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KMID : 0043320090320020243
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Archives of Pharmacal Research
2009 Volume.32 No. 2 p.243 ~ p.250
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Contribution of RhoA Kinase and Protein Kinase C to Weak Relaxant Effect of Pinacidil on Carbachol-Induced Contractions in Sensitized Guinea-Pig Trachealis
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Kamil Vural
Ahenk Izanli-Paksoy
Sule Gok
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Abstract
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The exact mechanisms underlying the weak bronchodilator effect of KATP channel openers on cholinergic stimulations is unknown. The present study was designed to examine the relaxant efect of pinacidil in guinea-pig trachea stimulated with carbachol by the presence of calcium sensitizer inhibitors; HA 1077, a rhoA kinase inhibitor, and chelerythrine, a protein kinase C inhibitor. Adenosine (10 μM) was used as other contractile agent for comparison. Tracheal tissues were isolated from ovalbumin sensitized guineapigs and changes in tension were recorded isometrically. Pinacidil (1-100 μM, cumulatively) and HA 1077 (0.01-30 μM, cumulatively) produced concentration-dependent relaxations in unstimulated tisues. The relaxant response to pinacidil decreased in carbachol contracted tissues, but increased in adenosinestimulated tissues. Pretreatment of the tissues with HA 1077 (0.1 μM) and chelerythrine (10 μM) increased the pinacidil-induced relaxations by ~%100 and %40, respectively. Glibenclamide, a KATP channel blocker, partially antagonized the pinacidil response in contracted tissues. Glibenclamide also inhibited the carbachol and adenosine induced contractions. These results suggest that diminish effect of pinacidil may have related to the enhanced calcium sensitization by cholinergic stimulation. Rho kinase inhibitors appear more effective than PKC inhibitors to achieve of this failure.
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KEYWORD
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KATP channel openers, Calcium sensitivity, Carbachol, Adenosine, Sensitized guinea-pig trachea, Rho kinase, Protein kinase C
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