ALTERED VENTRICULAR AND MYOCYTE RESPONSE TO ANGIOTENSIN-II IN PACING-INDUCED HEART-FAILURE

Alterations in the cardiac response to angiotensin II (Ang II) map con tribute to the functional impairment in tachycardia-induced heart fail ure (congestive heart failure [CHF]). Accordingly, we studied the resp onse to Ang II in eight conscious instrumented dogs before and after i nducing CHF. Left ventricular (LV) performance was assessed by measuri ng LV pressure and LV volume. Isolated myocyte function was evaluated using computer-assessed videomicroscopy. In conscious animals before C HF, Ang II produced a load-dependent slowing of the time constant of L V relaxation (tau) and did not depress intact LV contractile function. After CHF, although Ang II produced a similar increase in LV systolic pressure. the increases in LV diastolic pressure and time constant ta u were much greater, and contractile performance was depressed. These changes persisted when the elevation of end-systolic pressure was prev ented by nitroprusside. Similar changes were also present after autono mic blockade. In isolated myocytes, before CHF, Ang II (10(-6) mol/L) produced a slight positive inotropic effect. In contrast, after CHF, A ng II produced a negative inotropic effect and slowed the rare of rele ngthening. The effects in the intact LV and myocytes were reversed by an Ang II AT(1) receptor blocker (losartan). We conclude that pacing-i nduced CHF alters the LV and myocyte response to Ang II, so that Ang I I produces direct depressions in intact LV contraction, relaxation, an d filling and exacerbates myocyte contractile dysfunction. These effec ts are mediated through the activation of AT(1) receptors.