Neuronal NOS-cGMP-dependent ACh-induced relaxation in pial arterioles of endothelial NOS knockout mice.
We evaluated the effects of superfusing 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), eNOS null (B) an inhibitor of soluble guanylyl cyclase, and 7-nitroindazole sodium (7-NI), a selective neuronal nitric oxide synthase (nNOS) inhibitor, on the acetylcholine (ACh) response in endothelial NOS (eNOS) null mice. Pial arteriolar diameter was measured by intravital microscopy through a closed cranial window under alpha-chloralose anesthesia. NOS activity was measured by [3H]arginine-to-[3H]citrulline conversion in subjacent cortex in vitro. The density and distribution of muscarinic receptors in the brain were determined by quantitative [3H]quinuclidinyl benzilate autoradiography and did not differ between the eNOS mutants and wild-type mice. ACh superfusion (1 and 10 microM) dose dependently dilated pial arterioles in eNOS null and wild-type mice. ODQ (10 microM) attenuated ACh-induced dilation in both eNOS mutants (41% decrease at 10 microM ACh, P < 0.01, n = 6) and wild-type strains (n = 5 per group). By contrast, topical superfusion of 7-NI (100 microM) attenuated the ACh response in eNOS mutants only (66%, P < 0.05, and 25% decrease, P < 0.05, at 1 and 10 microM ACh, respectively). Our findings suggest that nNOS-guanosine 3',5'-cyclic monophosphate (cGMP)-dependent pathways dilate pial arterioles by compensatory mechanisms after eNOS gene disruption.
Meng
W
W
Department of Neurosurgery and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown 02129, USA.
Ayata
C
C
Waeber
C
C
Huang
P L
PL
Moskowitz
M A
MA
D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000378:metabolism; D001160:Arterioles / Q000187:drug effects / Q000502:physiology; D001345:Autoradiography; D001921:Brain / Q000378:metabolism; D002956:Citrulline / Q000378:metabolism; D006152:Cyclic GMP / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D010841:Pia Mater / Q000098:blood supply*; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000032:analysis / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*
D004791:Enzyme Inhibitors; D007191:Indazoles; D011976:Receptors, Muscarinic; D002956:Citrulline; D011813:Quinuclidinyl Benzilate; D001120:Arginine; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; D000109:Acetylcholine; C080122:7-nitroindazole