Effects on the Rabbit Coronary Artery of LP - 805 , a New Type of Releaser of Endothelium - Derived Relaxing Factor and a K ' Channel

In the rabbit epicardial coronary artery, 8-tert-butyl-6,7-dihydropyrolo[3,2-e]5-methylpyrazolo [1,5-aJpyrimidine-3-carbonitrile (LP-805, >0.1 ,uM) 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 ptM) depolarized the membrane, and LP-805 inhibited the depolarization. However, in +E tissues, ACh (>0.1 ,iM) transiently hyperpolarized the membrane that was not modified by glibenclamide (10 ,uM), charybdotoxin (100 nM), and NG_nitro-L-arginine (L-NNA, 100 FM). In -E tissues of both regions, LP-805 consistently inhibited the 10 jiM ACh-induced contraction (ICso, 2.8 ,uM), and 10 uM glibenclamide shifted this concentrationresponse curve to the right (IC5s, 20 ,uM). In +E tissues, LP805 more potently inhibited the ACh-induced contraction (IC_%, 0.3 uM), and this inhibition was prevented by L-NNA (100 ,uM) but not by indomethacin or glibenclamide (10 uM). 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 LP805 were prevented by glibenclamide (10 uM) 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 pM) 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. (Circulation Research 1992;71:859-869)