Vascular versus myocardial selectivity of calcium antagonists studied by concentration-time-effect relations.
The vascular versus myocardial selectivity of three structurally different calcium antagonists, felodipine, diltiazem, and verapamil, was studied in vitro. The model used was an isolated portal vein preparation and a paced (3 Hz) papillary muscle of the left ventricle of the rat, examined in the same organ bath. In previous experiments with the same tissues, used for screening and eventual selection of felodipine, it was found that the selectivity factors ranged as follows: felodipine much greater than nifedipine greater than diltiazem greater than verapamil = La3+. Since the effect of organic calcium antagonists is slow in onset, the present experiments were designed to determine the inhibitory potencies and the selectivity factor at equilibrium. This was possible by a computer-assisted collection of contractile force measurements and subsequent analysis of the results. In each experiment, one concentration only of one of the three calcium antagonists was given. The time-effect relation was determined for both tissues. After all experiments with a particular drug, when several concentrations had been administered, the hyperbolic concentration-effect relation was determined at various times of exposure. The ensuing pIC50 values, as related to time, for the vascular and the myocardial preparations, described by monoexponential curves and the corresponding potency values (pIC50), could be determined at equilibrium (t = infinity). It was concluded that the vascular over myocardial inhibitory selectivity was marked for felodipine (103), low for diltiazem (8.9), and none for verapamil (0.92).
D000818:Animals; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D004110:Diltiazem / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015736:Felodipine; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects*; D009568:Nitrendipine / Q000031:analogs & derivatives / Q000494:pharmacology; D010210:Papillary Muscles / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D009568:Nitrendipine; D014700:Verapamil; D004110:Diltiazem; D015736:Felodipine