ALTERED INOTROPIC RESPONSE OF ENDOTHELIN-1 IN CARDIOMYOCYTES FROM RATS WITH ISOPROTERENOL-INDUCED CARDIOMYOPATHY

Objective: The positive inotropic effect of endothelin-l (ET-I) on nor mal myocardial contraction may be altered in pathological states. The purpose of this study was to assess the direct effect of ET-1 on cardi omyocyte performance and its cellular mechanism in congestive heart fa ilure (CHF). Methods: We measured the plasma levels of ET-1 and compar ed the effects of ET-I (10(-10)-10(-8) M) on contractile performance a nd the [Ca2+](i) transient in the myocytes of left ventricles (LV) fro m 15 age-matched normal adult rats and 15 rats with isoproterenol (ISO )-induced CHF. Results: With CHF, the plasma levels of ET-1 (19.7+/-6. 3 vs. 4.1+/-0.5 fmol/ml, p<0.05) were markedly elevated. In normal myo cytes, superfusion of ET-1 caused significant increases in the systoli c amplitude (SA, 8-16%) and the peak velocity of shortening (dL/ldt(ma x), 20-35%; p<0.01) without causing a change in the peak [Ca2+](i) tra nsient. In contrast, in myocytes from CHF rats, ET-1 produced signific ant reductions in SA (9-13%) and in the velocity of relengthening, dR/ dt(max) (10-14%; p<0.05). The myocytes' dR/dt(max) also decreased by 8 -10% (p<0.05). These changes were associated with a significant decrea se in the peak [Ca2+], transient (20-23%, p<0.01). These responses to ET-1 were abolished by the incubation of myocytes with an ETA receptor antagonist (BQ123) or a protein kinase C (PKC) inhibitor (H-7 or stau rosporine). Conclusion: ISO-induced CHF is associated with elevated pl asma ET-1 and an altered cardiomyocyte response to ET-I. After CHF, ET -I produces a direct depression of cardiomyocyte contractile performan ce that is associated with a significant decrease in the peak [Ca2+](i ) transient. These effects are likely to be mediated through ETA recep tors and involve the PKC pathway. (C) 1998 Elsevier Science B.V. All r ights reserved.