Ranolazine, a Novel Anti‐Anginal Agent, Does Not Alter Isosorbide Dinitrate‐ or Sildenafil‐Induced Changes in Blood Pressure in Conscious Dogs

Abstract

Ranolazine is under clinical development for the treatment of chronic angina. Our goal was to determine effects of ranolazine on isosorbide dinitrate (ISDN)- or sildenafil-induced changes in mean arterial pressure (MAP) and heart rate (HR) in conscious dogs. Dogs (n=7) were chronically instrumented for measurements of MAP and HR. ISDN (0.2 mg/kg, IV) and, 2.5 hr later, sildenafil (0.5 mg/kg, IV) were given in the absence and presence of ranolazine. Bolus IV injections of ISDN or sildenafil caused a transient (~20 sec) decrease in MAP and an increase in HR followed by a prolonged (10-15 min) decrease in MAP by 11±1.6 and 11±2.2mmHg for ISDN and sildenafil, respectively, without significant changes in HR. Infusion of ranolazine alone (plasma level=4-5 or 8-10 μM) for 10 min did not significantly affect MAP and HR. During ranolazine infusion, ISDN and sildenafil still caused a prolonged decrease in MAP by 10±1.7 to 16±2.5 mmHg, respectively. The transient hypotension and tachycardia caused by ISDN were not altered by ranolazine. The sildenafil-induced transient tachycardia ( HR: 114±10) was significantly (P<0.05) blunted by 4-5 ( HR: 71±8 bpm) or 8-10 (( HR: 66±9 bpm) μM ranolazine. However, the sildenafil-induced transient decrease in MAP was not altered by ranolazine. The results indicate that except for a blunting of the 20-sec transient tachycardia caused by sildenafil, ranolazine at concentrations up to 10 μM (i.e., within the therapeutic range) does not alter changes in MAP and HR induced by ISDN or sildenafil.