Vasorelaxant Effect Of Duloxetine In Rat Isolated Arterial Rings

Objective:To investigate the vasorelaxant effect of duloxetine(DLX)in rat arterial rings and the mechanism, And further observed the effect of DLX on the other arterial rings.Methods:The isolated thoracic aortic ringss, renal arterial rings、middle cerebral arterial rings and coronary arterial rings of rats were suspended in the organ baths for isometric tension recording by BL-420and DMT systems. We observed the effect of DLX on the arterial rings precontracted by the potassium chloride (KCl,30or60mmol· L-1) or norepinphrine(NE,1μmol· L-1).We study on endothelium and inhibitors of K+channels,5-HT2receptors (cyproheptadine,1μmol· L-1), α1-adrenoceptors (prazosin,1μmol·L-1)AT1receptors (candesartan,10μmol·L-1), long-lasting calcium channel(nicardipine,1nmol·L-1) and NCX (KB-R7943,1μmol· L-1) about the vasorelaxant effect of DLX on the thoracic aortic rings reactions. Extracellular Ca2+and intracellular Ca2+were also observed since DLX relaxed the thoracic aortic rings.Results:(1) In resting state, DLX(0.01～100μmol· L-1)had no significant impact on tension of the rat isolated thoracic aortic ringss, renal arterial rings、middle cerebral arterial rings and coronary arterial rings.(2) DLX(3～100μmol· L-1)completely relaxed the contractions induced by KCl(30mmol· L-1)and NE(1μmol· L-1)in a concentration-dependent manner in endothelium-intact and endothelium-denuded rat aorta. The maximal relaxtion rate (Emax) of endothelium-intact and endothelium-denuded rat aorta precontracted by KCl was (-79.85±2.45)%and (-85.71±2.92)%, ECso was1.87X10-5mol·L-1and1.68X10-5mol·L-1. Emax of endothelium-intact and endothelium-denuded rat aorta precontracted by NE was (-82.13±8.55)%and (-80.53±9.04)%, ECso was8.21X10-5mol· L-1and7.79X10-5mol·L-1. There was no statistical significance between endothelium-intact and endothelium-denuded rat aortas, the vasorelaxant effect of DLX was endothelium-independence.(3) The vasodilator effect of DLX was not statistically inhibited by glibendamide (Gli,10μmol· L-1) tetraethtylamine (TEA,10mmol·L)、barium chloride (BaCl2, mmol·L-1)、4-aminopyridine (4-AP,1mmol· L-1)), cyproheptadine(1μmol· L-1) and candesartan(10μmol· L-1)in KCl(30mmol· L-1)pre-contracted thoracic aortic rings.The vasodilator effect of DLX was partially inhibited by prazosin (1μmol· L-1).(4) The vasorelaxant effect of DLX (30μmol· L-1)was partially inhibited by nicardipine (1nmol· L-1)and KB-R7943(1μmol· L-1) in NE(1μmol·L-1)pre-contracted thoracic aortic rings.(5) DLX(100μmol·L-1) can significantly inhibit the contraction induced by additions of NE in Ca2+-free PSS, and the contraction induced by additions of CaCl2.(6) DLX (0.1～10μmol· L-1) relaxed the contractions induced by KCl (60mmol· L-1) in a concentration-dependent manner in renal artery and middle cerebral artery. Emaxwas (-89.57±2.61)%and (-88.61±5.64)%, EC50was2.47X10-6mol· L-1and2.97X10-6mol· L-1DLX (0.01～10μmol· L-1)relaxed the contractions induced by KCl (60mmol· L-1) in a concentration-dependent manner in coronary artery, Emax was (-81.34±3.04)%andEC5owas8.66X10-7mol·L-1.Conclusions:1.In resting state, DLX had no significant impact on tension of the rat isolated thoracic aortic ringss, renal arterial rings、, middle cerebral arterial rings and coronary arterial rings.2.DLX relaxed the contractions induced by KCl or NE in a concentration-dependent manner in rat aorta, the vasorelaxant effect was endothelium-independence, and not related to K+channels,5-HT2receptors and ATi receptors. Furthermore, it is suggested that ai-adrenoceptors and NCX may be involved in the mechanisms of DLX vasorelaxant effect.3DLX-induced vasodilatation of the thoracic aortic rings is mainly related to blocking Ca2+influx from long-lasting calcium channel and intracellular Ca2+release.4. DLX relaxed the contractions induced by KCl in a concentration-dependent manner in rat renal artery, middle cerebral artery and coronary artery.