Mechanisms of endotoxin-induced dilatation of cerebral arterioles. Brian, Johnny E., Jr, Donald D. Heistad, Frank M. Faraci. Departments of Anesthesia, Internal Medicine, and Pharmacology, Cardiovascular Center and Center on Aging, University of Iowa College of Medicine and Veterans Affairs Medical Center, Iowa City, IA 52242
APStracts 2:0116H, 1995.
Lipopolysaccharide (LPS; endotoxin) produces dilatation of cerebral arterioles in vivo which may be due, in part, to expression of inducible nitric oxide (NO)-synthase. We tested the hypothesis that aminoguanidine, an inhibitor of inducible NO-synthase, would reduce endotoxin-induced dilatation of cerebral arterioles. Because mechanisms other than expression of inducible NO-synthase may contribute to endotoxin-induced dilatation of cerebral arterioles, we also tested the hypothesis that calcitonin gene-related peptide (CGRP) contributes to vascular responses to endotoxin. Cerebral arteriolar diameter was measured using a closed cranial window in anesthetized rabbits under control conditions (77 +/- 3 [mu]m; mean +/- SEM ) and during topical application of endotoxin (100 [mu]g/ml). After 4 hours, diameter of cerebral arterioles increased by 41 +/- 5%. Co-application of aminoguanidine (0.3 mM) with endotoxin reduced vasodilatation at all time points (30 minutes to 4 hours). Relative to control values, endotoxin treatment increased cyclic GMP (cGMP) concentration in CSF by approximately 20 fold at 4 hours. Aminoguanidine attenuated the endotoxin-induced increase in CSF cGMP concentration. Aminoguanidine (0.3 mM) did not alter acetylcholine -mediated dilatation of cerebral arterioles. Co-application of CGRP 8 -37 (0.5 [mu]M), a specific blocker of CGRP receptors, with endotoxin significantly reduced vasodilatation in response to endotoxin at 2, 3, and 4 hours. Thus, 1) aminoguanidine inhibits endotoxin- but not acetylcholine-mediated dilatation of cerebral arterioles, and 2) activation of CGRP receptors mediates a portion of endotoxin-induced dilation of cerebral arterioles. 

Received 5 December 1994; accepted in final form 15 March 1995.
APS Manuscript Number H1062-4.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on  4 April 1995.