Cardiovascular and pharmacokinetic interactions between nicorandil and adjunctive propranolol, atenolol or diltiazem in conscious dogs

In support of clinical antianginal studies, the vasodilator nicorandil (NIC ) was combined with the beta-adrenergic receptor antagonists propranolol (P RO) and atenolol (ATN) and with the calcium channel blocker diltiazem (DTZ) to determine their cardiovascular and pharmacokinetic interactions. Beagle dogs were chronically cannulated to record mean arterial pressure, heart r ate, and the lead II electrocardiogram under conscious conditions. Oral NIC (I, 3, and 10 mg/kg) was coadministered with i.v. PRO (5.0 mg/kg) or ATN (7 .5 mg/kg), both of which lessened NIC's reflex tachycardia. ECG rhythm rema ined normal, hut both beta-blockers restricted high dose NIC's QTc prolonga tion and ST segment depression, Intravenous DTZ (5-23 mu g/kg/min) did not affect i.v. NIC's hypotensive profile (10-80 mu g/kg/min) but attenuated it s tachycardia, whereas NIC reversed DTZ's PR interval shortening and freque ncy of ectopic beats. Similar cardiovascular interactions were seen with ch ronic oral DTZ (10 mg/kg/day) + NIC (3.0 or 7.5 mg/kg). Plasma analysis con firmed that none of the adjuncts affected NIC's disposition nor its concent ration-dependent hypotensive response profile. These studies establish the cardiovascular effects of NIC when combined with PRO, ATN or DTZ in dogs, a nd outline paradigms useful for evaluating such antianginal drug combinatio ns. (C) 1998 Prous Science. All rights reserved.