VASCULAR SELECTIVITY OF 7 PROTOTYPE CALCIUM-ANTAGONISTS - A STUDY AT THE SINGLE-CELL LEVEL

Vascular selective calcium antagonists (CAs) show an improved toleranc e and a reduced incidence of adverse cardiac effects, especially in tr eatment of hypertension. The effects of seven well-known CAs on contra ctions of single isolated rat myocytes were studied and compared with their effects on stimulated Ca-45(2+) uptake of rat aortic smooth musc le cells (A7r5 cell line). In the latter test system, the order of pot ency to inhibit Ca-45(2+) uptake was as follows (pIC25, -logM): isradi pine (9.2), felodipine (8.7), nifedipine (8.5), nisoldipine (8.5), nic ardipine (8.1), verapamil (6.7), and diltiazem (6.5). The potencies fo r 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, th e 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 verapami l (23). When ventricular cells were stimulated at 1 Hz, the order of s electivity 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 w ere less affected by the frequency of stimulation. CAs show different degrees of vascular selectivity and different frequency-dependent prof iles, and vascular selectivities are also dependent on experimental co nditions. Selectivity is thus not necessarily related to chemical clas ses 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 differen t voltage-dependent states.