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Effects of pinacidil on electrical and mechanical activities in the rabbit mesenteric artery
it I.V'J
References Nishida, A., Kimm'a, H., Nakano, M. and Goto, T., 1989, Clinica Chimica Acta, 179, 177.
P.th.081I Effects of pinacidil on electrical and mechanical activities in the rabbit mesenteric artery Itoh, T., Seki, N., Kajikuri, J. and Kuriyama, H.
Department of Pharmacology, Facultyof Medicine, Kyushu University, Fukuoka 812, Japan Pinacidil is a newly synthesized novel anti-hypertensive drug. This drug has a property as a K+-channel activator (opener) and produces membrane hyper-polarization and then induces muscle relaxation. The K+-channel opener is thought to produce vascular relaxation due to inhibition of the Ca 2+ influx activated by stimulants through hyperpolarization of the membrane. Pinacidil had more potent inhibitory action on contractions induced by agonists rather than high-K +. However, pinacidil inhibited the contraction induced by high K + in the rabbit mesenteric artery more potently than that induced by cromakalim, another K+-channel opener. Thus, in addition to the membrane hyperpolarizing action via activations of K +-permeability, other mechanisms may be involved in the pinacidil-induced vasorelaxation in the rabbit mesenteric artery. To clarify this, we examined the effects of pinacidil on the membrane potential, isometric contraction and production of inositol 1,4,5-trisphosphate(IP3) in the presence or absence of noradrenaline (NAd) in strips of the rabbit mesenteric artery. In this tissue, NAd(over 0.3 /tM) depolarized the membrane and occasionally produced oscillatory membrane depolarization which triggered action potentials. NAd(over 0.1 ttM) produced an initial phasic contraction which was followed by oscillatory contractions. The former is thought to be due to the release of Ca 2+ from the store site (mainly s~'coplasmic reticulum) following synthesis of !P3 and the latter is only observed in the presence of extracellular Ca 2+ and thus influxes of Ca 2+ may cause activations of the Ca2+-induced Ca 2+ releases mechanism. Pinacidil (over 0.1 ItM) hyperpolarized the membrane and inhibited the membrane depolarization induced by 10 pM NAd. At the same concentration range, this drug inhibited the phasic and oscillatory contractions induced by 10 pM NAd. In 5.9 mM K + with Ca2+-free so|ution containing 2 mM-EGTA, pinacidil inhibited the contraction induced by 10 ~tM NAd, but not 2 mM caffeine. These inhibitory effects of pinacidil on the NAd-induced contraction were also observed even in Ca2+-free high-K + solution. BaC! 2 (0.3 mM) or glybenclamide (1/tM), an ATP dependent K+-channel inhibitor, blocked the inhibition induced by I mM pinacidil on the NAd-induced contraction in the presence or absence of extracellular Ca 2+. Ten ~tM pinacidil inhibited the IP3 production induced by 10/tM NAd in Ca2+-free solution. These results indicate that in addition to the membrane hyperpolarizing action, some unidentified mechanism(s) which relate(s) to phosphatidyl inositol hydrolysis may be important on the pinacidil-induced vascular relaxation.
IV.th.O821 Effects of hypoxia on nicotine-induced catecholamine release from cultured bovine adrenal chromaffin cells Lee, K., Miwa, S., Koshimura, K., Ohue, T., Ninomiya, H. and Fujiwara, M.
Department of Pharmacology, Kyoto UniversityFaculty of Medicine, Kyoto 606, Japan Recently, we have shown that hypoxia severely inhibits the electrical stimulation-evoked overflow of [3H]noradrenaline from the rabbit thoracic aortic strips prelabelled with [3H]noradrenaline (Lee et al., 1988). However, the mechanism by which noradrenaline release is inhibited under hypoxic conditions is unknown. Therefore, in the present study, to clarify the effects of hypoxia on catecholamine (noradrenaline and adrenaline) release and its mechanism of action, we examined the effects of hypoxia on nicotine-induced increase in catecholamine release and
References Nishida, A., Kimm'a, H., Nakano, M. and Goto, T., 1989, Clinica Chimica Acta, 179, 177.
P.th.081I Effects of pinacidil on electrical and mechanical activities in the rabbit mesenteric artery Itoh, T., Seki, N., Kajikuri, J. and Kuriyama, H.
Department of Pharmacology, Facultyof Medicine, Kyushu University, Fukuoka 812, Japan Pinacidil is a newly synthesized novel anti-hypertensive drug. This drug has a property as a K+-channel activator (opener) and produces membrane hyper-polarization and then induces muscle relaxation. The K+-channel opener is thought to produce vascular relaxation due to inhibition of the Ca 2+ influx activated by stimulants through hyperpolarization of the membrane. Pinacidil had more potent inhibitory action on contractions induced by agonists rather than high-K +. However, pinacidil inhibited the contraction induced by high K + in the rabbit mesenteric artery more potently than that induced by cromakalim, another K+-channel opener. Thus, in addition to the membrane hyperpolarizing action via activations of K +-permeability, other mechanisms may be involved in the pinacidil-induced vasorelaxation in the rabbit mesenteric artery. To clarify this, we examined the effects of pinacidil on the membrane potential, isometric contraction and production of inositol 1,4,5-trisphosphate(IP3) in the presence or absence of noradrenaline (NAd) in strips of the rabbit mesenteric artery. In this tissue, NAd(over 0.3 /tM) depolarized the membrane and occasionally produced oscillatory membrane depolarization which triggered action potentials. NAd(over 0.1 ttM) produced an initial phasic contraction which was followed by oscillatory contractions. The former is thought to be due to the release of Ca 2+ from the store site (mainly s~'coplasmic reticulum) following synthesis of !P3 and the latter is only observed in the presence of extracellular Ca 2+ and thus influxes of Ca 2+ may cause activations of the Ca2+-induced Ca 2+ releases mechanism. Pinacidil (over 0.1 ItM) hyperpolarized the membrane and inhibited the membrane depolarization induced by 10 pM NAd. At the same concentration range, this drug inhibited the phasic and oscillatory contractions induced by 10 pM NAd. In 5.9 mM K + with Ca2+-free so|ution containing 2 mM-EGTA, pinacidil inhibited the contraction induced by 10 ~tM NAd, but not 2 mM caffeine. These inhibitory effects of pinacidil on the NAd-induced contraction were also observed even in Ca2+-free high-K + solution. BaC! 2 (0.3 mM) or glybenclamide (1/tM), an ATP dependent K+-channel inhibitor, blocked the inhibition induced by I mM pinacidil on the NAd-induced contraction in the presence or absence of extracellular Ca 2+. Ten ~tM pinacidil inhibited the IP3 production induced by 10/tM NAd in Ca2+-free solution. These results indicate that in addition to the membrane hyperpolarizing action, some unidentified mechanism(s) which relate(s) to phosphatidyl inositol hydrolysis may be important on the pinacidil-induced vascular relaxation.
IV.th.O821 Effects of hypoxia on nicotine-induced catecholamine release from cultured bovine adrenal chromaffin cells Lee, K., Miwa, S., Koshimura, K., Ohue, T., Ninomiya, H. and Fujiwara, M.
Department of Pharmacology, Kyoto UniversityFaculty of Medicine, Kyoto 606, Japan Recently, we have shown that hypoxia severely inhibits the electrical stimulation-evoked overflow of [3H]noradrenaline from the rabbit thoracic aortic strips prelabelled with [3H]noradrenaline (Lee et al., 1988). However, the mechanism by which noradrenaline release is inhibited under hypoxic conditions is unknown. Therefore, in the present study, to clarify the effects of hypoxia on catecholamine (noradrenaline and adrenaline) release and its mechanism of action, we examined the effects of hypoxia on nicotine-induced increase in catecholamine release and