DIFFERENTIAL-EFFECTS OF PINACIDIL AND CROMAKALIM ON VASCULAR RELAXATION AND SYMPATHETIC NEUROTRANSMISSION

We tested the hypothesis that pinacidil and cromakalim acted at differ ent sites to relax vascular smooth muscle, in vitro. We compared the e ffects of pinacidil and cromakalim on tension development in isolated canine and bovine pulmonary artery and vein and canine mesenteric arte ry and dorsal metatarsal vein, and on the pre- and post-synaptic respo nses of the canine blood vessels to transmural nerve stimulation. Both pinacidil and cromakalim relaxed bovine and canine blood vessels prec ontracted to 50% of maximal tension with U46619, prostaglandin F-2 alp ha, or norepinephrine. Pinacidil- and cromaklim-mediated relaxations o f the blood vessels were not mediated by endothelium-derived factors, prostanoids, muscarinic receptors, beta-adrenoceptors, or Ca2+-activat ed or voltage-dependent K+ channels, since they were unaffected by end othelium-rubbing, indomethacin, L-N-G-monomethyl-L-arginine, atropine, propranolol, and charybdotoxin. Glibenchlamide, an inhibitor of ATP-a ctivated K+ channels (K-ATP(+)), AND KCl (25-60 Mm) sufficient to mini mize the role of K+ channels almost abolished cromakalim- but not pina cidil-induced relaxation of the blood vessels. Pinacidil inhibited the contractions of the dorsal metatarsal vein and mesenteric artery to n orepinephrine and transmural nerve stimulation and the efflux of 2-[C- 14]norepinephrine during transmural nerve stimulation. In contrast, 1 and 10 nM cromakalim enhanced while 0.1 and 1 mu M cromakalim inhibite d the contractions of, and 2-[C-14]norepinephrine efflux from, the mes enteric artery and dorsal metatarsal vein during transmural nerve stim ulation. Thus, pinacidil and cromakalim relax smooth muscle by stimula tion of K-ATP(+) channels. Pinacidil also relaxes the blood vessels by a K+ channel independent mechanism. Pinacidil-induced relaxation may also result from presynaptic inhibition of norepinephrine release from the sympathetic neuron.