ENDOGENOUS ENDOTHELIN-1 MEDIATES CARDIAC-HYPERTROPHY AND SWITCHING OFMYOSIN HEAVY-CHAIN GENE-EXPRESSION IN RAT VENTRICULAR MYOCARDIUM

Objectives. We investigated the role of endogenous endothelin-1 in the development of cardiac hypertrophy in vivo under pressure overload co nditions. Background. Endothelin-1, a potent vasoconstrictor peptide, has recently been shown to act as a growth factor of myocardial cells in culture, Methods. We examined the effect of an endothelin-A recepto r antagonist (FR139317) on the development of right ventricular hypert rophy in rats with monocrotaline-induced pulmonary hypertension. Three groups of rats were studied: those given monocrotaline alone or monoc rotaline plus FR139317 and those given vehicle alone (control group). Results. The ratio of right ventricular systolic pressure to aortic sy stolic pressure was similarly elevated in rats treated with monocrotal ine and monocrotaline plus FR139317. The right ventricular/left ventri cular weight ratio was increased in monocrotaline-treated rats but low er in rats treated with monocrotaline plus FR139317 than in those trea ted with monocrotaline alone (p < 0.01). As a biochemical marker of hy pertrophy, the isoform ratio of beta-myosin heavy chain protein was de termined for the right ventricular tissue samples. This ratio was incr eased in all monocrotaline treated rats but was lower (p < 0.01) in ra ts given monocrotaline plus FR139317 than in those given monocrotaline alone, The isoform ratio of beta-myosin heavy chain messenger ribonuc leic acid quantitated by S1 nuclease mapping also was lower (p < 0.025 ) in rats receiving monocrotaline plus FR139317 than in those receivin g monocrotaline alone. Conclusions. These data suggest that blocking t he action of endothelin-1 with a receptor antagonist ameliorates cardi ac hypertrophy in this model system, and that this action is not media ted by ameliorating hemodynamic changes.