ACE and NEP inhibition and the superior antihypertensive effect of omapatrilat all contribute to the renoprotective effect conferred by omapatrilat treatment in the diabetic apo E-KO mouse.

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Comparison of the cardiovascular protection by omapatrilat and lisinopril treatments in DOCA-salt hypertension

Cited by 14 publications

References 24 publications

Nitric oxide and coronary vascular endothelium adaptations in hypertension

Nitric oxide and coronary vascular endothelium adaptations in hypertension

Recent clinical trials with omapatrilat: New developments

Anti-atherosclerotic and renoprotective effects of combined angiotensin-converting enzyme and neutral endopeptidase inhibition in diabetic apolipoprotein E-knockout mice

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