ENDOTHELIAL CALCIUM-CALMODULIN DEPENDENT NITRIC-OXIDE SYNTHASE IN THEIN-VITRO VASCULAR HYPOREACTIVITY OF PORTAL HYPERTENSIVE RATS

Background/Aims: Increased nitric oxide production has been implicated in impaired vascular responsiveness to vasoconstrictors in portal hyp ertension, However, there is no firm evidence concerning the involved nitric oxide synthase isoform, The present study investigated the poss ible contribution of one nitric oxide synthase isoform, the endothelia l constitutive Ca2+-calmodulin dependent, in the overproduction of nit ric oxide in portal hypertension. Methods: Vascular responses to norep inephrine and acetylcholine were evaluated in isolated thoracic aortic rings from normal and portal vein stenosed rats. Results: An impaired concentration-dependent contraction to norepinephrine was observed in intact rings from portal hypertensive rats compared to controls. The hyporeactivity to norepinephrine was reversed after endothelium denuda tion, the inhibition of nitric oxide synthase with L-NOARG or the inhi bition of calmodulin with W-7, but not after pre-incubation with indom ethacin, Stimulation of intact rings with norepinephrine after the inh ibition of calmodulin with calmidazolium was followed by a decreased v ascular response in vessels from normal rats but not in those from por tal hypertensive rats, Stimulation of intact rings with norepinephrine in a Ca2+-free medium was followed by a decreased vascular response i n vessels from both portal hypertensive and normal rats, No difference in vasoconstrictive responses was observed between the two groups aft er calmidazolium or in a Ca2+-free medium. Relaxation induced by acety lcholine in norepinephrine-precontracted rings was more marked in ring s from portal hypertensive rats than in controls, No differences in th e vasodilator responses were observed after relaxations had been inhib ited by the removal of the endothelium, pre-incubation with L-NOARG, i ndomethacin, W-7 or calmidazolium and in a Ca2+-free medium, Conclusio ns: This study demonstrates the involvement of the endothelial constit utive Ca2+-calmodulin dependent nitric oxide synthase isoform in the o verproduction of nitric oxide in portal hypertension.