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The permissive role of endothelial NO in CO-induced cerebrovascular dilation

Laboratory for Research in Neonatal Physiology, Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163

Submitted 19 April 2004 ; accepted in final form 5 June 2004

Carbon monoxide (CO) and nitric oxide (NO) are important paracrine messengers in the newborn cerebrovasculature that may act as comessengers. Here, we investigated the role of NO in CO-mediated dilations in the newborn cerebrovasculature. Arteriolar branches of the middle cerebral artery (100–200 µm) were isolated from 3- to 7-day-old piglets and cannulated at each end in a superfusion chamber, and intravascular pressure was elevated to 30 mmHg, which resulted in the development of myogenic tone. Endothelium removal abolished dilations of pressurized pial arterioles to bradykinin and to the CO-releasing molecule Mn₂(CO)₁₀ [dimanganese decacarbonyl (DMDC)] but not dilations to isoproterenol. With endothelium intact, N-nitro-L-arginine (L-NNA), 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), or tetraethylammonium chloride (TEA⁺), inhibitors of NO synthase (NOS), guanylyl cyclase, and large-conductance Ca²⁺-activated K⁺ (K_Ca) channels, respectively, also blocked dilation induced by DMDC. After inhibition of NOS, a constant concentration of sodium nitroprusside (SNP), a NO donor that only dilated the vessel 6%, returned dilation to DMDC. The stable cGMP analog 8-bromo-cGMP also restored dilation to DMDC in endothelium-intact, L-NNA-treated, or endothelium-denuded arterioles, and this effect was blocked by TEA⁺. Similarly, in the continued presence of ODQ, 8-bromo-cGMP restored DMDC-induced dilations. These findings suggest that endothelium-derived NO stimulates guanylyl cyclase in vascular smooth muscle cells and, thereby, permits CO to cause dilation by activating K_Ca channels. Such a requirement for NO could explain the endothelium dependency of CO-induced dilation in piglet pial arterioles.

nitric oxide; carbon monoxide

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