Vasodilation effect of MC-002 and its possible mechanisms

Abstract

Abstract: AIM: To investigate the vasodilation effect of MC-002 and its possible mechanisms. METHODS: The relaxation effect of MC-002 on rat aortic rings which was pre-constricted by norepinephrine or high-potassium Krebs’solution was measured and the influences of pretreatment with NG-Nitroarginine Methyl Ester (L-NAME), methylene blue, indometacin, glibenclamide ,apamin, barium chloride and 4-aminopyridine on this vasorelaxation effect were observed.RESULTS: MC-002(3-300μmol/L) showed a concentration-dependent dilation effect on rat aortic rings pre-constricted by norepinephrine. Endothelium denudation, pretreatment with methylene blue and indometacin incubation significantly blunted this effect whereas L-NAME did not affect it.Pre-incubation of glibenclamide or apamin, rather than Barium chloride or 4-aminopyridine, apparently inhibited vasodilation effect of MC-002 antagonizing high-potassium Krebs’ solution.The CaCl₂-induced contraction curves of endothelium-denuded arteries stimulated with norepinephrine(300 nmol/L ) in calcium-free medium were significantly shifted to the right and downward, in comparison with controls after pre-incubation with MC-002(10^-5 and 10^-4 mol/L) in a concentration-dependent manner.CONCLUSION: MC-002 had a vasorelaxation effect mediated by guanylate cyclase and cyclooxygenase pathway which was endothelium-dependent, and opening of KATP and SKCa channels which caused hyperpolarization along with the inhibition of calcium influx in smooth muscle cells could contribute to endothelium-independent relaxation.

Key words: MC-002, L-NAME, Methylene blue, Indometacin, Inhibiter of potassium channels

CLC Number:

R965.2

BAO Xu, LI Chen-hui, XU Jun, WU Yu-lin. Vasodilation effect of MC-002 and its possible mechanisms[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2012, 17(9): 1001-1006.

References

[1] 田晶, 吕吉元, 牛龙刚. 氯沙坦对大鼠离体胸主动脉的舒张作用及其机制[J].中国临床药理学与治疗学, 2011,16( 11) : 1252-1256.
[2] Wang GJ, Wu XC, Chen CF, et al.Vasorelaxing action of rutaecarpine: effects of rutaecarpine on calcium channel activities in vascular endothelial and smooth muscle cells[J]. J Pharmacol Exp Ther ,1999 ,289(3):1237-1244.
[3] 袁萱, 张波, 甘露, 等. 紫草素对大鼠离体胸主动脉舒张作用及机制研究[J].中国药理学通报, 2011,27( 4) : 587-588.
[4] Kim EY, Kim JH, Rhyu MR.Endothelium-independent vasorelaxation by ligusticum wallichii in isolated rat aorta: comparison of a butanolic fraction and tetramethylpyrazine, the main active component of ligusticum wallichii[J]. Biol Pharm Bull, 2010, 33(8):1360-1363.
[5] Kitazono T, Faraci FM, Taguchi H, et al.Role of potassium channels in cerebral blood vessels[J]. Stroke,1995,26(9):1713-1723.
[6] Peng W, Hucks D, Priest RM, et al.Ligustrazine-induced endothelium-dependent relaxation in pulmonary arteries via an NO-mediated and exogenous L-arginine-dependent mechanism[J]. Br J Pharmacol ,1996, 119(5):1063-1071.
[7] Sobey CG.Potassium channel function in vascular disease[J].Arterioscler Thromb Vasc Biol,2001,21(1):28-38.
[8] Stiles GL, Caron MG, Leftkowitz RJ.β-Adrenergic receptors: biochemical mechanisms of physiological regulation[J].Physiol Rev,1984, 64(2):661-743.
[9] Coleman HA, Tare M, Parkington HC.Endothelial potassium channels, endothelium-dependent hyperpolarization, and the regulation of vascular tone in health and in disease[J].Clin Exp Pharmacol Physiol,2004 ,31(9):641-649.
[10] Absi M,Burnham MP,Weston AH, et al.Effects of methyl β-cyclo- dextrin on EDHF responses in pig and rat arteries; association between SKCa channels and caveolin-rich domains[J].Br J Pharmacol,2007,151(3):332-340.
[11] Nelson MT, Quayle JM.Physiological roles and properties of potassium channels in arterial smooth muscle[J].Am J Physiol,1995,268(4 Pt 1):C799-C822.
[12] Sheng JS, Ella S, Davis, MJ, et al.Openers of SKCa and IKCa channels enhance agonist evoked endothelial nitric oxide synthesis and arteriolar vasodilation[J].FASEB J,2009,23(4):1138-1145.
[13] McNeish AJ, Sandow SL, Neylon CB, et al. Evidence for Involvement of Both IKCa and SKCa Channels in Hyperpolarizing Responses of the Rat Middle Cerebral Artery[J]. Stroke,2006,37(5):1277-1282.
[14] Dolga AM, Terpolilli N, Kepura F,et al.KCa2 channels activation prevents [Ca²+]i deregulation and reduces neuronal death following glutamate toxicity and cerebral ischemia[J]. Cell Death Dis, 2011,2:e147.
[15] Wickenden A.K+ channels as therapeutic drug targets[J].Pharmacol Ther,2002, 94(1/2): 157-182.