POSSIBLE FUNCTIONAL LINKAGE BETWEEN THE CARDIAC DIHYDROPYRIDINE AND RYANODINE RECEPTOR - ACCELERATION OF REST DECAY BY BAY-K-8644

The effect of the dihydropyridine L-type Ca chanel agonist Bay K 8644 on post-rest contractions in ferret; ventricular muscle and isolated m yocytes was investigated. Bay K 8644 was shown to abolish rest potenti ation and greatly accelerate rest decay. The post-rest contraction sup pressed by Bay K 8644 was accompanied by action potentials of large am plitude and longer duration, but voltage-clamp measurements showed tha t this suppression was not due to a supra-optimal I-Ca trigger. Caffei ne-induced contractures and rapid cooling contractures demonstrated an accelerated rest-dependent decline in sarcoplasmic reticulum (SR) Ca content in the presence of Bay K 8644, which was present even with Ca- free superfusion during rest. Thus, the Bay K 8644-induced decline of SR Ca during rest was independent of extracellular Ca or I-Ca. To expl ore whether the binding of Bay K 8644 to the dihydropyridine receptor could alter the SR Ca release channel/ryanodine receptor in a more dir ect way, ryanodine binding was measured in the absence and presence of Bay K 8644. Ryanodine binding to isolated ferret ventricular myocytes was increased by Bay K 8644 under conditions where sarcolemmal-SR jun ctions might be expected to be intact, but not after physical disrupti on. These results are consistent with a working hypothesis where Bay K 8644 may bind to the dihydropyridine receptor and this may lead to ph ysical changes in the linkage between the dihydropridine receptor and a subset of ryanodine receptors, thereby increasing the opening of the SR Ca release channel during rest (and accelerating resting Ca loss). (C) 1996 Academic Press Limited