CALCIUM-CHANNEL BLOCKING AND VASODILATING ACTIONS OF THE NOVEL DIHYDROPYRIDINE DERIVATIVE AE0047

1. The pharmacological characteristics of AE0047, a newly synthesized dihydropyridine (DHP) derivative, were investigated in vitro. 2. In bo vine aortic membrane, AE0047 and other DHP calcium channel blockers (n itrendipine, nicardipine) displayed concentration-dependent antagonism to specific [H-3]-PN200-110 binding sites with the following values f or inhibition constants (K-i) obtained: 20.8+/-8.9, 12.3+/-4.5 and 3.9 +/-1.0 nmol/L for AE0047, nitrendipine and nicardipine, respectively, 3. In guinea-pig ventricular myocytes, AE0047 blocked the L-type calci um current, with values for the dissociation constant (K-d) and Hill c oefficient of 11.4+/5.7 nmol/L and 0.852+/-0.061, respectively, indica ting in the terms of Hill's hypothesis that one drug molecule blocks o ne calcium channel molecule. 4. In rat aorta, AE0047 inhibited Ca-45 u ptake induced by high K+ (100 mmol/L) by 55%. 5. AE0047 and nitrendipi ne concentration dependently relaxed rat aortic strips contracted with 30 mmol/L KCl. The response to nitrendipine reached a plateau within 60 min and disappeared after drug washing, Interestingly, AE0047 requi red 5 h or more to produce a plateau of response, with no effect of dr ug washing, This confirmed the slow onset and long duration of its vas odilating action, 6. With AE0047, tissue content in rat aorta increase d more slowly than with nitrendipine and release of AE0047 from tissue was also slower. 7. The data suggest that AE0047 is incorporated slow ly into smooth muscle membranes, approaches receptors slowly through t he membrane bilayer and accumulates in the membrane because of its hig h lipophilicity, resulting in an antihypertensive action that is slow in onset and of long duration.