EFFECTS OF RANOLAZINE ON THE EXERCISE CAPACITY OF RATS WITH CHRONIC HEART-FAILURE INDUCED BY MYOCARDIAL-INFARCTION

Ranolazine was previously shown to stimulate cardiac glucose oxidation . Dichloroacetate (DCA) also does and was shown to improve exercise ca pacity in animals, but it has long-term toxicity problems. To test the hypothesis that ranolazine would increase exercise performance in the chronic heart failure (CHF) condition, we compared the exercise endur ance capacities of rats with a surgically induced myocardial infarctio n (MI) with those of noninfarcted sham-operated (Sham) controls both b efore and after 14 and 28 days of drug administration. Chronic adminis tration of ranolazine, 50 mg/kg twice daily (b.i.d.) oral, significant ly reduced the endurance capacities of both Sham and MI rats (measured after a 12-h fast to reduce liver glycogen stores), as indicated by t he reductions in run times to fatigue during a progressive treadmill t est. Ranolazine produced reductions in resting plasma lactate and gluc ose concentrations of animals fasted for 12 h (consistent with stimula ting glucose oxidation); however, tissue glycogen concentrations measu red in various locomotor muscles located in the animal's hindlimb were unaffected when measured 48 h after the last treadmill test and after 12 h of fasting. Chronic administration of ranolazine did not increas e the endurance capacity of rats with CHF induced by MI at the dosage and with the protocol used, To the contrary, the chronic administratio n of ranolazine appears to reduce the work capacity of all rats, sugge sting that this drug may not be useful therapeutically in the treatmen t of CHF. Whether the decrements in endurance capacity produced by ran olazine are related to the high plasma concentrations of the drug prod uced in this study as compared with previous studies in humans remains subject to further experimentation.