Role of Angiotensin-converting enzyme and neutral endopeptidase in flow-dependent remodeling.
ABSTRACT Omapatrilat inhibits neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE). We compared the effects of omapatrilat (40 mg/kg/day, p.o.) to fosinopril (40 mg/kg/day, p.o.) on flow-induced vascular remodeling in New Zealand genetically hypertensive (GH) rats. Both drugs equally reduced blood pressure (BP) initially, but systolic BP and pulse pressure were reduced more by omapatrilat after 1 week. Carotid remodeling was induced by partial ligation of the left common carotid artery (LCA). There was little remodeling in untreated GH rats - measured as outer diameter to body weight (OD/BW vs. before ligation): 97 +/- 1% of initial LCA (low flow) and 107 +/- 3% of initial right common carotid artery (RCA, high flow). In contrast, OD/BW increased to 118 +/- 5% (p < 0.05) of initial RCA after omapatrilat versus 108 +/- 2% (p = 0.96) after fosinopril. The major change was increased RCA lumen area which was significantly larger in omapatrilat-treated animals (127% vs. control) than fosinopril-treated animals (103% vs. control). The increase in outward remodeling after omapatrilat treatment correlated weakly with vascular cGMP levels and decreased systolic BP. The results suggest that dual inhibition of NEP/ACE may have greater effects than ACE inhibition alone on vessel remodeling in hypertension.
Journal of Hypertension 01/2005; 23(11):2071-2082. DOI:10.1097/01.hjh.0000184747.41565.a1 · 4.22 Impact Factor
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ABSTRACT: To investigate the effects of the combined angiotensin-converting enzyme (ACE)/neutral endopeptidase (NEP) inhibitor omapatrilat on atherosclerosis and renal injury in a model of diabetes-associated accelerated atherosclerosis and renal injury. The study was performed using diabetic apolipoprotein E-knockout (apo E-KO) mice, a model combining hyperlipidemia and hyperglycemia, which leads to accelerated atherosclerosis and renal injury. Diabetes was induced by the injection of streptozotocin in 6-week old apo E-KO mice. Diabetic animals received no treatment (n = 12) or treatment with the ACE/NEP inhibitor omapatrilat (30 mg/kg per day, via gavage, n = 12) or quinapril (10 mg/kg per day, in drinking water, n = 12) for 20 weeks. Non-diabetic apo E-KO mice (n = 12) served as controls. Omapatrilat reduced atherosclerosis and protected the mice from renal structural injury and albuminuria. The protective effects were associated with tissue inhibition of aortic and renal ACE and NEP as well as a significant reduction in blood pressure. Omapatrilat had similar anti-atherosclerotic effects compared with the ACE inhibitor quinapril in association with an almost complete inhibition of aortic ACE activity by both drugs. Omapatrilat conferred superior renoprotection in the diabetic apo E-KO mouse compared with quinapril in the context of greater renal ACE inhibition by omapatrilat than seen with quinapril, additional renal NEP inhibition and a modestly enhanced antihypertensive response. 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.Journal of Hypertension 12/2005; 23(11):2071-82. · 4.22 Impact Factor
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ABSTRACT: Several previous studies have demonstrated sex differences in cardiovascular autonomic control in healthy young women, but little is known about the regulation of blood pressure in hypertensive elderly women, who have the greatest risk of adverse cardiovascular events. Therefore, we examined sex differences in physiological responses to upright tilt in 21 healthy (13 men and 8 women), 22 controlled hypertensive (10 men and 12 women), and 18 uncontrolled hypertensive (9 men and 9 women) elderly men and women. Of these, 19 normotensives, 18 controlled hypertensives, and 14 uncontrolled hypertensives completed 6 months of observation or pharmacological therapy for uncontrolled hypertension. All of the subjects underwent continuous monitoring of cardiac (RR) interval (ECG), finger arterial pressure (photoplethysmography), and stroke volume (transthoracic impedance) and periodic measurements of forearm blood flow (venous occlusion plethysmography) while resting supine and during a graded head-up tilt. Blood pressure and RR-interval power spectra were computed. Baroreflex gain was estimated by the cross-spectral and sequence methods. In contrast to other groups, elderly hypertensive women increased systemic vascular resistance during tilt. This response was associated with greater low-frequency systolic pressure variability, a presumed marker of sympathetic vascular control. After 6 months of successful antihypertensive therapy, women showed attenuation of the systemic vascular resistance response and a reduction in low-frequency systolic blood pressure variability to levels similar to men and normotensive controls. These results highlight the beneficial effects of antihypertensive therapy on the systemic vasculature, particularly for elderly women in whom enhanced vasoreactivity may contribute to excessive cardiovascular morbidity and mortality.Hypertension 04/2006; 47(3):377-83. DOI:10.1161/01.HYP.0000202595.69583.42 · 7.63 Impact Factor