KCl-Depolarization Potentiates the Ca2+Sensitization by Endothelin-1 in Canine Coronary Artery

Okada, Yuji; Yanagisawa, Teruyuki; Taira, Norio

doi:10.1254/jjp.60.403

Cited by 10 publications

(11 citation statements)

References 9 publications

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“…Potassium influences the Ca 2ϩ handling by depolarization of the cell membrane of smooth muscle cells in the arterial wall, resulting in vasoconstriction. This simulation of arterial tone is commonly used in other studies on arterial vasoregulation (35)(36)(37). It is unlikely that the induced state of tone will bear impact on the results of insulin-mediated vasoreactivity and PKC activation because we found that insulin-mediated vasodilation is NO dependent and insulin-mediated vasoconstriction is ET-1 dependent.…”

Section: Discussionmentioning

confidence: 80%

Protein Kinase C θ Activation Induces Insulin-Mediated Constriction of Muscle Resistance Arteries

et al. 2008

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OBJECTIVE—Protein kinase C (PKC) θ activation is associated with insulin resistance and obesity, but the underlying mechanisms have not been fully elucidated. Impairment of insulin-mediated vasoreactivity in muscle contributes to insulin resistance, but it is unknown whether PKCθ is involved. In this study, we investigated whether PKCθ activation impairs insulin-mediated vasoreactivity and insulin signaling in muscle resistance arteries. RESEARCH DESIGN AND METHODS—Vasoreactivity of isolated resistance arteries of mouse gracilis muscles to insulin (0.02–20 nmol/l) was studied in a pressure myograph with or without PKCθ activation by palmitic acid (PA) (100 μmol/l). RESULTS—In the absence of PKCθ activation, insulin did not alter arterial diameter, which was caused by a balance of nitric oxide–dependent vasodilator and endothelin-dependent vasoconstrictor effects. Using three-dimensional microscopy and Western blotting of muscle resistance arteries, we found that PKCθ is abundantly expressed in endothelium of muscle resistance arteries of both mice and humans and is activated by pathophysiological levels of PA, as indicated by phosphorylation at Thr538 in mouse resistance arteries. In the presence of PA, insulin induced vasoconstriction (21 ± 6% at 2 nmol/l insulin), which was abolished by pharmacological or genetic inactivation of PKCθ. Analysis of intracellular signaling in muscle resistance arteries showed that PKCθ activation reduced insulin-mediated Akt phosphorylation (Ser473) and increased extracellular signal–related kinase (ERK) 1/2 phosphorylation. Inhibition of PKCθ restored insulin-mediated vasoreactivity and insulin-mediated activation of Akt and ERK1/2 in the presence of PA. CONCLUSIONS—PKCθ activation induces insulin-mediated vasoconstriction by inhibition of Akt and stimulation of ERK1/2 in muscle resistance arteries. This provides a new mechanism linking PKCθ activation to insulin resistance.

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Section: Discussionmentioning

confidence: 80%

Protein Kinase C θ Activation Induces Insulin-Mediated Constriction of Muscle Resistance Arteries

et al. 2008

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“…Other K + channel openers, such as levcromakalim, cromakalim, KRN2391, Ki4032, E4080 and Ki1769, have been shown to have a Ca 2+ desensitizing action in coronary arteries through membrane hyperpolarization (Okada et al 1992a(Okada et al , 1993aYokoyama et al 1995). Conversely, membrane depolarization potentiates Ca 2÷ sensitization induced by endothelin-1 in coronary artery (Okada et al 1992b). Thus, the Ca 2+ sensitivity of contractile elements in arterial smooth muscle may be partly regulated by the membrane potential (Yanagisawa and Okada 1994).…”

Section: Effect Of Krn 4884 Onmentioning

confidence: 99%

Effects of the potassium channel openers KRN4884 and levcromakalim on the contraction of rat aorta induced by A23187, compared with nifedipine

Kawahara

Izumi

Okada

et al. 1996

Naunyn-Schmiedeberg's Arch Pharmacol

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We examined the different vasodilatory effects of the K+ channel openers levcromakalim and 5-amino-N- [2-(2-chlorophenyl)ethyl]-N'-cyano-3-pyridinecarboxamidine (KRN4884), and the Ca2+ channel blocker nifedipine in the rat aorta. KRN 4884 (10(-10)-10(-5) M) and nifedipine (10(-10)-10(-5) M) produced concentration-dependent relaxation in the rat aorta precontracted by 25 mM KCl. The K+ channel blocker glibenclamide (1 microM) inhibited the relaxation induced by KRN4884 but did not influence nifedipine-induced relaxation. KRN4884 had almost no effect on contraction induced by 80 mM KCl, whereas nifedipine completely relaxed the muscle precontracted by 80 mM KCl, whereas nifedipine completely relaxed the muscle precontracted by 80 mM KCl. These results indicate that KRN4884 is a K+ channel opener. We investigated the relaxant effects of KRN4884 (10(-10)-10(-5) M), levcromakalim (10(-9)-10(-5) M) and nifedipine (10(-9)-10(-5) M) on A23187 (1 microM)-induced contraction. KRN4884 and levcromakalim had a potent relaxant effect but nifedipine only a weak effect on the smooth muscle contracted by A23187. Glibenclamide (1 microM) inhibited the relaxation induced by KRN4884 and levcromakalim, but did not influence the nifedipine-induced relaxation. KRN4884 (1 microM) produced a larger relaxation of A23187-induced contraction but had little effect on the increase in intracellular [Ca2+] induced by A23187. These results suggest that KRN4884 is a specific K+ channel opener and its vasodilating mechanisms involve not only deactivation of Ca2+ channels but also a decrease in the Ca2+ sensitivity of contractile elements.

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“…However, recently it has been found that in Ca 2+ -free physiological salt solution (pCa>9) containing endothelin, depolarization by high K + increases the force of contraction in canine coronary artery without any changes in [Ca 2+ ] i [33]. More recently, we demonstrated that K + evokes reversible and reproducible contractions in endothelium-denuded rat aorta bathed in Ca-free, K-rich isotonic salt solution containing EDTA [23].…”

Section: Introductionmentioning

confidence: 72%

“…K + -induced contraction in Ca-free, Mg-free medium may also be due to sensitization of the contractile elements. It has been proposed that the change of membrane potential by K + is a transducer mechanism for the alteration of myofilament Ca 2+ sensitivity in smooth muscle cells [33]. However, this seems unlikely, since it was also noted that high K + itself is unable to change the force of canine coronary artery in Ca-free, normal-Mg medium containing EGTA [33].…”

Section: Discussionmentioning

confidence: 99%

“…It has been proposed that the change of membrane potential by K + is a transducer mechanism for the alteration of myofilament Ca 2+ sensitivity in smooth muscle cells [33]. However, this seems unlikely, since it was also noted that high K + itself is unable to change the force of canine coronary artery in Ca-free, normal-Mg medium containing EGTA [33]. Possibly, sensitization of the contractile elements due to an enhancement of myosin light chain (MLC) To explore the effects of blocking Ca 2+ channels (Ni 2+ ) and inhibiting Ca 2+ -ATPase (calmidazolium), we used the same protocol; however, solutions 4 and 5 contained either 2 mM NiCl 2 or 5 mM calmidazolium.…”

Section: Discussionmentioning

confidence: 99%

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A new view of K+-induced contraction in rat aorta: the role of Ca2+ binding

Kravtsov

Bruce

Wong

et al. 2003

Pflugers Arch - Eur J Physiol

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Strong, K+ -induced contractions of rat aorta in Ca-free, Mg-free media were not accompanied by increased intracellular calcium concentration, [Ca2+](i), whereas such contractions in the presence of the divalent cations were correlated with rising [Ca2+](i) as assessed by fura-2. At the same time, calcium channel blockers, a modulator of Ca2+-binding proteins, and a modulator of actin polymerization, inhibited all types of K+ -induced contractions. Increasing the K+ in isotonic medium evoked a rise of (45)Ca2+ binding to the plasma membrane of freshly isolated aortic cells. Although Ca2+ -dependent events underlie the mechanism of K+ -induced vascular contractions in both the presence and absence of Ca2+, in contrast to the view that [Ca2+](i) is a key regulator of excitation-contraction coupling in smooth muscle, we suggest that the modulation of Mg2+ -dependent Ca2+ binding, probably within/at the L-type calcium channel by K+, is a trigger for aortic contraction. This Ca2+ binding may then activate actin-myosin interaction.

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KCl-Depolarization Potentiates the Ca2+Sensitization by Endothelin-1 in Canine Coronary Artery

Cited by 10 publications

References 9 publications

Protein Kinase C θ Activation Induces Insulin-Mediated Constriction of Muscle Resistance Arteries

Protein Kinase C θ Activation Induces Insulin-Mediated Constriction of Muscle Resistance Arteries

Effects of the potassium channel openers KRN4884 and levcromakalim on the contraction of rat aorta induced by A23187, compared with nifedipine

A new view of K+-induced contraction in rat aorta: the role of Ca2+ binding

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