Mechanisms of the potent and long-lasting antihypertensive action of the new calcium channel blocker pranidipine. Evidence for strong affinity to the calcium channels or membranes.
To elucidate the mechanisms of the potent and long-lasting antihypertensive action of pranidipine (CAS 99522-79-9, OPC-13340), a wash-out experiment in isolated rat aorta preparations and a displacement binding experiment of (+)[3H]PN200-110 (isradipine) with pranidipine and other dihydropyridines to porcine skeletal T-tubules was conducted. It was revealed that the inhibition of KCl-induced contraction by pranidipine remained complete even after washing out the drug 9 times. Also, pranidipine had the lowest Ki value for (+)[3H]PN200-110 binding in skeletal T-tubules. The lipophilicity of pranidipine measured by octanol-buffer partition coefficient was the highest among the tested compounds, and the order of lipophilicity coincided with the order of potency in the displacement binding experiments. These results suggest that pranidipine has a very high affinity to Ca channels or to T-tubule membranes, and strongly support the "membrane-bilayer pathway hypothesis" which assumes the partitioning of the drug into the lipid bilayer before drug binding to Ca channels as an explanation of the potent and long-lasting action of pranidipine compared with other dihydropyridines.
Miyakoda
G
G
2nd Tokushima Institute of New Drug Research, Otsuka Pharmaceutical Co., Ltd., Japan.
Nakayama
N
N
Matsui
K
K
Yabuuchi
Y
Y
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001667:Binding, Competitive / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004095:Dihydropyridines / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D017275:Isradipine / Q000378:metabolism; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013552:Swine
D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D011189:Potassium Chloride; C048161:pranidipine; D017275:Isradipine