Nitric oxide from perivascular nerves modulates cerebral arterial pH reactivity

In the isolated rat middle cerebral artery (MCA) we investigated the role o f nitric oxide (NO)/cGMP in the vasodilatory response to extraluminal acido sis. Acidosis increased vessel diameter from 140 +/- 27 mum (pH 7.4) to 187 +/- 30 mum (pH 7.0, P < 0.01). NO synthase (NOS) inhibition by N-w-nitro-L -arginine (L-NNA, 10 muM) reduced baseline diameter (103 +/- 20 mum, P < 0. 01) and attenuated response to acidosis (9 +/- 8 mum). Application of the N O-donors 3-morpholinosydnonimine (1 muM) or S-nitroso-N-acetylpenicillamine (1 muM), or of 8-bromoguanosine 3 ' ,5 ' -cyclic monophosphate (8-BreGMP, 100 muM) reestablished pre-L-NNA diameter at pH 7.4 and reversed L-NNA-indu ced attenuation of the vessel response to acidosis. Restoration of pre-L-NN A diameter (pH 7.4) by papaverine (20 LM) or nimodipine (30 nM) had no effe ct on the attenuated response to acidosis. Guanylyl cyclase inhibition with 1H-[1,2,4]oxadiazolo[4,3-a]-quinoxalin-1-one (5 muM) or NOS-inhibition wit h 7-nitro-indazole (7-NI, 100 muM) reduced baseline vessel diameter (109 +/ - 8 or 127 +/- 11 mum, respectively) and vasodilation to acidosis, and rest oration of baseline diameter with 8-BrcGMP (30 muM) completely restored dil ation to pH 7.0. Chronic denervation of NOS-containing perivascular nerves in vivo 14 days before artery isolation significantly reduced pl-l-dependen t reactivity in vitro (diameter increase sham: 48 +/- 14 mum, denervated: 1 4 +/- 8 mum), and 8-BrcGMP (30 muM) restored dilation to pH 7.0 (denervated : 49 +/- 31 mum). Removal of the endothelium did not change vasodilation to acidosis. We conclude that NO, produced by neuronal NOS of perivascular ne rves, is a modulator in the pH-dependent vasoreactivity.