In studies of liver disease, the prehepatic portal vein ligated portal hypertensive rat is a widely used model of cirrhosis in which shunts develop consistently. Shunts develop to increased portal pressure. A hyperdynamic circulation then develops (increased cardiac output, increased splanchnic blood flow) resulting in increased portal venous inflow (Groszmann et al., 1982). Vascular responsiveness of isolated blood vessels can be altered by portal hypertension, as least in the rat (Connolly et al., 1999). We have now examined the equivalent mouse model, and how deletion of inducible (NOS-2) or endothelial nitric oxide synthase (NOS-3) affects contractions to vasoconstrictors in aorta and mesenteric artery from sham mice and portal vein ligated portal hypertensive (PH) mice.

Mice were anaesthetised with ether and the portal vein was partially ligated employing a 25 gauge needle, or the animal was sham operated. Mouse aorta or mesenteric artery was set up in small vessel myographs at 90% of vessel diameter at 100 mmHg. Vessels were contracted with increasing concentrations of KCl. After recovery, a concentration-response curve to phenylephrine was obtained followed by one to acetylcholine.

In aorta, although deletion of NOS-3 significantly increased the maximum response to phenylephrine when comparing sham animals (wild-type: 1.62±0.22 mN; NOS-2-KO: 3.63±0.65 mN; NOS-3-KO: 9.06±0.81 mN; n=6-9; P<0.001), there were no differences between sham or portal hypertensive animals within groups in the potency or maximum response to phenylephrine.

In mesenteric artery, deletion of especially NOS-3 altered vascular responsiveness when comparing sham animals. However, in mesenteric artery, although no differences were found between wild-type sham and portal hypertensive mice in terms of contractions to KCl or phenylephrine, differences occurred in NOS-2-KO mice. In mesenteric artery from NOS-2-KO mice, the potency of phenylephrine, but not KCl, was reduced, without change in maximum response, in portal hypertensive animals as compared to sham operated (pD2 values of 5.14±0.12 and 5.73±0.10, n=5-6, P<0.01). In mesenteric artery from NOS-3-KO mice, there were no significant changes in contractions to KCl or phenylephrine in portal hypertensive animals as compared to sham operated.

In summary, portal hypertension in the wild-type mouse does not modify the responsiveness of isolated aorta or mesenteric artery to alpha1-adrenoceptor agonists or KCl. However, in NOS-2-KO mice the vascular responsiveness of mesenteric artery, but not aorta, was altered by the induction of portal hypertension. This suggests that NOS-2 is involved in the cardiovascular adaptation to portal hypertension.

Connolly, C. et al. (1999). Clinical Science 96, 41-47.
Groszmann RJ et al. (1982). Am. J. Physiol. 242, G156-160.

Supported by the Health Research Board (Ireland).