Dihydropyridines inhibit acetylcholine-induced hyperpolarization in cochlear artery via blockade of intermediate-conductance calcium-activated potassium channels

Zhi Gen Jiang, Xiao Rui Shi, Bing Cai Guan, Hui Zhao, Yu Qin Yang

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Acetylcholine (ACh) induces hyperpolarization and dilation in a variety of blood vessels, including the cochlear spiral modiolar artery (SMA) via the endothelium-derived hyperpolarization factor (EDHF). We demonstrated previously that the ACh-induced hyperpolarization in the SMA originated in the endothelial cells (ECs) by activating a Ca2+-activated K+ channel (KCa); the hyperpolarization in smooth muscle cells was mainly an electrotonic spread via gap junction coupling. In the present study, using intracellular recording, immunohistology, and vascular diameter tracking techniques on in vitro SMA preparations, we found that 1) ACh-induced hyperpolarization was suppressed by intermediate-conductance KCa (IK) blockers clotrimazole (IC50 = 116 nM) and nitrendipine and by the calmodulin antagonist trifluoperazine, but it was not suppressed by the big-conductance KCa blocker iberiotoxin. The immunoreactivity to anti-SK4/IK1 antibody was localized mainly in ECs. 2) The three dihydropyridines - nifedipine, nitrendipine, and nimodipine - all concentration-dependently inhibited the ACh-induced hyperpolarization, with an IC50 value of 455, 34, and 3.2 nM, respectively. 3) Among other L-type Ca2+ channel (IL) blockers, 10 μM verapamil exerted a 20% inhibition on ACh-induced hyperpolarization, whereas diltiazem and the metal ion Ca 2+ channel blockers Cd2+ and Ni2+ had no effect. 4) Nitrendipine and charybdotoxin abolished ACh-induced dilation in the SMA. We conclude that ACh-induced hyperpolarization in the SMA is generated mainly by activation of the IK in the ECs, and dihydropyridines suppress the EDHF-mediated hyperpolarization by blocking the IK channel, not the I L channel. The clinical relevance of this dihydropyridine action is discussed.

Original languageEnglish (US)
Pages (from-to)544-551
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume320
Issue number2
DOIs
StatePublished - Feb 1 2007

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Fingerprint Dive into the research topics of 'Dihydropyridines inhibit acetylcholine-induced hyperpolarization in cochlear artery via blockade of intermediate-conductance calcium-activated potassium channels'. Together they form a unique fingerprint.

  • Cite this