NITRIC-OXIDE-DEPENDENT AND NITRIC-OXIDE-INDEPENDENT VASCULAR HYPOREACTIVITY IN MESENTERIC-ARTERIES OF PORTAL HYPERTENSIVE RATS

1 Increased production of nitric oxide (NO) has been suggested to unde rlie both the vascular hyporeactivity to vasoconstrictors and the spla nchnic vasodilatation seen in portal hypertension. This study assessed the role of NO in the vasoconstrictor hyporeactivity of portal vein-l igated (PVL) rats in isolated and in situ perfused mesenteric arterial beds. 2 Isolated perfused mesenteric arteries of PVL rats were signif icantly less reactive to noradrenaline (NA), methoxamine (METH), argin ine vasopressin (AVP) and endothelin-1 (ET-1) than those from sham-ope rated (Sham) rats. 3 Blockade of NO synthesis with N-G-nitro-L-arginin e methyl ester (L-NAME, 100 mu M) in isolated perfused mesenteric arte ries 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. C yclo-oxygenase inhibition with indomethacin (5 mu M) likewise did not restore reactivity to METH of isolated perfused mesenteric arteries of PVL rats. 4 The hyporeactivity to METH seen in isolated perfused mese nteric 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 mu M) was combined with AVP (20 n M) or ET-1 (1 nM), respectively, reactivity to METH of isolated perfus ed mesenteric arteries of PVL rats was restored to the level seen in S ham rats. These effects of AVP and ET-1 were not mimicked by precontra cting the vessels with 5-hydroxytryptamine (5 mu M). 5 The differentia l effects of L-NAME and AVP on the hyporesponsiveness to methoxamine a nd AVP were corroborated by experiments performed with the in situ per fused mesenteric vascular bed preparation. 6 These data indicate that both NO-dependent and NO-independent mechanisms are involved in the va soconstrictor hyporesponsiveness of mesenteric arteries from portal hy pertensive 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 i nhibit the NO-independent mechanism of vascular hyporeactivity, since the hyporesponsiveness to METH was reduced in the presence of AVP or E T-1 and abolished by the combination of these peptides with L-NAME.