Mechanisms of endotoxin-induced dilatation of cerebral arterioles.
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 (SE) microns] and during topical application of endotoxin (100 micrograms/ml). After 4 h, diameter of cerebral arterioles increased by 41 +/- 5%. Coapplication of aminoguanidine (0.3 mM) with endotoxin reduced vasodilatation at all time points (30 min to 4 h). Relative to control values, endotoxin treatment increased guanosine 3',5'-cyclic monophosphate (cGMP) concentration in cerebrospinal fluid (CSF) by approximately 20 fold at 4 h. Aminoguanidine attenuated the endotoxin-induced increased in CSF cGMP concentration. Aminoguanidine (0.3 mM) did not alter acetylcholine-mediated dilatation of cerebral arterioles. Coapplication of CGRP-(8-37) (0.5 microM), a specific blocker of CGRP receptors, with endotoxin significantly reduced vasodilatation in response to endotoxin at 2, 3, and 4 h. 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.
Brian
J E
JE
Department of Anesthesia, University of Iowa College of Medicine, Iowa City 52242, USA.
Heistad
D D
DD
Faraci
F M
FM
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001158:Arteries; D001160:Arterioles / Q000187:drug effects / Q000502:physiology; D001696:Biomechanical Phenomena; D001794:Blood Pressure / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D002560:Cerebrovascular Circulation; D006152:Cyclic GMP / Q000134:cerebrospinal fluid; D004731:Endotoxins / Q000494:pharmacology*; D005260:Female; D005740:Gases / Q000097:blood; D006146:Guanidines / Q000494:pharmacology; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D011817:Rabbits; D014664:Vasodilation
D004731:Endotoxins; D005740:Gases; D006146:Guanidines; D010446:Peptide Fragments; C058636:calcitonin gene-related peptide (8-37); D009599:Nitroprusside; D006152:Cyclic GMP; D015740:Calcitonin Gene-Related Peptide; D000109:Acetylcholine; C004479:pimagedine