ROLE OF CYCLIC GUANOSINE-MONOPHOSPHATE AND K+ CHANNELS AS MEDIATORS OF THE MESENTERIC VASCULAR HYPORESPONSIVENESS IN PORTAL HYPERTENSIVE RATS

The mechanisms mediating the hyporesponsiveness to vasoconstrictors in portal hypertension are not completely established, In the present st udy, we evaluated the role of cyclic guanosine monophosphate (cGMP) an d potassium channels as contributors to the presser hyporesponsiveness to methoxamine (MTX) of the mesenteric vascular bed of portal vein-li gated (PVL) hypertensive rats. In basal conditions, and compared with sham-operated control rat (SHAM) vessels, PVL preparations showed a bl unted presser response (maximum: 39.3 +/- 6.1 vs. 94.5 +/- 8.9 mm Hg), which increased by pretreatment with methylene blue (MB), a guanylate cyclase inhibitor (118.7 +/- 8.9 vs, 152.0 +/- 10.0, respectively), a nd even more with the nitric oxide (NO) synthesis inhibitor N-omega-ni tro-L-arginine (NNA) (159.9 +/- 7.4 vs. 194.1 +/- 5.7, respectively), suggesting that NO acts through cGMP-dependent and independent mechani sms. In all cases, however, the presser responses of PVL vessels were lower than those of SHAM. Pretreatment of the vessels with the potassi um channel inhibitors, tetraethylammonium (TEA), glibenclamide (GLB), or charybdotoxin (CHX), did not improve the reduced presser responses of the PVL rats, However, when the preparations were simultaneously pr etreated with MB and TEA or with NNA and TEA, the presser responses we re potentiated with respect to groups treated with MB or NNA alone, an d the differences between PVL and SHAM vessels were completely correct ed. These data suggest that both NO and potassium channels mediate the vascular hyporesponsiveness to methoxamine of the PVL mesenteric vasc ulature. Our results also disclose that NO blunts the presser response of the PVL vessels by a dual mechanism of action, through activation of potassium channels and through the formation of cGMP. Finally the N O-independent component mediated by potassium channels can be only see n when the main cGMP-NO component is inactivated. In conclusion, both cGMP and potassium channels mediate the vascular hyporesponsiveness to MTX of the mesenteric bed of portal hypertensive rats.