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Guanosine 3’:5’-cyclic monophosphate and contraction in vascular smooth muscle

University of British Columbia

Presently, the literature regarding vascular smooth muscle contraction is coloured with many contradictory observations and conclusions. However, like many physiological systems, the biochemical pathways and functional events of vascular smooth muscle contraction vary between individual species and/or tissues. Therefore, determination of a ubiquitous excitation-contraction coupling mechanism is unlikely; variations between receptor classes, receptor density, excitation-contraction coupling pathways and the efficiency of the receptor-pathway interaction contribute to the various observations and conclusions. The inositol 1,4,5-trisphosphate (IP₃) second messenger cascade regulates the mobilization of intracellular Ca²⁺, and subsequently contraction, in vascular smooth muscle. However, phospholipase G-mediated production of IP₃ appears to be controlled by tissue-specific regulatory factors. This study examines the effects of three such factors, the presence of extracellular Ca²⁺, the sensitivity of the associated G-protein and inhibition by 8-bromoguanosine 3':5'-cyclic monophosphate (8-brombcGMP), in isolated rat caudal artery. Concentration-response curves were constructed for phenylephrine and isometric contractions measured in isolated tissues. In addition, phosphatidylinositol turnover was assessed using anion exchange chromatography. The effects of 8-bromo-cGMP on phenylephrine-induced contractions and phosphatidylinositol hydrolysis were compared to those of felodipine, a dihydropyridine Ca²⁺-channel antagonist, and ryanodine, a putative depletor of intracellular Ca2* stores in rat caudal artery. Pertussis toxin was used to determine the identity of the G-protein regulating phenyiephrine-induced contraction. Further, the effects of felodipine and ryanodine on contraction were determined in rat thoracic aorta to compare the contribution of extracellular and intracellular Ca²⁺ to contraction between a large conduit vessel and a small conduit vessel. The results of this investigation suggest that phospholipase C-activated phosphatidylinositol hydrolysis in the rat caudal artery is dependent on extracellular Ca²⁺, mediated, in part, through dihydropyridine sensitive Ca²⁺ channels. Phospholipase C activity is not directly inhibited by 8-bromo-cGMP. However, the nucleotide may regulate vascular smooth muscle contraction by inhibition of Ca²⁺ release from IP₃-mediated intracellular stores, but it is unlikely that 8-bromo-cGMP affects ryanodine-sensitive stores. None of the G-proteins coupled to the ctiadrenoceptor mediated excitation-contraction pathway in rat caudal artery appear to be sensitive to pertussis toxin. Rat aortic tissue does not rely on intracellular Ca²⁺ to the same extent that rat caudal artery does, confirming the tissue specificity of ctiadrenoceptor agonist induced excitation-contraction in vascular smooth muscle.

Thesis/Dissertation

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2009-01-16

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http://hdl.handle.net/2429/3710

Pharmacology

University of British Columbia

UBCV

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