Differential effects of pinacidil and cromakalim on vascular relaxation and sympathetic neurotransmission.
We tested the hypothesis that pinacidil and cromakalim acted at different sites to relax vascular smooth muscle, in vitro. We compared the effects of pinacidil and cromakalim on tension development in isolated canine and bovine pulmonary artery and vein and canine mesenteric artery and dorsal metatarsal vein, and on the pre- and post-synaptic responses of the canine blood vessels to transmural nerve stimulation. Both pinacidil and cromakalim relaxed bovine and canine blood vessels precontracted to 50% of maximal tension with U46619, prostaglandin F2 alpha, or norepinephrine. Pinacidil- and cromaklim-mediated relaxations of the blood vessels were not mediated by endothelium-derived factors, prostanoids, muscarinic receptors, beta-adrenoceptors, or Ca(2+)-activated or voltage-dependent K+ channels, since they were unaffected by endothelium-rubbing, indomethacin, L-NG-monomethyl-L-arginine, atropine, propranolol, and charybdotoxin. Glibenchlamide, an inhibitor of ATP-activated K+ channels (K+ATP), and KCl (25-60 mM) sufficient to minimize the role of K+ channels almost abolished cromakalim- but not pinacidil-induced relaxation of the blood vessels. Pinacidil inhibited the contractions of the dorsal metatarsal vein and mesenteric artery to norepinephrine and transmural nerve stimulation and the efflux of 2-[14C]norepinephrine during transmural nerve stimulation. In contrast, 1 and 10 nM cromakalim enhanced while 0.1 and 1 microM cromakalim inhibited the contractions of, and 2-[14C]norepinephrine efflux from, the mesenteric artery and dorsal metatarsal vein during transmural nerve stimulation. Thus, pinacidil and cromakalim relax smooth muscle by stimulation 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.
Cai
B
B
Department of Medicine, Louisiana State University Medical Center, New Orleans 70112.
Hao
Q
Q
Greenberg
S S
SS
deBoisblanc
B
B
Gillott
D
D
Goharderakhshan
R
R
Summer
W R
WR
Hyman
A
A
Lippton
H
H
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002417:Cattle; D019806:Cromakalim; D004285:Dogs; D004558:Electric Stimulation; D005260:Female; D006146:Guanidines / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000294:innervation; D009638:Norepinephrine / Q000378:metabolism; D020110:Pinacidil; D011189:Potassium Chloride / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D013564:Sympathetic Nervous System / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D001578:Benzopyrans; D006146:Guanidines; D011758:Pyrroles; D014665:Vasodilator Agents; D019806:Cromakalim; D011189:Potassium Chloride; D020110:Pinacidil; D009638:Norepinephrine