963-22 Gene Knockouts for Neuronal Nitric Oxide Synthase Demonstrate Compensatory Mechanisms of Cerebrovascular Blood Flow Regulation

Abstract

We have investigated the role of nitric oxide as a mediator of the cerebrovascular blood flow response to hypercapnia in wild-type mice and knock-out mice that lack the neuronal nitric oxide synthase (NOS) gene. Mice were anesthetized, intubated, and ventilated. Baseline measurements of arterial blood pressure, end-tidal CO2, and blood gases were monitored, and were comparable in both groups of mice. Relative cerebral blood flow (rCBF) was measured by lased Doppler flowmetry. Hypercapnia induced by inhalation of 5 and 10% CO2 resulted in a 38 ± 15 and 77 ± 34% increase in rCBF in both the mutant and wild-type mice. Superfusion with nitro-L-arginine (LNA) markedly attenuated the rCBF response in wild-type mice, but did not affect the response in the knock-out mice. Brain cGMP levels increased in response to hypercapnia in the wild-type animals, but not in the knock-out animals. Endothelium dependent dilation to topical acetylcholine was completely blocked by topical L-NA in both groups, demonstrating that endothelial NOS is not involved in the preserved hypercapnic response in the knockout animals. Based on these data, we conclude that (1) nitric oxide is not the sole mediator of the hypercapnic blood flow response, (2) neuronal NOS, and not endothelial NOS, contributes to hypercapnic hyperemia, (3) in the knock-out animals, mechanisms that do not involve nitric oxide or cGMP compensate for lack of the neuronal NOS gene to preserve the hypercapnic cerebrovascular blood flow response.