Vasodilator effects of KRN2391, levcromakalim and 3-morpholino-sydnonimin in human pial and omental arteries

Abstract.

The vasodilator action of KRN2391 (10 nM–10 µM), a combined ATP-sensitive potassium channel (K_ATP) opener and organic nitrate, was investigated in human pial and omental arteries. Previous animal studies have suggested that opening of K_ATP and activation of guanylate cyclase may contribute to varying extents to the vasodilator action of KRN2391, depending on the origin and size of the vascular preparation. Vasodilator responses were studied in isolated vascular segments (diameter 0.4–0.8 mm) pre-contracted with endothelin-1 in the presence or absence of glibenclamide (inhibitor of K_ATP), LY83583 (inhibitor of guanylate cyclase), zaprinast (inhibitor of cyclic GMP phosphodiesterase V) and N ^G-nitro-l-arginine (inhibitor of nitric oxide synthase). KRN2391 induced concentration-dependent vasodilator responses of similar potency in arteries from the two vascular regions. While glibenclamide (1 µM) had no effect in omental arteries, this compound produced a tenfold rightwards shift of the concentration-response curve for KRN2391 in pial arteries without affecting the maximal response (E _max). LY83583 (10 µM), zaprinast (10 µM) and N ^G-nitro-l-arginine (0.1 mM) all failed to affect the vasodilator responses to KRN2391 significantly in either artery. However, in ring segments of rat aorta LY83583 displaced the concentration-response curve for the nitric oxide donor 3-morpholino-sydnonimin (10 nM–0.1 mM) to the right, while zaprinast produced a leftwards shift. The prototype K_ATP opener levcromakalim (0.01–10 µM) elicited a larger relaxation in pial (E _max 80±6%) than in omental (E _max 47±13%) arteries, whereas 3-morpholino-sydnonimin produced a smaller relaxation in pial (E _max 50±18%) than in omental (E _max 90±4%) arteries. These results suggest that the vasodilator response to KRN2391 is mediated by K_ATP in human cerebral arteries, but dependent on neither K_ATP nor guanylate cyclase in human omental arteries. The results with levcromakalim and 3-morpholino-sydnonimin indicate that opening of K_ATP may be a more effective mechanism of vasodilatation in pial than in omental arteries from man, whereas the reverse appears to be true for guanylate cyclase activation.