Effect of milrinone on small mesenteric artery vasoconstriction: role of K+ channels

We examined whether milrinone-mediated attenuation of small mesenteric arte ry vasoconstriction results predominantly from the activation of vascular s mooth muscle K+ channels. Resistance arteries (similar to 150 mu m) were di ssected from rat mesentery and were mounted on a wire myograph. Isometric f orce development in response to increasing concentrations of norepinephrine (NE) was monitored before and after treatment with the type 3 phosphodiest erase inhibitor milrinone. Milrinone significantly reduced NE-induced vasoc onstriction, attenuating both NE sensitivity and maximal tension generation . Inhibition of ATP-sensitive K+ channels or voltage-gated K+ channels did not prevent the milrinone-induced attenuation of NE responses. Blockade of inwardly rectifying K+ channels or Ca2+-sensitive K+ channels prevented the milrinone-mediated reduction in NE sensitivity, but this effect was appare ntly due to direct enhancement of vasoconstrictor responsiveness rather tha n interference with the mechanism of milrinone action. In addition, milrino ne elicited substantial relaxation in vessels preconstricted with 100 mM KC l. This effect was mimicked by the adenylyl cyclase activator forskolin and was reversed by the Rp diastereomer of cAMP, which is a cAMP-dependent pro tein kinase (PKA) inhibitor. Our results indicate that cAMP/PKA-mediated im pairment of vasoconstriction may occur without the contribution of K+ chann el regulation.