title: Role of cGMP in carbon monoxide-induced cerebral vasodilation in piglets.
abstract: The hypothesis was addressed that CO-induced cerebral vasodilation requires a permissive cGMP signal that can be produced by nitric oxide (NO). Anesthetized piglets were implanted with cranial windows for measurement of pial arteriolar responses to stimuli. Pial arterioles dilated in response to isoproterenol (Iso), sodium nitroprusside (SNP), and CO or the CO-releasing molecule Mn2(CO)10 [dimanganese decacarbonyl (DMDC)]. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a soluble guanylyl cyclase inhibitor, decreased cerebrospinal fluid (CSF) cGMP and selectively inhibited dilations to SNP and DMDC without affecting the dilation to Iso. However, DMDC did not cause an increase in cortical periarachnoid CSF cGMP concentration. cGMP clamp with a threshold dilator level of 8-bromo-cGMP (10(-4) M) and ODQ restored the dilation to DMDC that had been blocked by ODQ alone. Under these conditions, cGMP was present but could not increase. Inhibition of the pial arteriolar dilation to glutamate by N-nitro-l-arginine, which blocks NO synthase, was similar to that by heme oxygenase inhibitors, which block endogenous CO production. The dilation to glutamate, similar to dilation to DMDC, was partially restored by 8-bromo-cGMP and completely restored by SNP (5 x 10(-7) M). These data suggest that the permissive role of NO in CO- and glutamate-induced vasodilation involves maintaining the minimum necessary cellular level of cGMP to allow CO to cause dilation independently of increasing cGMP.
authors.affiliation: Department of Physiology, University of Tennessee, 894 Union Ave., Rm. 426, Memphis, TN 38163, USA.
authors.forename: Padmaja
authors.initials: P
authors.lastname: Koneru
authors.forename: Charles W
authors.initials: CW
authors.lastname: Leffler
mesh_terms: D000818:Animals; D001160:Arterioles / Q000187:drug effects; D002248:Carbon Monoxide / Q000494:pharmacology*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D017895:Manganese Compounds / Q000008:administration & dosage / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019335:Nitroarginine / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D013552:Swine; D014664:Vasodilation / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D017895:Manganese Compounds; D020030:Nitric Oxide Donors; D014665:Vasodilator Agents; D009599:Nitroprusside; D019335:Nitroarginine; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D018698:Glutamic Acid; D002248:Carbon Monoxide; C481647:dimanganese decacarbonyl; D006152:Cyclic GMP