CHARACTERISTICS OF THE BINDING OF [H-3] NITRENDIPINE TO RABBIT VENTRICULAR MEMBRANES - MODIFICATION BY OTHER CA++ CHANNEL ANTAGONISTS AND BY THE CA++ CHANNEL AGONIST BAY K-8644

Abstract

[3H]Nitrendipine binding to cardiac membranes was characterized, and the hypothesis that high affinity binding of Ca2+ channel antagonists and agonists is to Ca2+ channels was tested. Binding was specific, rapid, reversible and stereoselective. The relative order of potency of nifedipine analogs for inhibition of binding was the same as that for inhibition of smooth and cardiac muscle contraction. Results with diltiazem, verapamil and lidoflazine were consistent with the hypothesis that nondihydropyridine Ca2+ channel antagonists act at 1 or more sites allosterically linked to the 1,4-dihydropyridine site in cardiac cells. The Ca2+ channel agonist Bay K 8644 displaced specifically bound [3H]nitrendipine in an apparently competitive manner with an IC50 [median inhibitory concentration] value of 5 nM. The results suggest that organic antagonists do not act by physically blocking the Ca2+ channel. Evidently, the high affinity binding sites for [3H]nitrendipine in isolated cardiac membranes are associated with Ca2+ channels that are inactivated or are otherwise unavailable for opening.