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 I(Kr) 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 sacrificed 24 h after the last dose of verapamil (or saline), and their hearts were isolated and retroperfused with cisapride, a gastrokinetic drug with I(Kr) 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 verapamil 15 mg.kg(-1).d(-1) for 5 d (p < 0.01). Treatment effects were dose- and time-dependent. Cardiac myocytes isolated from animals treated with vehicle or verapamil were incubated for 3 h with 100 ng/mL cisapride. Intracellular concentrations of cisapride in cardiac myocytes from animals treated with verapamil were 1.6-fold higher than those measured in myocytes from animals treated with vehicle (p < 0.01). The increase in intracellular concentrations of cisapride and potentiation of cisapride electrophysiological effects suggest that chronic treatment with drugs such as verapamil may modulate drug effects on the QT interval because of an increased access to intracellular binding sites on I(Kr) channels.
Morissette
Pierre
P
Faculty of Pharmacy, Université de Montréal, C.P. 6128 Succursale Centre-Ville, Montréal, QC H3C 3J7, Canada.
Hreiche
Raymond
R
Turgeon
Jacques
J
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000494:pharmacology*; D002478:Cells, Cultured; D020117:Cisapride / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006168:Guinea Pigs; D006329:Heart Conduction System / Q000187:drug effects*; D008133:Long QT Syndrome / Q000139:chemically induced; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors; D014700:Verapamil / Q000009:adverse effects / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D026902:Potassium Channel Blockers; D014700:Verapamil; D020117:Cisapride