title: Obligatory role of NO in glutamate-dependent hyperemia evoked from cerebellar parallel fibers.
abstract: Electrical stimulation of cerebellar parallel fibers (PF) increases cerebellar blood flow (BFcrb), a response that is attenuated by glutamate receptor antagonists and NO synthase (NOS) inhibitors. We investigated whether administration of NO donors could counteract attenuation by NOS inhibitors of vasodilation produced by PF stimulation. In halothane-anesthetized rats the cerebellar cortex was exposed and superfused with Ringer solution. PF were stimulated with microelectrodes (100 microA, 30 Hz), and BFcrb was recorded by a laser-Doppler probe. During Ringer superfusion, PF stimulation increased BFcrb by 56 +/- 7% and hypercapnia by 72 +/- 5% (n = 5). Superfusion with the nonselective NOS inhibitor N-nitro-L-arginine (L-NNA, 1 mM) reduced resting BFcrb and attenuated the response to PF stimulation (-47 +/- 5%) and hypercapnia (-46 +/- 7%; PCO2 = 50-60 mmHg). After L-NNA, superfusion with the NO donors 3-morpholinosydnonimine (100 microM, n = 5) or S-nitroso-N-acetyl-penicillamine (5 microM, n = 5) reestablished resting BFcrb (P > 0.05 vs. before L-NNA) and reversed L-NNA-induced attenuation of the response to hypercapnia (P > 0.05 vs. before L-NNA) but not PF stimulation (P > 0.05 vs. after L-NNA). Similar results were obtained when NOS activity was inhibited with the inhibitor of neuronal NOS 7-nitroindazole (50 mg/kg i.p.). Like NO donors, the guanosine 3',5'-cyclic monophosphate analog 8-bromoguanosine 3',5'-cyclic monophosphate (n = 5), administered after L-NNA, restored resting BFcrb and counteracted inhibition of the response to hypercapnia but not PF stimulation. In contrast to NO donors and 8-bromoguanosine 3',5'-cyclic monophosphate, the NO-independent vasodilator papaverine (100 microM, n = 5) had no effect on attenuation of responses to PF stimulation or hypercapnia. Thus NO donors are unable to reverse the effect of NOS inhibition on vasodilation produced by PF stimulation. The data support the hypothesis that the vascular response to PF stimulation, at variance with hypercapnia, requires NOS activation and NO production. Thus NO plays an obligatory role in vasodilation produced by increased functional activity in cerebellar cortex.
authors.affiliation: Laboratory of Cerebrovascular Biology and Stroke, University of Minnesota Medical School, Minneapolis 55455, USA.
authors.forename: G
authors.initials: G
authors.lastname: Yang
authors.forename: C
authors.initials: C
authors.lastname: Iadecola
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002245:Carbon Dioxide / Q000097:blood; D002531:Cerebellum / Q000098:blood supply*; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid; D006940:Hyperemia / Q000139:chemically induced / Q000503:physiopathology*; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology*; D010100:Oxygen / Q000097:blood; D010208:Papaverine / Q000494:pharmacology; D010313:Partial Pressure; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D026423:S-Nitroso-N-Acetylpenicillamine; D014664:Vasodilation / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D007191:Indazoles; D002245:Carbon Dioxide; D019335:Nitroarginine; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D018698:Glutamic Acid; C002385:linsidomine; D026423:S-Nitroso-N-Acetylpenicillamine; D008981:Molsidomine; D010208:Papaverine; D019001:Nitric Oxide Synthase; D010396:Penicillamine; D006152:Cyclic GMP; D010100:Oxygen; C080122:7-nitroindazole