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The mechanisms of the relaxation induced by vasoactive intestinal peptide in the porcine coronary artery
Author(s) -
Kawasaki Junya,
Kobayashi Sei,
Miyagi Yasushi,
Nishimura Junji,
Fujishima Masatoshi,
Kanaide Hideo
Publication year - 1997
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701206
Subject(s) - apamin , depolarization , vasoactive intestinal peptide , chemistry , channel blocker , charybdotoxin , thapsigargin , medicine , contraction (grammar) , glibenclamide , endocrinology , potassium channel , biophysics , calcium , biochemistry , intracellular , receptor , neuropeptide , biology , diabetes mellitus
This study was designed to investigate the mechanism of the relaxation induced by vasoactive intestinal peptide (VIP) in medial strips of the porcine coronary artery, by determining the effect on the cytosolic Ca 2+ concentration ([Ca 2+ ] i ), the [Ca 2+ ] i ‐force relation and the involvement of G‐protein. Front‐surface fluorometry of fura‐2 revealed that U46619, a thromboxane A 2 analogue, and the high K + ‐depolarization induced increases in both the [Ca 2+ ] i and force of the medial strips. At a steady state of contraction, the extent of an increase in [Ca 2+ ] i induced by 100 n M U46619 was similar to that induced by 30 m M K + ‐depolarization. VIP concentration‐dependently (1 n M –1 μ M ) induced transient decreases in both the [Ca 2+ ] i and force of the medial strips precontracted with 100 n M U46619. The decreases in the [Ca 2+ ] i and force induced by VIP during the contraction with U46619 were much greater than those with 30 m M K + ‐depolarization. The VIP‐induced decreases in the [Ca 2+ ] i and force were attenuated by K + channel blockers such as tetrabutylammonium (TBA: non‐selective K + channel blocker), charybdotoxin (large conductance Ca 2+ ‐activated K + channel blocker), and 4‐aminopyridine (4‐AP: voltage‐dependent K + channel blocker). However, neither glibenclamide (ATP‐sensitive K + channel blocker) nor apamin (small conductance Ca 2+ ‐activated K + channel blocker) had any significant inhibitory effect. In the 30 m M K + ‐depolarized strips, pretreatment with thapsigargin, a specific Ca 2+ ‐ATPase inhibitor of the Ca 2+ store sites, completely abolished the VIP‐induced decrease in [Ca 2+ ] i , but partially attenuated the VIP‐induced decrease in force. VIP shifted the [Ca 2+ ] i ‐force relation of the U46619‐induced contractions to the right in a concentration‐dependent manner. In the α‐toxin‐permeabilized strips, VIP decreased the force development at a constant [Ca 2+ ] i level (pCa=6.5) in a GTP‐dependent manner, which was antagonized by guanosine‐5′‐O‐(β‐thiodiphosphate) (GDPβS). We thus conclude that VIP relaxes the coronary artery via three mechanisms: (1) a decrease in [Ca 2+ ] i by inhibiting the Ca 2+ influx presumably through the membrane hyperpolarization mediated by the activation of the large conductance Ca 2+ ‐activated (charybdotoxin‐sensitive) K + channels and voltage‐dependent (4‐AP‐sensitive) K + channels; (2) a decrease in [Ca 2+ ] i by sequestrating cytosolic Ca 2+ into thapsigargin‐sensitive Ca 2+ store sites; and (3) a decrease in the Ca 2+ ‐sensitivity of the contractile apparatus through the activation of G‐protein.