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 selective 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 wash-out. Left-ventricular developed pressure (LVDP), left-ventricular end diastolic pressure (LVEDP) and the relaxation time constant,τ, were assessed with a fluid-filled LV intraventricular balloon. Both Tg and CPA induced a concentration-dependent reduction in LVDP and dose-dependently altered diastolic function parameters LVEDP andτ. After 60 min of perfusion, both Tg (0.01, 0.1 and 1.0μ ) and CPA (0.1, 1.0 and 10.0μ ) 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; whileτ elevated 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 1.0μ ) and CPA (0.1, 1.0 and 10.0μ ), respectively. The effects of Tg were more pronounced than those of CPA and were modulated by extracellular Ca2+. With 1 m Ca2+, both agents Tg (0.03μ ) and CPA (0.1 μ ) produced a vasodilatation (81.7±2.6 and 89.1±3.1% of pre-drug values, respectively). Pretreatment of the hearts with -NMMA, a specific inhibitor of nitric oxide production, completely abolished the relaxing effect of Tg and CPA as well as the production of cGMP. These data show that the two SR-Ca2+ATPase inhibitors, Tg and CPA, are negatively inotropic and lusitropic agents and that both Tg and CPA induce a vasodilatation mediated by a NO-dependent mechanism.