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Unique cardioprotective action of the new calcium antagonist mibefradil
1Abteilung für Pathophysiologie, Zentrum für Innere Medizin des Universitätsklinikums Essen, Germany.
Background:
Mibefradil is a calcium antagonist with few negative inotropic effects at therapeutic concentrations.
Methods And Results:
The effect of mibefradil on infarct size (IS) was compared with those of placebo, amlodipine, and verapamil in 64 anesthetized pigs. In placebo pigs, after 90 minutes of ischemia and 120 minutes of reperfusion, IS (by triphenyl tetrazolium chloride staining) was 15.3+/-10.8% (SD) of the area at risk. Mibefradil (0.60 mg/kg IV) reduced heart rate and left ventricular (LV) pressure, and IS was 1. 9+/-3.9% (P<0.05 versus placebo). Verapamil (0.15 mg/kg IV) also decreased heart rate, LV pressure, and IS (6.1+/-4.2%, P<0.05 versus placebo). Amlodipine (0.20 mg/kg IV) did not alter heart rate, LV pressure, or IS (9.9+/-5.4%, P=NS versus placebo). When heart rate was maintained constant by left atrial pacing and LV pressure was adjusted to that of the placebo group by an intra-aortic balloon, mibefradil still decreased IS (3.8+/-3.0%, P<0.05 versus placebo), but verapamil did not (11.6+/-8.3%, P=NS versus placebo). With glibenclamide infusion, mibefradil no longer reduced IS (13.1+/-4.3% versus 17.8+/-5.6% with glibenclamide alone, P=NS).
Conclusions:
The IS-limiting effect of mibefradil, in contrast to that of verapamil, was not dependent on favorable hemodynamics but was abolished by glibenclamide, suggesting a direct cardioprotective action of mibefradil.
Insights
Mibefradil effectively reduces infarct size in pigs, unlike amlodipine, and its protective effect is independent of hemodynamic changes, suggesting direct cardioprotection. This action is abolished by glibenclamide, indicating a novel therapeutic mechanism.
Area of Science:
- Cardiology
- Pharmacology
- Ischemic Heart Disease Research
Background:
- Mibefradil is a calcium antagonist known for minimal negative inotropic effects at therapeutic doses.
- Understanding its impact on myocardial infarction is crucial for developing new cardioprotective strategies.
Purpose of the Study:
- To investigate the efficacy of mibefradil in limiting infarct size (IS) compared to placebo, amlodipine, and verapamil in a porcine model.
- To determine if mibefradil's cardioprotective effects are dependent on hemodynamic alterations or mediated by a direct action.
Main Methods:
- Anesthetized pigs (n=64) underwent 90 minutes of ischemia followed by 120 minutes of reperfusion.
- Infarct size was assessed using triphenyl tetrazolium chloride staining.
- Drugs (mibefradil, amlodipine, verapamil) were administered intravenously, with experiments conducted under normal and controlled hemodynamic conditions (heart rate and left ventricular pressure).
- The role of glibenclamide in modulating mibefradil's effect was also examined.
Main Results:
- Mibefradil significantly reduced infarct size (1.9+/-3.9%) compared to placebo (15.3+/-10.8%), an effect sustained even when hemodynamics were normalized.
- Verapamil also reduced infarct size (6.1+/-4.2%) but this effect was lost when hemodynamics were controlled.
- Amlodipine showed no significant effect on infarct size (9.9+/-5.4%).
- Glibenclamide abolished mibefradil's infarct-limiting effect.
Conclusions:
- Mibefradil demonstrates a direct cardioprotective action by limiting infarct size, independent of its hemodynamic effects.
- This protective mechanism is likely mediated through pathways sensitive to glibenclamide, differentiating it from verapamil's action.
- Mibefradil presents a promising therapeutic agent for managing myocardial infarction.
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