A comparison of the cardiotonic effects of AR-L115 and AR-L57: evidence for distinct inotropic mechanisms.
AR-L57 and AR-L115 have been of interest as inotropic agents for management of heart failure. Although their physiological effects are well documented, their mechanism(s) of action are unclear. Both AR-L57 and AR-L115 increased contractile force of cat papillary muscles in concentration-dependent manners; these effects were independent of either alpha- or beta-adrenoceptor stimulation. To determine if these effects occurred via a cAMP-dependent mechanism, cardiotonic actions were studied in the presence of carbachol. Muscarinic stimulation of papillary muscles attenuated contractile responses to AR-L115 thus implying a cAMP-mediated response. By contrast, carbachol did not alter the dose-response profile to AR-L57. In addition, AR-L115 potentiated the inotropic actions of isoproterenol whereas AR-L57 was ineffective. Both AR-L57 and ouabain increased diastolic resting tension in papillary muscles--a phenomenon associated with a state of Ca2+ overload; AR-L115 was without effect. In anesthetized dogs, i.v. AR-L57 and AR-L115 increased contractility and heart rate while reducing mean arterial blood pressure. Both agents had similar rates of onset (10-15 s) and durations of action (40-60 min). Although in vitro studies clearly indicate that AR-L57 and AR-L115 enhance inotropic state by distinct mechanisms, their in vivo cardiovascular profiles are comparable.
Hayes
J S
JS
Wyss
V L
VL
Wilson
H
H
Pollock
G D
GD
D000758:Anesthesia; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002415:Cats; D004285:Dogs; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010042:Ouabain / Q000494:pharmacology; D010210:Papillary Muscles / Q000502:physiology; D011224:Prazosin / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors
D002316:Cardiotonic Agents; D007093:Imidazoles; D010042:Ouabain; C012633:AR-L 57 CL; D002217:Carbachol; D011433:Propranolol; D000254:Sodium-Potassium-Exchanging ATPase; C029758:sulmazole; D007545:Isoproterenol; D011224:Prazosin