Endothelin 1 versus endothelin 3 in the development of the slow force response to myocardial stretch

Background: Myocardial stretch promotes an increase in developed force (DF) in two phases: a rapid initial phase, and a slowly developing second phase called the slow force response (SFR) to myocardial stretch. The SFR results from an autocrine/paracrine mechanism of angiotensin II and endothelin (ET) release that is triggered by the stretch. Objective: To explore whether exogenous ET-1 and/or ET-3 could mimic the SFR. Methods: Experiments were performed in isometrically contracting (0.2 Hz) rat papillary muscles at 30°C. DF was measured either after stretch or after the addition of ET-1 or ET-3 (in doses that increase contractility to a similar magnitude as does the SFR), with or without the selective ET_A receptor antagonist BQ123 (300 nmol/L). Results and Conclusions: After 15 min, the SFR was 17.6±1.4% greater than the initial rapid phase (n=4; P<0.05) and was abolished by BQ123. ET-1 (5.0 nmol/L) increased DF by 25.9±1.7% (n=4; P<0.05) after 30 min, an effect that was not altered by BQ123 (22.6±3.9%; n=5). ET-3 (5.0 nmol/L) increased DF by 23.8±3.2% (n=5; P<0.05), an effect that was suppressed by BQ123 (-5.4±1.9%; n=5; P<0.05). Given that BQ123 eliminated the SFR and the inotropic response to ET-3 but not to ET-1, the results suggest that the SFR that follows myocardial stretch is due to the endogenous release of ET-3 acting in an autocrine/paracrine fashion.