Cardiac microvasculature in DOCA-salt hypertensive rats : effect of endothelin ET(A) receptor antagonism.
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 x kg(-1) x d(-1)) was administered for 4 weeks. Arterioles (</=20 microm in lumen diameter) were identified in the myocardium by use of immunolabeling with an anti-smooth muscle alpha-actin antibody, and capillaries with an anti-laminin antibody with nuclear counterstaining by nuclear fast red. Systolic blood pressure was 103+/-1.6 mm Hg in unilaterally nephrectomized rats (UniNx), 202+/-3.2 mm Hg in DOCA-salt (P<0.01 versus UniNx), and 182+/-3.1 mm Hg in ET(A) antagonist-treated DOCA-salt (P<0.01 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 18.1+/-1.48 in UniNx, 31.9+/-3.26 in DOCA-salt (P<0.01 versus UniNx), and 24.2+/-1.36 in ET(A) antagonist-treated DOCA-salt (P<0.05 versus DOCA-salt or UniNx). Capillary density per square millimeter was 2395+/-148 in UniNx, 1576+/-107 in DOCA-salt (P<0.01 versus UniNx), and 1982+/-31 in ET(A) antagonist-treated DOCA-salt (P<0.01 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.
Larouche
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MRC Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montréal, Montréal, Quebec, Canada.
Schiffrin
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D000818:Animals; D000077868:Atrasentan; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology*; D003331:Coronary Vessels / Q000503:physiopathology; D003900:Desoxycorticosterone; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology*; D006321:Heart / Q000503:physiopathology*; D006978:Hypertension, Renovascular / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000502:physiology*; D017673:Sodium Chloride, Dietary
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D017673:Sodium Chloride, Dietary; D003900:Desoxycorticosterone; D000077868:Atrasentan