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Am J Physiol Heart Circ Physiol 282: H1724-H1731, 2002. First published January 10, 2002; doi:10.1152/ajpheart.00699.2001
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Vol. 282, Issue 5, H1724-H1731, May 2002

Mechanism of cGMP contribution to the vasodilator response to NO in rat middle cerebral arteries

Ming Yu, Cheng-Wen Sun, Kristopher G. Maier, David R. Harder, and Richard J. Roman

Department of Physiology and Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

This study examined the mechanism by which cGMP contributes to the vasodilator response to nitric oxide (NO) in rat middle cerebral arteries (MCA). Administration of a NO donor, diethylaminodiazen-1-ium-1,2-dioate (DEA-NONOate), or 8-bromo-cGMP (8-BrcGMP) increased the diameter of serotonin-preconstricted MCA by 79 ± 3%. The response to DEA-NONOate, but not 8-BrcGMP, was attenuated by iberiotoxin (10-7 M) or a 80 mM high-K+ media, suggesting that activation of K+ channels contributes to the vasodilator response to NO but not 8-BrcGMP. The effects of NO and cGMP on the vasoconstrictor response to Ca2+ were also studied in MCA that were permeabilized with alpha -toxin and ionomycin. Elevations in bath Ca2+ from 10-8 to 10-5 M decreased the diameter of permeabilized MCA by 76 ± 5%. DEA-NONOate (10-6 M) and 8-BrcGMP (10-4 M) blunted this response by 60%. Inhibition of guanylyl cyclase with 1H-[1,2,4]oxadiazole[4,3-a] quinoxalin-1-one (10-5 M) blocked the inhibitory effect of the NO donor, but not 8-BrcGMP, on Ca2+-induced vasoconstriction. 8-BrcGMP (10-4 M) had no effect on intracellular Ca2+ concentration ([Ca2+]i) in control, serotonin-stimulated, or alpha -toxin- and ionomycin-permeabilized vascular smooth muscle cells isolated from the MCA. These results indicate that the vasodilator response to NO in rat MCA is mediated by activation of Ca2+-activated K+ channels via a cGMP-independent pathway and that cGMP also contributes to the vasodilator response to NO by decreasing the contractile response to elevations in [Ca2+]i.

vascular smooth muscle; calcium sensitivity; cytochrome P-450


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