Beneficial effects of the T- and L-type calcium channel antagonist, mibefradil, against exercise-induced myocardial stunning in dogs

Abnormalities in calcium homeostasis such as calcium overload have been sho wn to participate in the pathogenesis of myocardial stunning. The goal of t his study was to investigate the effects of mibefradil, a mixed T- and L-ty pe calcium channels antagonist on exercise-induced ischemia (i.e., high-flo w ischemia). Nine dogs were permanently instrumented to measure left ventri cular wall thickening (Wth) and coronary blood flow (Doppler). Infusion of saline or mibefradil (30 and 40 mu g/kg/min, i.v., for 20 min) was started 10 min before exercise (10 min, 14 km/h; slope, 13%) and stopped at its end . Circumflex coronary artery stenosis (pneumatic occluders) was set up 5 mi n before exercise to suppress exercise-induced increase in mean coronary bl ood flow without simultaneously affecting Wth at rest. Mibefradil (30 mu g/ kg/min) was also administered at the beginning of the recovery period in a subset of four dogs. During exercise with saline, Wth was dramatically redu ced (-77 +/- 7%; p < 0.05) and recovered only after 24 h. Mibefradil at bot h doses significantly limited tachycardia during exercise (211 +/- 7 and 21 0 +/- 5 beats/min vs. 240 +/- 8 beats/min for mibefradil, 30 mu g/kg/min, m ibefradil, 40 mu g/kg/min, and saline, respectively) but exerted no negativ e inotropic effects. Mibefradil at both doses significantly reduced the int ensity of myocardial stunning and the time to recovery in Wth (3 h). Admini stration of mibefradil at the beginning of the recovery period did not prot ect against myocardial stunning. Administration of a mixed T- and L-type ca lcium channel antagonists before ischemia confers cardioprotection against exercise-induced myocardial stunning. This may potentially be related to th e limitation of exercise-induced tachycardia and/or the prevention of calci um overload.