title: Nitric oxide from perivascular nerves modulates cerebral arterial pH reactivity.
abstract: In the isolated rat middle cerebral artery (MCA) we investigated the role of nitric oxide (NO)/cGMP in the vasodilatory response to extraluminal acidosis. Acidosis increased vessel diameter from 140 +/- 27 microm (pH 7.4) to 187 +/- 30 microm (pH 7.0, P < 0.01). NO synthase (NOS) inhibition by N(omega)-nitro-L-arginine (L-NNA, 10 microM) reduced baseline diameter (103 +/- 20 microm, P < 0.01) and attenuated response to acidosis (9 +/- 8 microm). Application of the NO-donors 3-morpholinosydnonimine (1 microM) or S-nitroso-N-acetylpenicillamine (1 microM), or of 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP, 100 microM) reestablished pre-L-NNA diameter at pH 7.4 and reversed L-NNA-induced attenuation of the vessel response to acidosis. Restoration of pre-L-NNA diameter (pH 7.4) by papaverine (20 microM) or nimodipine (30 nM) had no effect on the attenuated response to acidosis. Guanylyl cyclase inhibition with 1H-[1,2,4]oxadiazolo[4,3-a]-quinoxalin-1-one (5 microM) or NOS-inhibition with 7-nitroindazole (7-NI, 100 microM) reduced baseline vessel diameter (109 +/- 8 or 127 +/- 11 microm, respectively) and vasodilation to acidosis, and restoration of baseline diameter with 8-BrcGMP (30 microM) completely restored dilation to pH 7.0. Chronic denervation of NOS-containing perivascular nerves in vivo 14 days before artery isolation significantly reduced pH-dependent reactivity in vitro (diameter increase sham: 48 +/- 14 microm, denervated: 14 +/- 8 microm), and 8-BrcGMP (30 microM) restored dilation to pH 7.0 (denervated: 49 +/- 31 microm). Removal of the endothelium did not change vasodilation to acidosis. We conclude that NO, produced by neuronal NOS of perivascular nerves, is a modulator in the pH-dependent vasoreactivity.
authors.affiliation: Department of Experimental Neurology, Humboldt University, Charité Hospital, 10098 Berlin, Germany. ute.lindauer@charite.de
authors.forename: U
authors.initials: U
authors.lastname: Lindauer
authors.forename: A
authors.initials: A
authors.lastname: Kunz
authors.forename: S
authors.initials: S
authors.lastname: Schuh-Hofer
authors.forename: J
authors.initials: J
authors.lastname: Vogt
authors.forename: J P
authors.initials: JP
authors.lastname: Dreier
authors.forename: U
authors.initials: U
authors.lastname: Dirnagl
mesh_terms: D000138:Acidosis / Q000378:metabolism; D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism / Q000494:pharmacology; D003714:Denervation; D004730:Endothelium, Vascular / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006851:Hydrochloric Acid / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D020768:Middle Cerebral Artery / Q000187:drug effects / Q000294:innervation* / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D014654:Vascular Patency / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D014665:Vasodilator Agents; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; C496322:Nos1 protein, rat; C496316:Nos3 protein, rat; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D006851:Hydrochloric Acid