title: Relaxation of potassium chloride-induced contractions by amlodipine and its interaction with the 1,4-dihydropyridine-binding site in pig coronary artery.
abstract: Amlodipine is a light-insensitive and water soluble 1,4-dihydropyridine with prolonged vasodilatory action and plasma half-life. To determine whether the vasodilatory action of amlodipine is due to inhibition of voltage-dependent Ca2+ influx through the calcium channel, its effects on KCl-induced contraction of pig coronary artery rings and its interaction with the 1,4-dihydropyridine binding site in isolated sarcolemmal membranes were studied. The contractile function of artery rings was studied in an organ bath system, and the interaction with the 1,4-dihydropyridine binding site was studied in isolated sarcolemmal membranes of pig coronary artery using [3H](+)PN200-110 as a radioligand. Amlodipine, (+)PN200-110 and (-)PN200-110 inhibited KCl-induced contractions of arterial rings in a dose-dependent manner. The half-maximal inhibition (IC50) was observed at 0.46 +/- 0.02, 36 +/- 8 and 55 +/- 9 nM of (+)PN200-110, (-)PN200-110 and amlodipine, respectively. [3H](+)PN200-110 was found to bind to isolated sarcolemmal membranes with high affinity (KD = 0.04 nM, Bmax = 312 fmoles/mg protein) and stereospecifically, (+)PN200-110 (Ki = 0.05 nM) having about 130-fold higher affinity than (-)PN200-110 (Ki = 6.61 nM). Amlodipine also inhibited [3H](+)PN200-110 binding with high affinity (Ki = 4.41 nM). The inhibition was characterized by an increase in KD of binding of [3H](+)PN200-110 with very little effect on Bmax. The order of relative potency of inhibition of KCl-induced contraction was almost identical to the order of relative affinity for the 1,4-dihydropyridine binding site, as indicated by Ki.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati, College of Medicine, Ohio 45267-0575.
authors.forename: M A
authors.initials: MA
authors.lastname: Matlib
mesh_terms: D017311:Amlodipine; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002121:Calcium Channel Blockers; D003331:Coronary Vessels / Q000187:drug effects*; D004095:Dihydropyridines / Q000378:metabolism*; D017275:Isradipine; D009543:Nifedipine / Q000494:pharmacology; D010069:Oxadiazoles / Q000378:metabolism / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology*; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism; D013237:Stereoisomerism; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects*; D014664:Vasodilation
chemical_list: D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D010069:Oxadiazoles; D017311:Amlodipine; D011189:Potassium Chloride; D009543:Nifedipine; D017275:Isradipine