PHARMACOLOGY OF LY175326 - A POTENT CARDIOTONIC AGENT WITH VASODILATOR ACTIVITIES

  • 1 January 1985
    • journal article
    • research article
    • Vol. 233  (2) , 318-326
Abstract
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. 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 h. 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 per h reversed the hemodynamic symptoms of heart failure by increasing left ventricular dP/dt50 [change in pressure at 60 mm Hg with time], cardiac output and stroke volume and reducing left atrial filling pressure and vascular resistance; heart rate was unchanged and calculated myocardial O2 consumption was reduced. This balance of inotropic:vasodilator activities may provide a means of improving cardiac function while maintaining the myocardial O2 supply:demand.

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