ET(A) receptor-mediated collagen deposition in hearts of DOCA-salt rats results from increased procollagen synthesis associated with an initial increment in expression of TGF-beta(1). These results support the hypothesis of a role for endothelin-1 in cardiac collagen deposition in mineralocorticoid hypertension, which may have pathophysiological and pharmacological implications in hypertensive heart disease.

Abstract-The cardiac abnormalities associated with hypertension include left ventricular hypertrophy and vascular changes. The latter may affect the cardiac microvasculature and predispose to myocardial ischemia. To test the hypothesis that endothelin-1 contributes to changes in the microcirculation of the heart, we studied cardiac microvessels of the deoxycorticosterone acetate-salt (DOCA-salt) model of hypertension in the rat, in which the endothelin system is activated, and the effect of the endothelin-A (ET A ) subtype-selective endothelin receptor antagonist A-127722. A-127722 (30 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ) was administered for 4 weeks. Arterioles (Յ20 m in lumen diameter) were identified in the myocardium by use of immunolabeling with an anti-smooth muscle ␣-actin antibody, and capillaries with an anti-laminin antibody with nuclear counterstaining by nuclear fast red. Systolic blood pressure was 103Ϯ1.6 mm Hg in unilaterally nephrectomized rats (UniNx), 202Ϯ3.2 mm Hg in DOCA-salt (PϽ0.01 versus UniNx), and 182Ϯ3.1 mm Hg in ET A antagonist-treated DOCA-salt (PϽ0.01 versus DOCA-salt or UniNx). Arteriolar and capillary densities were altered significantly in the subendocardial myocardium but not in the subepicardial myocardium of the left ventricle. Arteriolar density per square millimeter was 18.1Ϯ1.48 in UniNx, 31.9Ϯ3.26 in DOCA-salt (PϽ0.01 versus UniNx), and 24.2Ϯ1.36 in ET A antagonist-treated DOCA-salt (PϽ0.05 versus DOCA-salt or UniNx). Capillary density per square millimeter was 2395Ϯ148 in UniNx, 1576Ϯ107 in DOCA-salt (PϽ0.01 versus UniNx), and 1982Ϯ31 in ET A antagonist-treated DOCA-salt (PϽ0.01 versus DOCA-salt or UniNx). In conclusion, in DOCA-salt hypertensive rats, subendocardial arteriolar growth and capillary rarefaction were observed in the left ventricular myocardium, and both were partially corrected by ET A receptor antagonism. This suggests a role for endothelin-1 in cardiac arteriolar growth and capillary rarefaction, which may have pathophysiological implications by contributing to myocardial ischemia in hypertension. Key Words: microcirculation Ⅲ arterioles Ⅲ growth Ⅲ capillaries Ⅲ hypertension, experimental Ⅲ myocardium Ⅲ ischemia E ndothelin-1 (ET-1), a potent 21-amino-acid vasoconstrictor peptide produced by the endothelium of blood vessels, has been implicated as a mediator of blood pressure elevation 1 and in the induction of vascular smooth muscle growth. 2,3 These effects of ET-1 are mediated by the endothelin-A (ET A ) subtype of endothelin receptor on vascular smooth muscle cells. The potential involvement of ET-1 in some models of experimental hypertension, such as deoxycorticosterone acetate (DOCA)-salt hypertension, has been suggested by the vascular overexpression of ET-1. 4,5 Overexpression of ET-1 occurs in DOCA-salt hypertensive rats in blood vessels of different organs, including the heart, in which enhanced expression was found in the endothelium of epicardial and intramyocardial blood vessels and in the endocardium. 6 Hypertension is often associated with cardiac complicati...

Microvascular remodeling contributes to increased cardiovascular risk in hypertension. The dual angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) inhibitor omapatrilat improves small artery remodeling in hypertension. The aim of the present study was to compare effects of omapatrilat to the ACE inhibitor fosinopril and the AT(1) antagonist irbesartan on the coronary microvasculature in spontaneously hypertensive rats (SHR). Ten-week-old SHR were treated for 10 weeks with omapatrilat (20 or 40 mg/kg/d), irbesartan (50 mg/kg/d), or fosinopril (20 mg/kg/d). Arterioles and capillaries were identified in the myocardium by immunolabeling. After 10 weeks, systolic blood pressure (BP) was significantly reduced in treated versus untreated SHR (P <.01). Myocardial arteriolar density/mm(2) was higher (P <.05) in untreated SHR versus Wistar-Kyoto (WKY), and was reduced by omapatrilat (at both high and low doses) and by fosinopril (P <.01). Irbesartan decreased only subepicardial arteriolar density (P <.05). Myocardial capillary density/mm(2) was decreased in untreated SHR versus WKY (P <.01), associated with increase in cardiomyocyte cross-sectional area and cardiomyocyte-to-capillary ratio, and a decrease in myocyte density. Omapatrilat (at both high and low doses) resulted in increased capillary density, decreased myocyte hypertrophy and cardiomyocyte to capillary ratio, and increased myocyte density (P <.01). Fosinopril and irbesartan reduced myocyte hypertrophy of SHR, but had no effect on capillary density. Dual ACE/NEP inhibition was more effective than ACE inhibition or AT(1) antagonism in improving microvascular and cardiomyocyte remodeling in the hypertensive heart. This suggests a role for NEP inhibition added to blockade of the renin-angiotensin system that may explain the greater efficacy of omapatrilat.

No abstract