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Responses of cerebral arterioles to ADP: eNOS-dependent and eNOS-independent mechanisms

¹Departments of Internal Medicine and Pharmacology, Cardiovascular Center, and ²Veterans Affairs Medical Center, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242

Submitted 29 April 2004 ; accepted in final form 30 July 2004

ADP mediates platelet-induced relaxation of blood vessels and may function as an important intercellular signaling molecule in the brain. We used pharmacological and genetic approaches to examine mechanisms that mediate responses of cerebral arterioles to ADP, including the role of endothelial nitric oxide synthase (eNOS). We examined responses of cerebral arterioles (control diameter 30 µm) in anesthetized wild-type (WT, eNOS+/+) and eNOS-deficient (eNOS–/–) mice using a cranial window. In WT mice, local application of ADP produced vasodilation that was not altered by indomethacin but was reduced by 50% by N^G-nitro-L-arginine (L-NNA) or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (inhibitors of NOS and soluble guanylate cyclase, respectively). In eNOS–/– mice, responses to ADP were largely preserved, and a significant component of the response was resistant to L-NNA (a finding similar to that in WT mice treated with L-NNA). In the absence of L-NNA, responses to ADP were markedly reduced by charybdotoxin plus apamin [inhibitors of Ca²⁺-dependent K⁺ channels and responses mediated by endothelium-derived hyperpolarizing factor (EDHF)] in both WT and eNOS–/– mice. Thus pharmacological and genetic evidence suggests that a significant portion of the response to ADP in cerebral microvessels is mediated by a mechanism independent of eNOS. The eNOS-independent mechanism is functional in the absence of inhibited eNOS and most likely is mediated by an EDHF.

endothelium; microcirculation; nitric oxide; acetylcholine; genetically altered mice; endothelial nitric oxide synthase

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