Vascular Selectivity of Seven Prototype Calcium Antagonists

Vascular selective calcium antagonists (CAs) show an improved tolerance and a reduced incidence of adverse cardiac effects, especially in treatment of hypertension. The effects of seven well-known CAs on contractions of single isolated rat myocytes were studied and compared with their effects on stimulated 45Ca2+ uptake of rat aortic smooth muscle cells (A7r5 cell line). In the latter test system, the order of potency to inhibit 45Ca2+ uptake was as follows (pIC25, -logM): isradipine (9.2), felodipine (8.7), nifedipine (8.5), nisoldipine (8.5), nicardipine (8.1), verapamil (6.7), and diltiazem (6.5). The potencies for inhibition of ventricular myocyte contraction at 0.5 Hz were (pIC25): isradipine (6.9), nisoldipine (6.7), felodipine (6.6), nicardipine (6.5), nifedipine (6.5), verapamil (5.3), and diltiazem (4.8). Thus, the order of vascular selectivity (i.e., the ratios of IC25 cardiocytes/IC25 A7r5 cells) was: isradipine (184), felodipine (128), nifedipine (107), nisoldipine (63), diltiazem (48), nicardipine (43), and verapamil (23). When ventricular cells were stimulated at 1 Hz, the order of selectivity was changed: Diltiazem was the least selective. Verapamil, diltiazem, and felodipine showed a highly frequency-dependent negative inotropic effect, whereas the effects of the other dihydropyridines were less affected by the frequency of stimulation. CAs show different degrees of vascular selectivity and different frequency-dependent profiles, and vascular selectivities are also dependent on experimental conditions. Selectivity is thus not necessarily related to chemical classes of drugs (e.g., dihydropyridines) or to different binding sites at the channel protein but could instead be due to varying dissociation rates from the respective binding sites at the channel in its different voltage-dependent states.