title: Mechanism of cGMP contribution to the vasodilator response to NO in rat middle cerebral arteries.
abstract: 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 Ca(2+) were also studied in MCA that were permeabilized with alpha-toxin and ionomycin. Elevations in bath Ca(2+) 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 Ca(2+)-induced vasoconstriction. 8-BrcGMP (10(-4) M) had no effect on intracellular Ca(2+) concentration ([Ca(2+)](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 Ca(2+)-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 [Ca(2+)](i).
authors.affiliation: Department of Physiology and Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Yu
authors.forename: Cheng-Wen
authors.initials: CW
authors.lastname: Sun
authors.forename: Kristopher G
authors.initials: KG
authors.lastname: Maier
authors.forename: David R
authors.initials: DR
authors.lastname: Harder
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Roman
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002463:Cell Membrane Permeability / Q000187:drug effects; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology; D015759:Ionomycin / Q000494:pharmacology; D008297:Male; D020768:Middle Cerebral Artery / Q000187:drug effects* / Q000502:physiology*; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000494:pharmacology; D010738:Type C Phospholipases / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000502:physiology*
chemical_list: D020030:Nitric Oxide Donors; D010455:Peptides; D015221:Potassium Channels; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D012701:Serotonin; D015759:Ionomycin; C064719:iberiotoxin; D010738:Type C Phospholipases; D006152:Cyclic GMP; D000109:Acetylcholine; D002118:Calcium