Nitric oxide-dependent and -independent vascular hyporeactivity in mesenteric arteries of portal hypertensive rats.

1. Increased production of nitric oxide (NO) has been suggested to underlie both the vascular hyporeactivity to vasoconstrictors and the splanchnic vasodilatation seen in portal hypertension. This study assessed the role of NO in the vasoconstrictor hyporeactivity of portal vein-ligated (PVL) rats in isolated and in situ perfused mesenteric arterial beds. 2. Isolated perfused mesenteric arteries of PVL rats were significantly less reactive to noradrenaline (NA), methoxamine (METH), arginine vasopressin (AVP) and endothelin-1 (ET-1) than those from sham-operated (Sham) rats. 3. Blockade of NO synthesis with NG-nitro-L-arginine methyl ester (L-NAME, 100 microM) in isolated perfused mesenteric arteries from PVL rats restored the reactivity to bolus injections of AVP and ET-1, but had little effect on the hyporeactivity to NA or METH. Cyclo-oxygenase inhibition with indomethacin (5 microM) likewise did not restore reactivity to METH of isolated perfused mesenteric arteries of PVL rats. 4. The hyporeactivity to METH seen in isolated perfused mesenteric arteries from PVL rats was reduced by low concentrations of AVP (20 nM) or ET-1 (1 nM) which per se caused only a slight increase in perfusion pressure. When L-NAME (100 microM) was combined with AVP (20 nM) or ET-1 (1 nM), respectively, reactivity to METH of isolated perfused mesenteric arteries of PVL rats was restored to the level seen in Sham rats. These effects of AVP and ET-1 were not mimicked by precontracting the vessels with 5-hydroxytryptamine (5 microM). 5. The differential effects of L-NAME and AVP on the hyporesponsiveness to methoxamine and AVP were corroborated by experiments performed with the in situ perfused mesenteric vascular bed preparation. 6. These data indicate that both NO-dependent and NO-dependent mechanisms are involved in the vasoconstrictor hyporesponsiveness of mesenteric arteries from portal hypertensive rats. The hyporeactivity to AVP and ET-1 is mediated by NO whereas the reduced responsiveness to adrenoceptor agonists appears to be predominantly NO-independent AVP and ET-1, in addition, seem to inhibit the NO-independent mechanism of vascular hyporeactivity, since the hyporesponsiveness to METH was reduced in the presence of AVP or ET-1 and abolished by the combination of these peptides with L-NAME.