EFFECTS OF PHOSPHORAMIDON, BQ-788, AND BQ-123 ON CORONARY AND CARDIACDYSFUNCTIONS OF THE FAILING HAMSTER HEART

Coronary dysfunctions identified in the presence of chronic heart Fail ure are an important pathophysiologic abnormality that influences the prognosis of the disease. Because the endothelin pathway plays a signi ficant role in the increased peripheral vascular tone associated with heart failure, we hypothesized that the endothelin pathway may be invo lved in the abnormal coronary vasomotion associated with this patholog ic condition. Experiments were carried out in failing hearts (UM-X7.1 cardiomyopathic hamsters, aged 225-250 days) and normal hearts (Syrian LVG hamsters, also aged 225-250 days). Isolated hearts were perfused at constant flow and exposed to the blocker of the generation of endot helin-1 (ET-1), phosphoramidon (10 mu M infusion), as well as to the s elective ETA-receptor antagonist BQ 123 (10 mu M infusion) and to a se lective ETB-receptor antagonist BQ 788 (1 mu M infusion). Coronary and cardiac effects of exogenous ET-I (0.01-100 pmol) were also studied. Phosphoramidon, BQ 788, and BQ 123 did not altered coronary perfusion pressure either in normal or in failing hearts, whereas cardiac contra ctility was significantly impaired in the presence of phosphoramidon a nd BQ 123, Coronary sensitivity to exogenous ET-1 did not demonstrate a significant difference between normal and failing hearts [median eff ective concentration (EC50), 7 pmol in failing hearts vs. 12 pmol in n ormal hearts; p = NS]. In the presence of exogenous ET-1, cardiac cont ractility was significantly increased in both groups. In normal hearts , the exogenous ET-1-induced increase in coronary perfusion pressure w as completely antagonized by BQ 123, whereas combined administration o f BQ 788 and BQ 123 was necessary to induce complete inhibition in fai ling hearts. The positive inotropic effect elicited by exogenous ET-1 (EC50) was completely abolished in the presence of BQ 123, whereas BQ 788 had no significant effect. Results indicate that the endothelin pa thway does not play a significant role in the altered coronary vasomot ion observed in this model of chronic heart failure. On the contrary, the endothelin pathway appears to participate in the maintenance of my ocardial contractility. According to these observations, administratio n of an inhibitor of ET-1 synthesis, as well as the use of an ETA-rece ptor antagonist, may be contraindicated in the presence of poor left v entricular function because the endothelin pathway contributes signifi cantly to the maintenance of cardiac contractility.