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Acidosis-induced depolarization is due to activation of chloride channels in SHR and WKY rat aorta

Acidosis-induced depolarization is due to activation of chloride channels in SHR and WKY rat aorta. Dileep K. Rohra, T Yamakuni, Y Ohizumi. Introduction. The contractile state of vascular smooth muscle can be regulated by many factors including changes in pH.

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Acidosis-induced depolarization is due to activation of chloride channels in SHR and WKY rat aorta

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  1. Acidosis-induced depolarization is due to activation of chloride channels in SHR and WKY rat aorta Dileep K. Rohra, T Yamakuni, Y Ohizumi

  2. Introduction • The contractile state of vascular smooth muscle can be regulated by many factors including changes in pH. • Although the pH of blood and extracellular fluids is generally maintained at around 7.4, there are various pathophysiological conditions such as diabetes mellitus, renal dysfunction, and pulmonary edema, in which a significant decrease in pH occurs

  3. Introduction • Acidic pH induces a contraction (APIC) in aortas from SHR rats. • A significant component of the APIC is associated with depolarization and Ca2+ entry through voltage-dependent Ca2+ channels.

  4. Aim of study • The aim of this study was to investigate the mechanism underlying the acidosis-induced depolarization and contraction in vascular tissue from SHR and WKY rats.

  5. Representative tracings showing the effects of acidosis on SHR and WKY rat aortas SHR 0.5 g 5 min // 64.8 mM KCl // pH 7.4 pH 7.4 pH 6.5 WKY // 64.8 mM KCl // pH 7.4 pH 6.5 pH 7.4

  6. pH-contraction relationship in SHR aorta 125 ** 100 ** 75 Contraction (%) n = 8 * 50 * 25 0 7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 pHo

  7. Effect of verapamil on acidosis-induced contraction of SHR and WKY rat aortas SHR 0.5 g 5 min 64.8 mM KCl 1 mM verapamil pH 7.4 pH 6.5 pH 7.4 WKY 64.8 mM KCl 1 mM verapamil pH 7.4 pH 6.5 pH 7.4

  8. Comparative analysis of the effects of Ca2+ channel inhibitors on APIC in SHR aorta 100 **p < 0.01 versus control n = 7- 8 75 ** ** Contraction (%) 50 25 0 Verapamil (1 mM) Control Nifedipine (0.1 mM)

  9. Comparative effects of Cl- channel inhibitors and verapamil on acidic pH-induced contraction in SHR and WKY aortas SHR WKY 100 **p < 0.01 versus control n = 8 100 ** ** 75 75 ** ** ** ** ** ** Contraction (%) 50 50 ** ** 25 25 0 0 Control Control 0.5 mM DIDS 0.5 mM DIDS 0.5 mM 9-AC 30 mM IAA-94 0.5 mM 9-AC 30 mM IAA-94 1 mM Verapamill 1 mM Verapamill 3 mM Niflumic acid 3 mM Niflumic acid

  10. Effects of niflumic acid on acidic pH-induced Ca2+ mobilization and contraction in SHR aorta pH 6.5 3 mM niflumic acid 1.2 pH 7.4 R340/380 0.8 0.25 g 2 m

  11. Effect of niflumic acid on acidic pH-induced depolarization in cultured vascular smooth muscle cells from SHR aorta 3 mM niflumic acid pH 6.5 5 3 Membrane potential (arbitrary units) 1 1 min

  12. Conclusion • Acidic pH activates Cl- channels resulting in membrane depolarization of smooth muscle cells of both SHR and WKY aortas. • Consequent to depolarization, opening of voltage-dependent Ca2+ channels occurs resulting in Ca2+ influx and contraction.

  13. Scheme of events occurring under acidic pH conditions leading to contraction in SHR and WKY aortas Cl- Ca2+ H+ Outside Depolarization VDCC Inside Cl- H+ Ca2+ Tyrosine phosphorylation (activation) of PI3-kinase Via Akt, Rho kinase (?) Contraction

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