Selective interaction of the calcium antagonist amlodipine with calcium channels in arteries of spontaneously hypertensive rats.

The mechanism of the antihypertensive action of the 1,4-dihydropyridine Ca2+ antagonist amlodipine was investigated by measuring dihydropyridine receptor occupation and the contractile responses to Ca2+ channel activation in aortas and mesenteric arteries from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) after chronic administration of amlodipine. Amlodipine treatment (10 mg/kg/day orally) significantly reduced the increase in blood pressure (BP) in SHR, but did not change BP in WKY. It more potently decreased the contractile response induced by Bay K 8644 in SHR than in WKY aorta. In both SHR and WKY arteries, the functional effect of chronic amlodipine treatment was related to occupation of the specific dihydropyridine binding sites similar to that which occurs after in vitro exposure to amlodipine 5 nM. Resting membrane potential (RMP) of aortic smooth muscle cells (SMC) from SHR was depolarized by 12 mV as compared with SMC from WKY, indicating that the higher potency of amlodipine in arteries from SHR could be related to the depolarization-induced increase in affinity for amlodipine of Ca2+ channels in SHR.