Nitric oxide releases calcitonin-gene-related peptide from rat dura mater encephali promoting increases in meningeal blood flow.
Nitric oxide (NO) and calcitonin-gene-related peptide (CGRP) are implicated in the pathophysiology of vascular headaches. We studied the interaction of these two vasodilatory mediators in an animal model and suggest that NO may increase meningeal blood flow not only by its direct vasodilatory action but also by stimulating CGRP release. First, CGRP release from the rat cranial dura mater was measured in vitro using an enzyme immunoassay. Hemisected skulls with adhering dura mater were filled with synthetic interstitial fluid and stimulated with the NO donor diethylamine-NONOate (10(-5)-10(-3) M) or with NO gas (1,000 ppm), which caused concentration-dependent increases in CGRP release up to 166.8%. Second, meningeal blood flow was recorded in vivo in the exposed dura mater using laser Doppler flowmetry. Topical application of the NO donors NONOate, S-nitroso-N-acetylpenicillamine and N-ethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydrazino)-ethenamine (10(-5)-10(-3) M) caused concentration-dependent increases in blood flow. These increases were significantly reduced by local preliminary application of the CGRP receptor antagonist CGRP(8-37) (10(-4) M). We conclude that NO stimulates the release of CGRP from dural afferents. The blood-flow-increasing effect of NO seems to be partly mediated by CGRP. The interaction of NO and CGRP may be relevant for the development of vascular headaches.
Strecker
Thomas
T
Department of Physiology and Experimental Pathophysiology, University of Erlangen-Nürnberg, Universitätsstrasse 17, D-91054 Erlangen, Germany.
Dux
Mária
M
Messlinger
Karl
K
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D004388:Dura Mater / Q000098:blood supply* / Q000378:metabolism*; D006834:Hydrazines / Q000494:pharmacology; D008297:Male; D008881:Migraine Disorders / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009589:Nitrogen Oxides; D009603:Nitroso Compounds / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D006834:Hydrazines; C118603:NOC 12; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; D009603:Nitroso Compounds; D010446:Peptide Fragments; C110881:S-nitro-N-acetylpenicillamine; C058636:calcitonin gene-related peptide (8-37); D009569:Nitric Oxide; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine; D010396:Penicillamine; D015740:Calcitonin Gene-Related Peptide