Vascular contractile response and signal transduction in endothelium-denuded aorta from cirrhotic rats.
OBJECTIVE
The mechanism of decreased vascular reactivity to vasoconstrictors in portal hypertension is still unclear. In addition to nitric oxide, defects in post-receptor signal transduction pathway have been suggested to play a role. However, substantial evidences observed equivocal changes of vascular reactivity following different agonists that challenged the hypothesis of the post-receptor defect. The current study was to evaluate the vascular reactivity to different agonists and the inositol trisphosphate (IP(3)) changes in signal transduction cascade from cirrhotic rats with portal hypertension.


METHODS
The endothelial denuded aortic rings from cirrhotic and sham-operated rats were obtained for ex vivo tension study and measurement of the corresponding [(3)H] IP(3) formation following different receptor and nonreceptor-mediated agonists' stimulation. Additionally, iNOS protein expression was measured in thoracic aorta. The contractile response curves to phenylephrine were performed in endothelial denuded aortic rings with and without preincubation with a specific iNOS inhibitor (L-N(6)-(1-iminoethyl)-lysine, L-NIL).


RESULTS
In endothelial denuded aortic rings of cirrhotic rats, the vascular responses were reduced with phenylephrine and arginine vasopressin (AVP) stimulation but were normal with U-46619, NaF/AlCl(3), and phorbol esterdibutyrate (PdBU) stimulation. Compared to the corresponding control groups, the degree of the increment of [(3)H] IP(3) formation from basal level was also decreased with phenylephrine and AVP stimulation, but was normal with U-46619 and NaF/AlCl(3) stimulation. The preincubation with L-NIL did not modify the hyporesponsiveness to phenylephrine. Additionally, the iNOS protein expression in thoracic aorta was not different in cirrhotic and sham-operated rats.


CONCLUSIONS
Without the influence of nitric oxide, vascular hyporeactivity to vasoconstrictors persisted in cirrhotic rats with portal hypertension. However, the decreased vascular reactivity is an agonist-specific phenomenon. In addition, G-protein and phospholipase C pathway associated with the IP(3) productions may be intact in cirrhotic rats with portal hypertension.
Lin
Han-Chieh
HC
Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 11217, Taiwan, China. hclin1956@yahoo.com
Yang
Ying-Ying
YY
Huang
Yi-Tsau
YT
Lee
Tzung-Yan
TY
Hou
Ming-Chih
MC
Lee
Fa-Yauh
FY
Lee
Shou-Dong
SD
D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology; D006975:Hypertension, Portal / Q000503:physiopathology*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008103:Liver Cirrhosis / Q000503:physiopathology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D014661:Vasoconstriction / Q000502:physiology*
D015544:Inositol 1,4,5-Trisphosphate; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D011493:Protein Kinase C