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Dihydropyridines Block IK‐Channel Activation by Acetylcholine in Guinea Pig Cochlear Artery
Author(s) -
Yang YuQin,
Guan BingCai,
Shi XiaoRui,
Nuttall Alfred L,
Jiang ZhiGen
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1157-c
Subject(s) - hyperpolarization (physics) , apamin , chemistry , acetylcholine , potassium channel , pharmacology , charybdotoxin , nitrendipine , vasodilation , medicine , endocrinology , calcium , stereochemistry , nuclear magnetic resonance spectroscopy
Dihydropyridines (DHPs) are L‐type Ca 2+ ‐channel (I L ) blockers and widely used as anti‐hypertension drugs. One DHP, nitrendipine, was found to be a potent blocker for intermediate conductance Ca 2+ ‐activated K + ‐channel (IK, Jensen et al., Am J Physiol. 1998). We demonstrated previously that, in spiral modiolar artery (SMA), ACh induces a hyperpolarization in cells that have a resting potential ~−40 mV. The ACh‐hyperpolarization originated in the endothelial cells (ECs) by activating a Ca 2+ ‐activated K + ‐channel (K Ca ). In the present study, using intracellular recording and immunohistochemistry methods on SMA segments, we found: The ACh‐hyperpolarization was blocked by IK blockers, clotrimazole and nitrendipine, and by a calmodulin antagonist trifluoperazine, but not by BK blocker iberiotoxin. The antigen reactive to anti‐SK4/IK1 antibody was localized in endothelial cells. The three DHPs, nifedipine, nitrendipine and nimodipine all concentration‐dependently inhibited the ACh‐hyperpolarization with an IC 50 of 455, 34 and 3.2 nM, respectively. Verapamil (10 μM) inhibited ACh‐hyperpolarization by 20%, while diltiazem and the metal ion Cd 2+ and Ni 2+ had no effect. We conclude that ACh‐hyperpolarization in the SMA is generated mainly by IK activation in the ECs, and DHPs suppress ACh‐hyperpolarization by blocking IK, not BK or I L . As IK activation is a primary & essential step in EDHF‐mediated vasodilation, which plays an important role in keeping blood flow to vital organs in several clinical conditions, clinicians thus should note that DHP administration might compromise EDHF‐mediated vasodilation in these patients. Supported by NIH NIDCD DC 004716 (ZGJ) and DC00141 (ALN).