Mechanisms of positive inotropic action of flosequinan, hydralazine, and milrinone on mammalian myocardium.
Flosequinan is an arterial and venous dilator that also has a positive inotropic effect at relatively higher doses. The purpose of this study was to determine the mechanism of this positive inotropic effect in ferret papillary muscles loaded with the Ca2+ indicator, aequorin. Over the range of doses from 10(-6) to 10(-3) M, flosequinan produced a 61 +/- 9% increase in peak tension that was accompanied by a corresponding increase in [Ca2+]i. This positive inotropic effect was not selectively blocked by addition to the perfusate of procaine 0.6 microM, tetrodotoxin 10(-6) M or by verapamil, 5 x 10(-8) M. In contrast, the positive inotropic effect of flosequinan, but not milrinone or hydralazine, was potentiated by prior addition of ouabain 3 nM to enhance intracellular Ca2+ via reduction of the Na+/Ca2+ exchange. Moreover, antagonists of Na+/Ca2+ exchange, including cadmium 10 microM, amiloride 600 microM and choline substitution for 1/3 Na+ in the perfusate, blocked the response to flosequinan but not hydralazine or milrinone. These results indicate that flosequinan produces a positive inotropic effect by reduction of Na+/Ca2+ exchange in mammalian myocardium. Moreover, flosequinan has the potential to interact synergistically with other positive inotropic agents such as digoxin that affect Na+/Ca2+ exchange by direct or indirect actions.
Miao
L
L
Charles A. Dana Research Institute, Beth Israel Hospital, Boston, MA, USA.
Perreault
C L
CL
Travers
K E
KE
Morgan
J P
JP
D000331:Aequorin / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005289:Ferrets; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006830:Hydralazine / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D020105:Milrinone; D009200:Myocardial Contraction / Q000187:drug effects*; D010042:Ouabain / Q000494:pharmacology; D011343:Procaine / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D019831:Sodium-Calcium Exchanger; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors; D013268:Stimulation, Chemical; D013779:Tetrodotoxin / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D002316:Cardiotonic Agents; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D011728:Pyridones; D011804:Quinolines; D019831:Sodium-Calcium Exchanger; D017923:Sodium-Hydrogen Exchangers; D014665:Vasodilator Agents; D006830:Hydralazine; D013779:Tetrodotoxin; D011343:Procaine; D000331:Aequorin; D010042:Ouabain; C047316:flosequinan; D014700:Verapamil; D000254:Sodium-Potassium-Exchanging ATPase; D020105:Milrinone