Role of nitric oxide synthase and cyclooxygenase in hyperdynamic splanchnic circulation of portal hypertension.
BACKGROUND
Nitric oxide (NO) and prostacyclin (PGI2) are both powerful vasoactive substances correlated with the hyperhemodynamics of portal hypertension (PHT), a common syndrome characterized by a pathological increase in portal venous pressure. The purpose of the present study was to evaluate the possible interaction between these two endothelial vasodilators, together with their respective roles in the hyperdynamic splanchnic circulation of PHT.


METHODS
Ninety-six male Sprague-Dawley rats were randomly divided into three groups: intrahepatic portal hypertension (IHPH) induced by injection of CCl4 (n=31), prehepatic portal hypertension (PHPH) induced by partial stenosis of the portal vein (n=33), and sham-operated controls (SO) (n=32). Animals of each group received indomethacin (INDO), a cyclooxygenase (COX) inhibitor, either short-term (7 days) or long-term (15 days), with saline as control. Free portal pressure (FPP), together with the concentration of NO and PGI2 in serum were measured. The activity of constitutive nitric oxide synthase (cNOS) and inducible nitric oxide synthase (iNOS) in the abdominal aorta and small intestine were determined by spectrophotometry. RT-PCR was performed to measure the levels of cNOS and iNOS mRNA in the arteries and small intestines.


RESULTS
Compared with SO rats, the concentrations of NO and PGI2 in PHT rats were elevated, which were consistent with the increased FPP (P<0.05). Although administration of INDO persistently decreased the concentration of PGI2 in serum (P<0.05), the long-term INDO-treated IHPH and PHPH groups had restored splanchnic hyperdynamic circulation, demonstrated by the enhanced FPP (P<0.05). Furthermore, the changes of dynamic circulatory state in both IHPH and PHPH rats were concomitant with the expression and activity of iNOS and the concentration of NO (P<0.05). Although the expression and activity of cNOS in abdominal aorta of PHT rats were higher than in SO rats (P<0.05), there was no difference in small intestinal tissues between PHT and SO rats (P>0.05). Moreover, the changes of iNOS activity and mRNA expression were more marked than cNOS in PHT rats, and there was no difference in expression and activity of cNOS between PHT rats treated by short- and long-term INDO (P>0.05).


CONCLUSIONS
iNOS plays an important role in the hemodynamic abnormalities of PHT induced by overproduction of NO. There is a possible interaction between PGI2 and NO in hyperhemodynamics of PHT, but PGI2 may not be a mediator in the formation and development of the hyperdynamic circulatory state in PHT rats.
Department of General Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.
Jia
J
Xu
Hui
H
Cao
Hua
H
Liu
Zhi-Yong
ZY
Wu
D000818:Animals; D001012:Aorta, Abdominal / Q000201:enzymology* / Q000503:physiopathology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D011464:Epoprostenol / Q000097:blood; D006975:Hypertension, Portal / Q000201:enzymology* / Q000503:physiopathology; D007213:Indomethacin / Q000494:pharmacology; D007421:Intestine, Small / Q000201:enzymology* / Q000503:physiopathology; D008297:Male; D009569:Nitric Oxide / Q000097:blood; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D017082:Portal Pressure; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013152:Splanchnic Circulation / Q000187:drug effects; D013997:Time Factors
D016861:Cyclooxygenase Inhibitors; D012333:RNA, Messenger; D009569:Nitric Oxide; D011464:Epoprostenol; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin