Endothelin receptor blockade as a therapeutic strategy in ameliorating postischemic damage to the liver microcirculation

Ischemia leads to profound endothelin- (ET) related constriction of hepatic microvessels, causing disturbances in blood and oxygen supply. The aim of the study was to modulate hepatic microvascular diameters by blocking ET re ceptors to find the optimal therapeutic vessel width for reduction of ische mia-reperfusion injury. In an in vivo model (84 female Wistar rats, 250-300 g) with portal decompression by means of a splenocaval shunt, nonmothermic hepatic ischemia was induced for 30 min by crossclamping of the hepatoduod enal ligament. The ET receptor antagonist (ERA) bosentan was administered b efore induction of ischemia in different dosages [0.1. 1.0 and 10.0 mg/kg b ody weight (BW) i.v. and 10 mg/kg BW intraportally (i.p.)]. The effect on m icrocirculation was assessed by in vivo microscopy and influence on hepatoc ellular function by measurement of aspartate aminotransferase (AST) levels. Sinusoidal diameters were reduced as a result of ischemia to 76.3 +/- 7.4% compared with values received from sham-operated animals. After applicatio n of 0.1 mg/kg of bosentan, sinusoids remained constricted (89.7 +/- 9.9%, AST 255.0 +/- 12.8 U/I). Blocking ET receptors with 1 mg/kg bosantan avoide d sinusoidal constriction (99.0 +/- 8.88, p < 0.05) and led to the most eff ective reduction of AST level peak after 6 h of reperfusion (244.0 +/- 34.2 U/l vs 422.9 +/- 163.3 U/l in untreated ischemia). Bosentan (10 mg/kg i.v. ) caused an increase in sinusoidal diameter to 109.1 +/- 6.4% (AST 311.7 +/ - 33.6 U/l) and 10 mg/kg i.p. to 136.8 +/- 19.3% and even an increase in AS T levels (618.90 +/- 209.32 U/l). After intravenous application of 1 and 10 mg/kg BW bosentan the perfusion rare was significantly increased and stick ing of leukocytes in sinusoids and venules reduced (p < 0.05). In our model , diameters of sinusoids and postsinusoidal venules could be regulated grad ually. We conclude that the avoidance of constriction, but not an excessive vasodilation leads to increased perfusion rate and hence improved hepatoce llular function.