The mechanisms mediating the hyporesponsiveness to vasoconstrictors in portal hypertension are not completely established. In the present study, we evaluated the role of cyclic guanosine monophosphate (cGMP) and potassium channels as contributors to the pressor hyporesponsiveness to methoxamine (MTX) of the mesenteric vascular bed of portal vein-ligated (PVL) hypertensive rats. In basal conditions, and compared with sham-operated control rat (SHAM) vessels PVL preparations showed a blunted pressor 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), and even more with the nitric oxide (NO) synthesis inhibitor Nω-nitro-L-arginine (NNA) 159.9 ± 7.4 vs. 194.1 ± 5.7, respectively), suggesting that NO acts through cGMP-dependent and independent mechanisms. In all cases, however, the pressor responses of PVL vessels were lower than those of SHAM. Pretreatment of the vessels with the potassium channel inhibitors, tetraethylammonium (TEA), glibenclamide (GLB), or charybdotoxin (CHX), did not improve the reduced pressor responses of the PVL rats. However, when the preparations were simultaneously pretreated with MB and TEA or with NNA and TEA, the pressor responses were potentiated with respect to groups treated with MB or NNA alone, and the differences between PVL and SHAM vessels were completely corrected. These data suggest that both NO and potassium channels mediate the vascular hyporesponsiveness to methoxamine of the PVL mesenteric vasculature. Our results also disclose that NO blunts the pressor response of the PVL vessels by a dual mechanism of action, through activation of potassium channels and through the formation of cGMP. Finally, the NO-independent component mediated by potassium channels can be only seen 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.
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