Cyclooxygenase-1 participates in selected vasodilator responses of the cerebral circulation

Cyclooxygenase (COX) is a prostanoid-synthesizing enzyme present in 2 isofo rms: COX-1 and COX-2. Although it has long been hypothesized that prostanoi ds participate in cerebrovascular regulation, the lack of adequate pharmaco logical tools has led to conflicting results and has not permitted investig ators to define the relative contribution of COX-1 and COX-2. We used the C OX-1 inhibitor SC-560 and COX-1-null (COX-1(-/-)) mice to investigate wheth er COX-1 plays a role in cerebrovascular regulation. Mice were anesthetized (urethane and chloralose) and equipped with a cranial window. Cerebral blo od flow (CBF) was measured by laser Doppler flowmetry or by the C-14-iodoan tipyrine technique with quantitative autoradiography. In wild-type mice, SC -560 (25 mu mol/L) reduced resting CBF by 21+/-4% and attenuated the CBF in crease produced by topical application of bradykinin (-59%) or calcium iono phore A23187 (-49%) and by systemic hypercapnia (-58%) (P<0.05 to 0.01). Ho wever, SC-560 did not reduce responses to acetylcholine or the increase in somatosensory cortex blood flow produced by vibrissal stimulation. In COX-1 (-/-) mice, resting CBF assessed by C-14-iodoantipyrine was reduced (-13% t o -20%) in cerebral cortex and other telencephalic regions (P<0.05). The CB F increase produced by bradykinin, A23187, and hypercapnia, but not acetylc holine or vibrissal stimulation, were attenuated (P<0.05 to 0.01). The free radical scavenger superoxide dismutase attenuated responses to bradykinin and A23187 in wild-type mice but not in COX-1(-/-) mice, suggesting that CO X-1 is the source of the reactive oxygen species known to mediate these res ponses. The data provide evidence for a critical role of COX-1 in maintaini ng resting vascular tone and in selected vasodilator responses of the cereb ral microcirculation.