Modulatory role of verapamil treatment on the cardiac electrophysiological effects of cisapride

The role of transport proteins in the distribution of drugs in various tissues has obvious implications for drug effects. Recent reports indicate that such transporters are present not only in the liver, intestine, or blood−brain barrier but also in the heart. The objective of our study was to determine whether treatment of animals with verapamil, a well-known L-type calcium channel blocker with modulatory properties of membrane transporters, would alter distribution and cardiac electrophysiological effects of an IKr blocker. Male guinea pigs (n = 72) were treated with either saline or verapamil at various doses (1.5 to 15 mg/kg) and for various durations (1 to 7 d). Animals were sacrified 24 h after the last dose of verapamil (or saline), and their hearts were isolated and retroperfused with cisapride, a gastrokinetic drug with IKr blockade properties. In hearts obtained from animals treated with vehicle, 50 nmol/L cisapride prolonged MAPD90 by 15 ± 5 ms vs. 36 ± 8 ms in hearts from animals treated with ...