Abstract 15308: Reduction of LV Diastolic Wall Tension by Ranolazine Led to Improved Diastolic Coronary Blood Flow During Demand-Induced Acute Myocardial Ischemia in Anesthetized Canine
Ranolazine (RAN) is a first in class late Na current inhibitor approved for the treatment of angina. It has been postulated that the anti-ischemic effect of RAN is due to a decrease in Na+-dependent Ca2+ overload that leads to an improvement in diastolic function and blood flow to the ischemic area. The purpose of present study was to determine whether acute treatment with RAN reduces LV diastolic tension during demand-induced ischemia. Anesthetized beagles (n=11) were subjected to demand-induced ischemia by causing stenosis (~50% blood flow reduction) in both LCX and LAD coronary arteries and followed by a period of 5 min of pacing at 2X basal heart rate. After 30 min i.v. infusion of vehicle (Veh, n=5) or RAN (n=6, 0.1 mg/kg + 0.03 mg/kg/min), the fast pacing period was repeated. RAN significantly decreased ischemia-induced elevation of S-T segment in an epicardial ECG lead (1.2±0.4 vs. pre-treat 4.6±1.0 p<0.05 and Veh 3.5±1.3 fold of baseline), and reduced the increase in LVEDP (7.1±1.6 vs. pre-treat 12.1±1.6, p<0.05 and Veh 12.4±2.1 mmHg, p<0.05). RAN, however, had no effect on rate pressure product (RPP, 8426±777 vs. pre-treat 7579±355 and Veh 8039±496 mmHg/min), systolic function (LVP, LV±dp/dtmax) and other ECG parameters during demand-induced ischemia. The integrated blood flow in LCX during diastolic cardiac cycle was improved by RAN (3.5±1.1 vs. pre-treat 2.6±0.6, p<0.05 and Veh 2.7±0.8 ml/min·s) during ischemia. In a separate group of dogs (n=10) subjected to 1 hr LAD total occlusion followed by 2 hr reperfusion, the same dose of RAN, given prior to ischemia, significantly reduced myocardial infarct size (RAN 7±2%, n=5; vs. Veh 30±4%, n=5, p<0.05) and the increase in plasma troponin levels during reperfusion (RAN 1.8±0.6 vs. Veh 5.9±1.7 ng/ml, p<0.05). In summary, during demand-induced ischemia RAN attenuates the rise in LV diastolic tension (LVEDP), and improves diastolic coronary blood flow without affecting the rate pressure product. Based on the above findings the anti-ischemic effect of RAN is consistent with an improvement in the balance between oxygen supply and demand of the ischemic area.
- © 2013 by American Heart Association, Inc.