Antiarrhythmic and electrophysiologic effects of ibutilide in a chronic canine model of atrial flutter.

We studied the effects of orally administered ibutilide, a class III antiarrhythmic agent, in a model of reentrant atrial flutter in conscious dogs. After baseline determination of atrial effective refractory period (AERP) and demonstration of reproducible induction of atrial flutter by rapid atrial pacing, 8 dogs received either placebo or one of six doses of ibutilide ranging from 0.1 to 5 mg/kg. Refractory periods and the ability to induce atrial flutter were then assessed at periodic intervals for 8 hours. Ibutilide produced dose-related increases in AERP which were well correlated with prevention of initiation of atrial flutter after doses > or = 0.25 mg/kg. Placebo and 0.1 mg/kg ibutilide had no effect on AERP or the ability to induce atrial flutter. Doses of 0.25 to 1.0 mg/kg ibutilide significantly increased AERP and prevented induction of atrial flutter for 4-6 h. After treatment with 2.5 or 5 mg/kg ibutilide, significant increases in AERP and prevention of induction of atrial flutter persisted throughout the 8-h study period. The cycle length of inducible atrial flutter was significantly increased after administration of 5 mg/kg ibutilide. The results demonstrate oral efficacy of ibutilide with rapid onset of action (in 30-60 min), resulting in increased AERP and prevention of induced atrial flutter in this model.

The effect of monensin, a Na+-selective carboxylic ionophore, on coronary circulation.

Carboxylic ionophores are antibiotics that selectively complex with cations and facilitate their transport across biological membranes. Monensin is a monovalent ionophore that has been reported to exhibit a high degree of in vitro selectivity to transport Na+ ions. In anesthetized dogs, intravenous injections of 5-25 micrograms/kg of monensin produce a selective coronary vasodilator action. A maximal increase in coronary blood flow (CBF) with little or no effect on other cardiovascular parameters was produced. In the 50-200-micrograms/kg dose range, additional positive inotropic and systemic vasopressor effects were elicited. In dogs with normal coronary arteries, 25 micrograms/kg i.v. of monensin increased both subendocardial (ENDO) and subepicardial (EPI) blood flows, such that the ENDO/EPI ratio was changed from 1.10 +/- 0.03 before to 0.75 +/- 0.05 after monensin. The large dose (75 micrograms/kg i.v.) of monensin produced a maximum increase in ENDO flow but the EPI flow was less than that with the small dose; the ENDO/EPI ratio was increased to 1.19 +/- .14. In dogs with 80%-90% occlusion of the left anterior descending (LAD) coronary artery, both doses of monensin increased blood flow to normal and "border" zones but not the central ischemic zone. There was no evidence of "coronary steal" after monensin. This ionophore may be useful in increasing blood pressure and cardiac output after acute myocardial infarction.