Endocardial endothelium mediates positive inotropic response to alpha1-adrenoceptor agonist in mammalian heart

Abstract

Although the positive inotropic response to alpha 1-agonists has been well documented, the mechanism is incompletely understood. In isolated papillary muscle of cat and rabbit, low physiological concentrations of phenylephrine (PE) (10(-9)-10(-7) M; 35 degrees C) under beta-blockade (propranolol 10(-6) M) and in physiological [Ca2+]o (1.25 mM), significantly increased peak twitch tension (TT) with typical unchanged or slightly prolonged twitch contraction duration. This typical response necessitated the presence of an intact endocardial endothelium (EE) since no inotropic response was observed at or below 10(-7) M PE in muscles where the EE had been damaged by 1 s exposure to 1% Triton X-100 prior to the first PE addition. After Triton-induced EE damage prior to the first PE addition, a direct myocardial inotropic response could be demonstrated, but this response required higher concentrations of PE (10(-6)-10(-3) M) and was significantly less pronounced than in muscles with intact EE. At elevated (2.5 mM) or high (7.5 mM) Ca2+, a concentration dependent inotropic response to PE could be induced at the higher concentrations of PE (10(-6) M or higher), but the inotropic response to low concentrations of PE (10(-7) M or below) was absent even in the presence of an intact EE. In papillary muscles with intact EE at physiological [Ca2+]o of 1.25 mM, the higher concentrations of PE (10(-6) M or higher) destroyed the EE. Indeed, after washing with fresh bathing solution following prolonged exposure to these high concentrations of PE, the baseline twitches resembled twitches in muscles where the EE had been experimentally damaged. Selective destruction of the EE by PE in these conditions with no morphological damage to the subjacent myocardium was confirmed on electron microscopy. A second concentration-response curve to PE was significantly depressed, shifted to the right and with no response at or below 10(-7) M PE. Subsequent successive curves were not significantly different from the second one. At the higher Ca2+ (2.5 mM or 7.5 mM), neither functional nor morphological evidence of damage to the EE was observed regardless of the PE concentration and exposure time; in some muscles EE damage did occur at high Ca2+, however, but only after multiple exposures to high PE each followed by abundant wash. At all concentrations of PE, the alpha 1-antagonist prazosin (10(-5) M) blocked the inotropic response regardless of [Ca2+]o and prevented morphological endothelial damage at 1.25 mM Ca2+.