Increase in calcium sensitivity of cardiac myofibrils contributes to the cardiotonic action of sulmazole.
The aim of this study was to investigate whether increasing calcium sensitivity of myofibrils plays a role in the positive inotropic activity of the cardiotonic agent sulmazole. We studied the effects of the stereoisomers of sulmazole on cardiac contractility in vivo and in vitro, arterial blood pressure, cardiac (Na-K)ATPase activity, cAMP/cGMP-phosphodiesterase activity of cardiac and smooth muscle tissue and calcium sensitivity of skinned myocardial fibres. Both stereoisomers of sulmazole were equipotent vasodilators in vivo and this can be explained by their equipotent cAMP- and cGMP-phosphodiesterase inhibitory activities in smooth muscle tissue. However, (+)sulmazole was a much stronger positive inotropic agent than (-)sulmazole in vivo and in vitro. This difference in inotropic activity cannot be explained by cAMP- or cGMP-phosphodiesterase inhibition or (Na-K)ATPase inhibition in cardiac tissue. Only (+)sulmazole produced a dose-dependent increase in calcium sensitivity of skinned myocardial fibres. Therefore, the calcium sensitizing effect on myofibrils evoked by (+)sulmazole might be responsible for the difference in inotropic activity observed between the stereoisomers of sulmazole.
van Meel
J C
JC
Department of Cardiovascular Pharmacology, Dr Karl Thomae GmbH, Biberach/Riss, Federal Republic of Germany.
Zimmermann
R
R
Diederen
W
W
Erdman
E
E
Mrwa
U
U
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002415:Cats; D002462:Cell Membrane / Q000201:enzymology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology; D009210:Myofibrils / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D010042:Ouabain / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011955:Receptors, Drug / Q000187:drug effects / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors
D002316:Cardiotonic Agents; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D011955:Receptors, Drug; C028996:cardiac glycoside receptors; D010042:Ouabain; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000254:Sodium-Potassium-Exchanging ATPase; C029758:sulmazole; D002118:Calcium