Vascular contractile response and signal transduction in endothelium-denuded aorta from cirrhotic rats

Aim: 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 (IP₃) 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 [³H] IP₃ 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/AlCl₃, and phorbol esterdibutyrate (PdBU) stimulation. Compared to the corresponding control groups, the degree of the increment of [³H] IP₃ formation from basal level was also decreased with phenylephrine and AVP stimulation, but was normal with U-46619 and NaF/AlCl₃ 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. Conclusion: 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 IP₃ productions may be intact in cirrhotic rats with portal hypertension.