Hyperpolarization induced by K+ channel openers inhibits Ca2+ influx and Ca2+ release in coronary artery

Teruyuki Yanagisawa, Toshio Yamagishi, Yuji Okada

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

The vasodilating mechanisms of the K+ channel openers-cromakalim, pinacidil, nicorandil, KRN2391, and Ki4032-were examined by measurement of the cytoplasmic Ca2+ concentration ([Ca2+]i) using the fura-2 method in canine or porcine coronary arterial smooth muscle. The five K+ channel openers all produced a reduction of [Ca2+]i in 5 and 30 mM KCl physiological salt solution (PSS), the effects of which were antagonized by tetrabutylammonium (TBA) or glibenclamide, but failed to affect [Ca2+]i in 45 and 90 mM MCl-PSS. Cromakalim and Ki4032 only partially inhibited the 30 mM KCl-induced contractures, whereas pinacidil, nicorandil, and KRN2391 nearly abolished contractions produced by high KCl-PSS. The increased [Ca2+]i and force produced by a thromboxane A2 analogue, U46619, were inhibited by K+ channel openers and verapamil. In the absence of extracellular Ca2+, U46619 induced a transient increase in [Ca2+]i with a contraction, which is effectively inhibited by cromakalim and Ki4032. Their inhibitory effects were blocked by TBA and counteracted by 20 mM KCl-induced depolarization. Cromakalim and Ki4032 did not affect caffeine-induced Ca2+ release. Cromakalim reduced U46619-induced IP3 production and TBA blocked this inhibitory effect. Thus, cromakalim and Ki4032 are more specific K+ channel openers than pinacidil, nicorandil, and KRN2391. The vasodilation related with a reduction of [Ca2+]i produced by K+ channel openers is due to the hyperpolarization of the plasma membrane resulting in not only the closure of voltage-dependent Ca2+ channels but also inhibition of the production of IP3 and Ca2+ release from intracellular stores related to stimulation of the thromboxane A2 receptor.

Original languageEnglish
Pages (from-to)565-574
Number of pages10
JournalCardiovascular Drugs and Therapy
Volume7
Issue number3 Supplement
DOIs
Publication statusPublished - 1993 Aug

Keywords

  • Ca channels
  • Ca release
  • K channel openers
  • caffeine
  • coronary artery
  • cytoplasmic Ca concentration
  • fura-2
  • inositol 1,4,5,-triphosphate (IP)
  • thromboxane A analogue

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine
  • Pharmacology (medical)

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