EFFECTS ON THE RABBIT CORONARY-ARTERY OF LP-805, A NEW TYPE OF RELEASER OF ENDOTHELIUM-DERIVED RELAXING FACTOR AND A K+ CHANNEL OPENER

In the rabbit epicardial coronary artery, 8-tert-butyl-6,7-dihydropyrolo[3,2-e]5-methylpyrazolo [1,5-a]pyrimidine-3-carbonitrile (LP-805, >0.1-mu-M) hyperpolarized the muscle membrane in both proximal (diameter, 1-1.2 mm) and distal (diameter, 0.1-0.2 mm) regions of intact (+E) tissue, in which endothelium is present, and endothelium-denuded (-E) tissue. LP-805-induced hyperpolarization was inhibited by glibenclamide. In -E tissues in both regions, acetylcholine (ACh, >0.1-mu-M) depolarized the membrane, and LP-805 inhibited the depolarization. However, in +E tissues, ACh (>0.1-mu-M) transiently hyperpolarized the membrane that was not modified by glibenclamide (10-mu-M), charybdotoxin (100 nM), and N(G)-nitro-L-arginine (L-NNA, 100-mu-M). In -E tissues of both regions, LP-805 consistently inhibited the 10-mu-M ACh-induced contraction (IC50, 2.8-mu-M), and 10-mu-M glibenclamide shifted this concentration-response curve to the right (IC50, 20-mu-M). In +E tissues, LP-805 more potently inhibited the ACh-induced contraction (IC50, 0.3-mu-M), and this inhibition was prevented by L-NNA (100-mu-M) but not by indomethacin or glibenclamide (10-mu-M). In -E and +E tissues of both regions, LP-805 repolarized the high K+-induced depolarization (<20 mM) and relaxed the tissues precontracted by high K+ (<30 mM); these electrical and mechanical effects of LP-805 were prevented by glibenclamide (10-mu-M) in +E tissues. In +E tissues, the K+-induced contraction (<30 mM) was more strongly inhibited than in -E tissues, but after treatment with L-NNA, LP-805 relaxed -E and +E tissues precontracted to the same extent in the presence of high K+. LP-805 (10-mu-M) did not inhibit the Ca2+-induced contraction in skinned muscle tissues but did slightly inhibit the ACh-induced contraction in Ca2+-free solution containing 2 mM EGTA. Thus, LP-805 has a potent releasing action on endothelium-derived relaxing factor and also the potential to open the glibenclamide-sensitive K+ channel. These events would account for the dilation of the rabbit coronary artery exposed to LP-805.