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. 2005 Apr 21;11(15):2306-12.
doi: 10.3748/wjg.v11.i15.2306.

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

Han-Chieh Lin  1 , Ying-Ying Yang, Yi-Tsau Huang, Tzung-Yan Lee, Ming-Chih Hou, Fa-Yauh Lee, Shou-Dong Lee
Affiliations

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

Han-Chieh Lin et al. World J Gastroenterol. .

Abstract

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 (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.

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 IP(3) productions may be intact in cirrhotic rats with portal hypertension.

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Figures

Figure 1
Figure 1
Maximum cumulative concentration-response curves to (A) phenylephrine (PEP) (10-10 to 10-4 mol/L), (B) AVP (10-10 to 10-4 mol/L) in thoracic aorta from CBL (◆) and sham (□) rats. aP<0.05 vs sham rats (n = 12 in each group with different agonist stimulation). Sham: sham-operated rats; CBL: common bile duct-ligated rats.
Figure 2
Figure 2
Maximum cumulative concentration-response curves to (A) synthetic TXA2 analog U-46619 (10-9 to 10-5 mol/L), (B) receptor-independent G-protein stimulus NaF (10-3-1 mol/L)/AlCl3 (30 μmol/L), (C) direct activation of protein kinase C by PdBU (10-8 to 3×10-5 mol/L) in thoracic aorta from CBL (◆) and sham-operated (□) rats, n = 10 in each group with different agonist stimulation.
Figure 3
Figure 3
(A) Phenylephrine (PEP) (10-7 to 10-5 mol/L) and (B) AVP (10-7 to 10-5 mol/L)-induced [3H] IP3 formation in the aortic ring from CBL (black bars) and sham (white bars) rats. [3H] IP3 formation was expressed as the percentage of counts (cpm) per minute in the presence of agonist divided by the counts without agonist (basal formation). The data are expressed as mean±SE. aP<0.05 vs sham rats, n = 8 in each group with different agonist stimulation. Sham: sham-operated rats; CBL: common bile duct-ligated rats.
Figure 4
Figure 4
(A) U-46619, a synthetic TXA2 analog (10-7 and 10-6 mol/L), (B) NaF/AlCl3 (0.1 and 1 mol/L)-induced [3H] IP3 formation in the aortic ring from CBL (black bars) and sham (white bars) rats. [3H] IP3 formation was expressed as the percentage of counts (cpm) per minute in the presence of agonist divided by the counts without agonist (basal formation). The data are expressed as mean±SE, n = 8 in each group with different agonist stimulation.
Figure 5
Figure 5
(A) Maximum cumulative concentration-response curves to phenylephrine (PEP) (10-10 to 10-4 mol/L) in thoracic aorta from CBL (◆) and sham (□) rats with and without preincubation with L-NIL (L-N(6)-(1-iminoethyl)-lysine, a selective iNOS inhibitor). n = 10 in each group with different agonist stimulation. CBL: common bile duct-ligated rats; sham: sham-operated rats. (B) Western blot analysis of inducible nitric oxide synthase (iNOS) protein expression from thoracic aorta in CDL and sham-operated rats. Lanes A and B: CBL rats; lanes C and D: sham rats.
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