HEMODYNAMIC TOLERANCE AND PHARMACOKINETICS OF NICORANDIL IN EXPERIMENTAL HEART-FAILURE

We tested whether nicorandil (NCR), a nitrovasodilator which also possesses K+ channel action, will produce in vivo hemodynamic tolerance commonly observed with other nitrovasodilators such as nitroglycerin (NTG). NCR was infused at 50 mug/kg/min for 10 h through a femoral cannula into conscious rats (n = 5) with congestive heart failure (CHF). Left ventricular end-diastolic pressure (LVEDP), LV peak-systolic pressure (LVPSP), and heart rate (HR) were measured periodically through an implanted catheter. Under these conditions, NCR produced a 40% reduction (p < 0.05) in LVEDP from baseline at 40 min after the start of the infusion. This reduction lasted approximately 6 h, followed by a slow return to baseline between 6 and 10 h. LVPSP was reduced (p < 0.05) from 2 h and leveled at -8 h. HR increased by 12% from baseline at 40 min (p < 0.05). Plasma NCR concentrations were identical at 5 h (pretolerant state) and at 10 h (tolerant state) in these animals, suggesting that plasma pharmacokinetics were unrelated to NCR pharmacodynamics. NCR kinetics were not changed by the presence of CHF. Thus, in this animal model, tolerance to NCR developed in LVEDP but not LVPSP, and the K+ channel action of NCR apparently could not prevent tolerance development to venodilation arising from nitrate action.