Diabetes diminishes the portal-systemic collateral vascular response to vasopressin via vasopressin receptor and G α proteins down-regulation in cirrhotic rats

Jing-Yi LEE1, Teh-Ia HUO1,4, Sun-Sang WANG2,5, Hui-Chun HUANG2,4, Fa-Yauh LEE2,4, Han-Chieh LIN2,4, Chiao-Lin CHUANG2,3, Shou-Dong LEE2,6. 1National Yang-Ming University, nstitute of Pharmacology, 11221, Taiwan, 2National Yang-Ming University, Faculty of Medicine, 11221, Taiwan, 3Taipei Veterans General Hospital, Division of General Medicine, 11217, Taiwan, 4Taipei Veterans General Hospital, Division of Gastroenterology, 11217, Taiwan, 5Taipei Veterans General Hospital, Department of Medical Affair and Planning, 11217, Taiwan, 6Cheng Hsin General Hospital, Division of Gastroenterology, 11217, Taiwan

Liver cirrhosis may lead to portal-systemic shunting formation and gastroesophageal bleeding. The hemostatic effect is influenced by the collateral vasoresponse to vasoconstrictors. Cirrhosis is associated with glucose intolerance, but whether the vasoresponse is influenced remains unexplored. This study explored the impact of diabetes or glucose application on the portal-systemic collateral vascular responses to arginine vasopressin (AVP; 10-10-10-7 M) in cirrhosis. Spraque-Dawley rats with cirrhosis received vehicle (BDL) or 60 mg/kg streptozotocin (diabetic, BDL/STZ). The in situ collateral perfusion were done after hemodynamic measurements: BDL groups perfused with Krebs solution (vehicle), D-glucose (45 mM); BDL/STZ groups perfused with Krebs solution, D-glucose or D-glucose and NaF (10 mM). Splenorenal shunt vasopressin receptors and Gα proteins mRNA expressions were evaluated. STZ injection decreased the body weight (324±8 vs. 260±11, P<0.01) and survival rate (87% vs. 48.9%, P=0.0019) of cirrhotic rats. The collateral perfusion pressure changes to AVP were lower in STZ-injected groups, which could be reversed by a G protein activator, NaF. The V2 receptor and Gα proteins mRNA expressions of splenorenal shunt were down-regulated in BDL/STZ rats compared to BDL rats (0.000037±0.000010 vs. 0.000152±0.000038, P=0.023). Compared to BDL rats, mRNA expressions of Gα q and Gα 11 proteins were significantly decreased in the BDL/STZ rats (Gα q/β-actin: 0.01788±0.00260 vs. 0.01102±0.00118, P=0.021; Gα 11/β-actin: 0.01051±0.00147 vs. 0.00666±0.00092, P=0.045). The Gα q and Gα 11 mRNA expressions were furthermore correlated with the maximal perfusion pressure changes to AVP (P =0.002, R=0.550 and P=0.043, R=0.379). In conclusion, diabetes diminished the portal-systemic collateral vascular response to AVP in rats with BDL-induced cirrhosis, probably related to V2 receptor up-regulation and Gα proteins down-regulation.