ANGIOTENSIN AT(1) RECEPTOR-MEDIATED ATTENUATION OF CARDIAC-HYPERTROPHY DUE TO VOLUME OVERLOAD - INVOLVEMENT OF ENDOTHELIN

The role of angiotensin II via the angiotensin type 1 (AT(1)) receptor in the development of volume overload cardiac hypertrophy was investigated in adult male Wistar rats with aortic insufficiency. We examined the effects of specific angiotensin AT(1) receptor blockade with losartan (2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1 H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidazole potassium) on left ventricular weight and left ventricular angiotensin II and endothelin-1 level to test the possibility that the cardiac action of angiotensin II may be mediated by endogenous endothelin-1. Moreover, to verify the possible involvement of endothelin-1, we measured left ventricular endothelin-1 levels during the hypertrophic process and evaluated the effect of the endothelin ET(A) receptor specific antagonist, FR139317 ((R)2-[(R)-2-[(S)-2-[[1-(hexahydro-1H-azepinyl)]carbonyl]amino-4-methylpentanoyl]amino-3-[3-(1-methyl-1H-indolyl)propionyl]amino-3-(2-pyridyl) propionic acid), on left ventricular weight. Two weeks after production of aortic insufficiency, left ventricular weight and left ventricular endothelin-1 concentration were markedly elevated in the rats with aortic insufficiency as compared with the sham-operated control rats, but left ventricular angiotensin II was not changed. Losartan (10 mg/kg/day p.o., 2 weeks) significantly reduced left ventricular weight and left ventricular endothelin-1 level in the rats with aortic insufficiency without affecting blood pressure and there was a significant positive correlation between left ventricular weight and left ventricular endothelin-1 content. Left ventricular endothelin-1 content correlatively increased to left ventricular weight during the development of left ventricular hypertrophy. The left ventricular hypertrophy was significantly attenuated by chronic treatment with FR139317 (10 mg/kg/day i.p.) for 2 weeks. These findings indicate that endogenous angiotensin II may contribute, via the angiotensin AT(1) receptor, to the development of volume overload cardiac hypertrophy and that endogenous endothelin-1 may mediate some of the hypertrophic effects of angiotensin II.