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,tau, 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 and tau. After 60 min of perfusion, both Tg (0.01, 0.1 and 1.0 microM) and CPA (0.1, 1.0 and 10.0 microM) 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 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 1.0 microM) and CPA (0.1, 1.0 and 10.0 microM), respectively. The effects of Tg were more pronounced than those of CPA and were modulated by extracellular Ca2+. With 1 mm Ca2+, both agents Tg (0.03 microM) and CPA (0.1 microM) produced a vasodilatation (81.7+/-2. 6 and 89.1+/-3.1% of pre-drug values, respectively). Pretreatment of the hearts with L-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.
Khandoudi
N
N
SmithKline Beecham Laboratoires Pharmaceutiques, 4, rue du Chesnay-Beauregard, BP 58, 35762 Saint-Grégoire, Cédex, France.
Percevault-Albadine
J
J
Bril
A
A
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000494:pharmacology / Q000502:physiology*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors*; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D009569:Nitric Oxide / Q000502:physiology*; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000201:enzymology*; D019284:Thapsigargin / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007211:Indoles; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019284:Thapsigargin; D000252:Calcium-Transporting ATPases; D002118:Calcium; C000543:cyclopiazonic acid