Pharmacology of LY175326: a potent cardiotonic agent with vasodilator activities.
Compound LY175326 is one of a series of novel cardiovascular agents with both inotropic and vasodilator activities. In cat papillary muscles, LY175326 increased contractility in a concentration-dependent manner; these actions were not blocked by prazosin, propranolol or cimetidine. Inotropic responses were observed in unpaced, perfused guinea-pig hearts and these effects were associated with modest increases in heart rate and coronary flow. An i.v. dose of 0.1 mg/kg of LY175326 caused 54 and 95% increases in contractility in either the anesthetized cat or dog, respectively; corresponding heart rates were increased by less than 10%. Oral administration of 0.5 mg/kg to dogs was associated with an inotropic response that was maximal between 60 and 90 min and lasted in excess of 3 hr. These effects were not accompanied by increases in heart rate, gross behavioral changes or emesis. The pharmacology of LY175326 was evaluated in a propranolol-induced heart failure model using anesthetized beagle dogs. A bolus injection of 0.15 mg/kg of LY175326 followed by an infusion of 0.4 mg/kg/hr reversed the hemodynamic symptoms of heart failure by increasing left ventricular dP/dt60, cardiac output and stroke volume and reducing left atrial filling pressure and vascular resistance; heart rate was unchanged and calculated myocardial oxygen consumption was reduced. This balance of inotropic:vasodilator activities may provide a means of improving cardiac function while maintaining the myocardial oxygen supply:demand.
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002303:Cardiac Output, Low / Q000188:drug therapy; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002415:Cats; D003326:Coronary Circulation / Q000187:drug effects*; D004285:Dogs; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects*; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000494:pharmacology*
D002316:Cardiotonic Agents; D007093:Imidazoles; D014665:Vasodilator Agents; D011433:Propranolol; C029758:sulmazole