Myocardial Contractile Actions of Endothelin-1 in Rat and Rabbit Papillary Muscles

The actions of endothelin on the contractile and twitch configuration characteristics of rat and rabbit papillary muscles were evaluated before and after endocardial endothelium removal. In rabbit papillary muscles, endothelin produced a dose-dependent (10`-" to 10` M) increase in tension (T) (from 2.7±0.2 to 8.9±0.7 g/mm2, p<0.01), dT/dt, and Vmax (from 1.14±0.03 to 3.0±0.13 Lma.sec, p<0.01), a decrease in time to peak tension (from 251+9 to 216±7 msec, p <0.05), and an increase in time to half relaxation (from 168±9 to 293+14 msec, p <0.01). Increasing calcium concentration in the bath from 1.25 to 15 mM greatly attenuated these changes. In the presence of propranolol (10-` M), endothelin increased all indexes of contractility but to a lesser extent (T=2.6+0.3 to 6.5±0.2 g/mm2, p<0.01; Vm.=1.16+0A10 to 2.06±0.10 Lmaj/sec, p<0.01). Myocardial catecholamine depletion with reserpine had effects similar to those of propranolol. The myocardial contractile and twitch configuration characteristics of endothelin were similar to those of phenylephrine (10-4 M), a strong stimulator of the phosphatidylinositol pathway and a moderate ,B-adrenergic stimulator. The effects of phenylephrine and endothelin were modified in a similar manner by propranolol (10-` M). The presence of nicardipine (3 X 10` M) decreased the absolute increase in contractility caused by endothelin but did not alter the percent change or shift the dose-response curve of endothelin. The actions of endothelin in rat papillary muscles studied at physiological calcium concentrations (CaZ+=1.25 mM) were less marked than those of rabbit studied at physiological calcium (Ca2 = 1.25 mM) but similar to those of rabbit studied at high calcium concentrations (Ca2' = 15 mM). Removing the endocardial endothelial layer of rabbit papillary muscles did not alter the absolute changes in contractility caused by endothelin but shifted the dose-response curve to the left and markedly altered the effects of endothelin on twitch configuration characteristics. Thus, it would appear that endothelin increases contractility and modifies twitch configuration. It does so more at lower rather than higher extracellular calcium concentrations and in a species, such as rabbit, that responds more to interventions that increase intracellular calcium. In addition to exerting its effects via direct stimulation of the myocardium, endothelin also appears to act by causing endogenous release of catecholamines. These effects of endothelin occur independent of dihydropyridine calcium channel receptors. Finally, endocardial endothelial removal substantially decreases the concentration at which endothelin has its myocardial effects and also substantially modifies the characteristics of these effects. (Circulation Research 1991;69:301-312)