Vasodilator effects of KRN2391, levcromakalim and 3-morpholino-sydnonimin in human pial and omental arteries.
The vasodilator action of KRN2391 (10 nM-10 microM), a combined ATP-sensitive potassium channel (KATP) opener and organic nitrate, was investigated in human pial and omental arteries. Previous animal studies have suggested that opening of KATP 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 KATP), LY83583 (inhibitor of guanylate cyclase), zaprinast (inhibitor of cyclic GMP phosphodiesterase V) and NG-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 microM) 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 (Emax). LY83583 (10 microM), zaprinast (10 microM) and NG-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 KATP opener levcromakalim (0.01-10 microM) elicited a larger relaxation in pial (Emax 80+/-6%) than in omental (Emax 47+/-13%) arteries, whereas 3-morpholino-sydnonimin produced a smaller relaxation in pial (Emax 50+/-18%) than in omental (Emax 90+/-4%) arteries. These results suggest that the vasodilator response to KRN2391 is mediated by KATP in human cerebral arteries, but dependent on neither KATP nor guanylate cyclase in human omental arteries. The results with levcromakalim and 3-morpholino-sydnonimin indicate that opening of KATP 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.
Department of Clinical Pharmacology, Institute of Laboratory Medicine, Lund University Hospital, Sweden.
J
J
Petersson
T
T
Ryman
E D
ED
Högestätt
D018528:ATP-Binding Cassette Transporters; D000368:Aged; D001158:Arteries / Q000187:drug effects; D019806:Cromakalim / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006801:Humans; D066298:In Vitro Techniques; D054086:KATP Channels; D008875:Middle Aged; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D009852:Omentum / Q000098:blood supply; D010841:Pia Mater / Q000098:blood supply; D015221:Potassium Channels / Q000187:drug effects; D024661:Potassium Channels, Inwardly Rectifying; D011725:Pyridines / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D018528:ATP-Binding Cassette Transporters; D004791:Enzyme Inhibitors; D054086:KATP Channels; D020030:Nitric Oxide Donors; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011725:Pyridines; D014665:Vasodilator Agents; C092520:uK-ATP-1 potassium channel; D019806:Cromakalim; C070492:N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide methanesulfonate; C002385:linsidomine; D008981:Molsidomine; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D006162:Guanylate Cyclase