Vascular versus myocardial effects of calcium antagonists.
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)
Little
W C
WC
Department of Medicine, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina.
Cheng
C P
CP
D017311:Amlodipine / Q000627:therapeutic use; D000818:Animals; D004285:Dogs; D015736:Felodipine / Q000627:therapeutic use*; D006333:Heart Failure / Q000188:drug therapy; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects*; D009543:Nifedipine / Q000627:therapeutic use; D011311:Pressoreceptors / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
D017311:Amlodipine; D009543:Nifedipine; D015736:Felodipine