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Vascular versus myocardial effects of calcium antagonists
1Department of Medicine, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina.
Insights
Felodipine, a calcium channel blocker, demonstrates high vascular selectivity, causing vasodilation without negative inotropic effects. Unlike other calcium antagonists, felodipine enhances myocardial relaxation and filling, indicating superior vasoselectivity.
Area of Science:
- Cardiovascular Pharmacology
- Calcium Channel Blockers
- Myocardial Contractility
Background:
- Calcium entry is crucial for vascular smooth muscle tone and myocardial contractility.
- Calcium antagonists are potent vasodilators but may have negative inotropic effects.
- Verapamil affects vascular and myocardial contraction similarly, while felodipine shows high vascular selectivity.
Purpose of the Study:
- To evaluate the inotropic effects of felodipine in conscious dogs.
- To compare the vasoselectivity of felodipine with amlodipine and nifedipine.
- To determine if felodipine exhibits negative inotropic effects at clinically relevant doses.
Main Methods:
- Utilized left ventricular (LV) pressure-volume analysis in conscious dogs.
- Administered felodipine at a plasma concentration of 16 nmol/L.
- Conducted studies with and without adrenergic blockade.
Main Results:
- Felodipine caused a 25 mm Hg fall in arterial pressure and reduced peripheral vascular resistance by 10%.
- No negative inotropic effects were observed; myocardial contractile performance was slightly enhanced.
- Felodipine improved LV relaxation and early diastolic filling, unlike amlodipine and nifedipine.
Conclusions:
- Felodipine exhibits significantly greater vasoselectivity compared to amlodipine and nifedipine.
- Clinically relevant doses of felodipine do not appear to have negative inotropic effects.
- Felodipine's unique profile enhances myocardial relaxation and diastolic filling.
Abstract:
As vascular smooth muscle tone and myocardial contractility both depend on calcium entry, the calcium antagonists are not only potent arterial vasodilators, but may also have important negative inotropic effects. For example, verapamil is nearly equipotent in reducing vascular smooth muscle tone and myocardial contraction in isolated tissue preparations. In contrast, felodipine has high vascular selectivity in such preparations, and drug concentrations required to depress myocardial contraction are more than 100 times greater than those required to relax vascular smooth muscle. In the isolated, isovolumetrically contracting canine left ventricle, clinically relevant concentrations of felodipine (14 nmol/L) produce coronary vasodilation and a mild positive inotropic response. Using left ventricular (LV) pressure-volume analysis, we evaluated a similar dose of felodipine (plasma drug concentration 16 nmol/L) in conscious dogs. Felodipine produced a 25mm Hg fall in arterial pressure and a 10% reduction in peripheral vascular resistance. There was no negative inotropic effect. Instead, myocardial contractile performance was slightly but significantly enhanced. These results were not altered by adrenergic blockade. Further studies in our laboratory showed that doses of amlodipine and nifedipine producing arterial vasodilation of a magnitude similar to that produced by felodipine had negative inotropic effects in the conscious dog. Only felodipine enhanced the rate of LV relaxation and the rate of early diastolic filling. Thus, felodipine was significantly more vasoselective than amlodipine and nifedipine. The direct inotropic effects of calcium antagonists are difficult to evaluate in clinical studies because of the load-dependence of most conventional measures of LV performance. However, no negative inotropic effects are clinically relevant doses of felodipine have been identified.(ABSTRACT TRUNCATED AT 250 WORDS)