Enhanced Release of Nitric Oxide in Response to Changes in Flow and Shear Stress in the Superior Mesenteric Arteries of Portal Hypertensive Rats

Abstract

Increased nitric oxide (NO) release has been implicated in the pathogenesis of the hyperdynamic circulation in portal hypertension. NOS 3 (eNOS) causes NO release from the endothelium in response to physical stimuli, such as increased blood flow and shear stress. We evaluated the functional activity of the endothelium in the superior mesenteric arterial bed of portal hypertensive rats through direct measurement of NO metabolites (NO x ) during changes in flow and shear stress. The in vitro perfusion system (McGregor) was used in sham and portal vein-ligated (PVL) rats. Shear stress was applied gradually to superior mesenteric arterial beds by increasing the perfusion rate. Flow studies were performed serially before and after incubation with either Krebs solution alone or with the NO-inhibitor, N G -monomethyl-L-arginine (L-NMMA). NO x concentrations in the perfusate were measured using chemiluminescence. The slope of NO x release versus flow-induced shear stress was calculated. Before L-NMMA administration, NO x concentrations and release of NO in PVL rats were significantly elevated in comparison with sham rats at flow rates of 32, 40, and 48 mL/min. The slope of NO x production versus shear stress index was significantly higher in PVL than in sham rats. After L-NMMA incubation, the decrease in slope was significantly larger in PVL rats. This study provides direct evidences of an increased NO synthesis by the superior mesenteric arterial vascular endothelium of PVL animals in response to shear stress. The increased NO output in response to shear stress suggests an adaptative mechanism developed by the vascular endothelial cells in response to a chronic increase in flow-mediated shear stress. (HEPATOLOGY 1998;28:1467-1473.)Patients with cirrhosis 1 and animals with portal hypertension 2 are characterized by having a hyperdynamic circulation, especially in the splanchnic vessels. Splanchnic vasodilatation may arise from an excess production of vasodilatory substances, 3 which in turn leads to hyporeactivity to endogenous vasoconstrictors. 4 In studies using systemic administration of stereospecific nitric oxide synthase (NOS) inhibitors, increased synthesis of NO has been implicated in the pathogenesis of the hyperdynamic circulation in portal hypertension. 5,6 In clinical studies in patients with cirrhosis, increased NO production has been suggested by measurement of increased concentrations of NO metabolites in serum and urine. 7,8 Normally, NOS present in the vascular endothelium (NOS 3 or eNOS) produces NO transiently in response to physical stimuli, such as an increased blood flow and shear stress. 9,10 This is a unique function of eNOS. Flow-mediated vasodilatation is proportional to the shear stress induced by blood flow and independent of changes in luminal pressure. It is now recognized that this constitutive mechanism requires the integrity of the endothelium and in most conduit vessels is caused by the release of NO. This is the normal mechanism that mediates vascular dilatation secondary to increases...

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