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Functional consequences of overexpression of ETA in adult rat ventricular myocytes

Activation of ETA, the predominant ET‐1 receptor subtype in myocardium, is known to induce a positive inotropic effect (PIE). In heart failure, ETA is often upregulated presumably as a compensatory measure. In this study, we explored functional consequences of upregulation of ETA in adult rat ventricular myocytes (ARVM). To investigate physiological function, we examined three twitch parameters (PIE, diastolic shortening and twitch broadening) and measured [Ca2+]i in control and ETA overexpressed ARVM. In control ARVM, ET‐1 induced ~30% PIE and ~1% diastolic shortening, but twitches were not broadened. Overexpression of ETA significantly increased PIE to ~60%, diastolic shortening to ~7% and twitch broadening by ~15%. Peak [Ca2+]i and basal [Ca2+]i correlated with PIE and diastolic shortening respectively, but the slopes were larger in ETA overexpressed ARVM. Therefore, changes in [Ca2+]i induced significantly more twitch responses in ETA overexpressed ARVM. These results suggest that ETA‐overexpression has a substantial impact on the twitch properties including i) prolongation of twitch duration, and ii) an increase in diastolic cell shortening. Such ET‐1 effects mediated through upregulated ETA may contribute to diastolic dysfunction (delayed relaxation and elevated ventricular end diastolic pressure) in heart failure.