CONSEQUENCES OF THE INHIBITION OF THE SARCOPLASMIC-RETICULUM CALCIUM-ATPASE ON CARDIAC-FUNCTION AND CORONARY FLOW IN RABBIT ISOLATED-PERFUSED HEART - ROLE OF CALCIUM AND NITRIC-OXIDE

The effects of thapsigargin (Tg) and cyclopiazonic acid (CPA), two sel ective blockers of the sarcoplasmic reticulum Ca2+-ATPase were studied in rabbit isolated perfused hearts, Tg and CPA were infused into the hearts for 60 min followed by 60 min of washout. Left-ventricular deve loped pressure (LVDP), left-ventricular end diastolic pressure (LVEDP) and the relaxation time constant, w tau, were assessed with a fluid-f illed LV intraventricular balloon. Both Tg and CPA induced a concentra tion-dependent reduction in LVDP and dose-dependently altered diastoli c function parameters LVEDP and tau. After 60 min of perfusion, both T g (0.01, 0.1 and 1.0 mu M) and CPA (0.1, 1.0 and 10.0 mu M) decreased LVDP from 98 +/- 1 mmHg in control to 83 +/- 4; 81 +/- 5 and 55 +/- 7 mmHg and to 91 +/- 3, 80 +/- 5 and 65 +/- 4 mmHg, respectively. LVEDP increased from 5 +/- 1 mmHg in controls to 6 +/- 0.2, 10 +/- 1 and 29 +/- 4 mmHg and to 7 +/- 0.2, 9 +/- 1 and 11+/- mmHg; while tau elevate d from 28 +/- 1 ms to 32 +/- 1, 38 +/- 4 and 99 +/- 18 ms and to 34 +/ - 1, 38 +/- 2 and 48 +/- 4 ms in Tg (0.01, 0.1 and 1.0 mu M) and CPA ( 0.1, 1.0 and 10.0 mu M), respectively, The effects of Tg were more pro nounced than those of CPA and were modulated by extracellular Ca2+, Wi th 1 mM Ca2+, both agents Tg (0.03 mu M) and CPA (0.1 mu M) produced a vasodilatation (81.7 +/- 2.6 and 89.1 +/- 3.1% of pre-drug values, re spectively). Pretreatment of the hearts with L-NMMA, a specific inhibi tor of nitric oxide production, completely abolished the relaxing effe ct of Tg and CPA as well as the production of cGMP. These data show th at the two SR-Ca2+ ATPase inhibitors, Tg and CPA, are negatively inotr opic and lusitropic agents and that both Tg and CPA induce a vasodilat ation mediated by a NO-dependent mechanism. (C) 1998 Academic Press.