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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 (PRO) 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 rate, and the lead II electrocardiogram under conscious conditions. Oral NIC (1, 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 remained normal, but both beta-blockers restricted high dose NIC's QTc prolongation and ST segment depression. Intravenous DTZ (5-23 micrograms/kg/min) did not affect i.v. NIC's hypotensive profile (10-80 micrograms/kg/min) but attenuated its tachycardia, whereas NIC-reversed DTZ's PR interval shortening and frequency of ectopic beats. Similar cardiovascular interactions were seen with chronic oral DTZ (10 mg/kg/day) + NIC (3.0 or 7.5 mg/kg). Plasma analysis confirmed that none of the adjuncts affected NIC's disposition nor its concentration-dependent hypotensive response profile. These studies establish the cardiovascular effects of NIC when combined with PRO, ATN or DTZ in dogs, and outline paradigms useful for evaluating such antianginal drug combinations.
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