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 bovine aortic membrane, AE0047 and other DHP calcium channel blockers (nitrendipine, nicardipine) displayed concentration-dependent antagonism to specific [3H]-PN200-110 binding sites with the following values for inhibition constants (Ki) 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 calcium current, with values for the dissociation constant (Kd) and Hill coefficient of 11.4 +/- 5.7 nmol/L and 0.852 +/- 0.061, respectively, indicating in the terms of Hill's hypothesis that one drug molecule blocks one calcium channel molecule. 4. In rat aorta, AE0047 inhibited 45Ca uptake induced by high K+ (100 mmol/L) by 55%. 5. AE0047 and nitrendipine 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 required 5 h or more to produce a plateau of response, with no effect of drug washing. This confirmed the slow onset and long duration of its vasodilating action. 6. With AE0047, tissue content in rat aorta increased more slowly than with nitrendipine and release of AE0047 from tissue was also slower. 7. The data suggest that AE0047 is incorporated slowly into smooth muscle membranes, approaches receptors slowly through the membrane bilayer and accumulates in the membrane because of its high lipophilicity, resulting in an anti-hypertensive action that is slow in onset and of long duration.
Nishikawa
M
M
Pharmacology Laboratories, Research Division, The Green Cross Corporation, Osaka, Japan. gcc43451@greencross.co.jp
Gohda
M
M
Shinyama
H
H
Matzno
S
S
Yamanaga
K
K
Kido
H
H
Nakamura
N
N
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001011:Aorta; D001665:Binding Sites; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002417:Cattle; D004095:Dihydropyridines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects; D009529:Nicardipine / Q000494:pharmacology; D009568:Nitrendipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D051381:Rats; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000494:pharmacology*
D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D014665:Vasodilator Agents; C064970:AE0047; D009568:Nitrendipine; D009529:Nicardipine; D002118:Calcium