The Mode of Action of Pinacidil and Its Analogs P1060 and P1368: PDF OnlyThe Mode of Action of Pinacidil and Its Analogs P1060 and P1368 Results of Studies in Rat Blood VesselsWeston, A. H.; Southerton, J. S.; Bray, Katharine M.; Newgreen, D. T.; Taylor, S. G.†Author Information Smooth Muscle Research Group, Physiological Sciences Department, Manchester University Medical School, Manchester, England †Present address: Beecham Pharmaceuticals, Biosciences Research Centre, Great Burgh, Epsom, Surrey KT18 5XQ, England. Address correspondence and reprint requests to Dr. A. H. Weston at Smooth Muscle Research Group, Physiological Sciences Department, Manchester University Medical School, Oxford Road, Manchester M13 9PT, England. Journal of Cardiovascular Pharmacology: Volume 12 - Issue - p S10-S16 Free Abstract Summary: In rat portal vein and aorta, pinacidil (0.3-100 μM) inhibited spontaneous mechanical activity (portal vein) and responses to norepinephrine (0.001-100 μM) and to KCI (5-80 mM). Pinacidil and its analogs P1060 and P1368 inhibited established contractions to 20 mM KCI but had little effect on responses to 80 mM KCI. The order of spasmolytic potency was P1060 > pinacidil > P1368. Intracellular electrical recording showed that in a portal vein, pinacidil (0.3-10 μM) abolished spontaneous electrical activity and hyperpolarised the cells to the region of the calculated EK. Pinacidil (3-10 μM) produced a similar hyperpolarisation in rat aorta, and in both tissues the hyperpolarisation was maintained in the continuing presence of pinacidil. Using 86Rb as a K+ marker, pinacidil increased 86Rb exchange in both the rat portal vein and aorta. The analog P1060 also increased 86Rb efflux in the rat portal vein; P1368 had no significant effect. It is concluded that the inhibitory effects of pinacidil in rat blood vessels are associated with the opening of 86Rb-permeable K+ channels. This mechanism produces a low-resistance pathway in the membrane and this inhibits the ability of pressor agents to produce smooth muscle contraction. © Lippincott-Raven Publishers.