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Acute and chronic effects of capsaicin in perfused rat muscle: the role of tachykinins and calcitonin gene-related peptide

Citation

Griffiths, CD and Geraghty, DP and Eldershaw, TPD and Colquhoun, EQ, Acute and chronic effects of capsaicin in perfused rat muscle: the role of tachykinins and calcitonin gene-related peptide, Journal of Pharmacology and Experimental Therapeutics, 287, (2) pp. 697-704. ISSN 0022-3565 (1998) [Refereed Article]

Abstract

In perfused rat skeletal muscle (hindlimb), capsaicin either stimulates (submicromolar concentrations) or inhibits (micromolar concentrations) oxygen consumption (VO2). Both VO2 effects are associated with vasoconstriction, evident as an increase in perfusion pressure (PP), under constant flow. We have proposed that these effects are mediated by two vanilloid receptor subtypes: VN1 (stimulation of VO2) and VN2 (inhibition of VO2) (Colquhoun et al., 1995; Griffiths et al., 1996). In the present study, the role of capsaicin-sensitive neurons and sensory neuropeptides in the VN1/VN2 receptor actions of capsaicin was investigated. The observed maximum stimulation of VO2 by capsaicin (0.4 μM; "VO2, 1.35 ± 0.14 μmol g-1 h-1) was accompanied by mild vasoconstriction ("PP, 5.8 ± 0.6 mm Hg). In contrast, 2 μM capsaicin produced strong inhibition of VO2 ("VO2, -2.25 ± 0.23 μmol g-1 h-1) with pronounced vasoconstriction ("PP, 28.0 ± 1.3 mm Hg). VO2 stimulation was significantly inhibited (P < .05) by the selective NK1 receptor antagonist CP-99994 (1 μM) and the NK2 receptor antagonist SR 48968 (1 μM) (by 42% and 51%, respectively), but PP was not altered. Infused SP and neurokinin A (NKA) stimulated VO2 (observed maximum "VO2, 0.52 ± 0.06 and 0.53 ± 0.08 μmol g-1 h-1, respectively; EC50 values, 269 ± 23 and 21.2 ± 3.0 nM, respectively) and induced mild vasoconstriction (4.30 ± 0.33 and 6.75 ± 1.18 mm Hg, respectively; EC50 values, 352 ± 25.7 and 25.5 ± 2.7 nM, respectively). Neurokinin B (NKB) also stimulated VO2 (maximum not determined) and vasoconstriction (maximum "PP, 3.40 ± 0.25 mm Hg; EC50, 34.4 ± 5.2 nM). The rank order of potency for the tachykinins in this preparation was NKA > NKB > SP, which suggests stimulation primarily of NK2 receptors. Although infused calcitonin gene- related peptide (CGRP) did not alter hindlimb VO2 or PP, the selective CGRP antagonist CGRP((8-37)) markedly potentiated the inhibition of VO2 produced by 1 μM capsaicin (84%) and the maximum capsaicin-induced vasoconstriction (57%), which indicates that endogenously released CGRP may act as a vasodilator. Hindlimbs perfused 1 day after capsaicin pretreatment showed attenuation of capsaicin-induced (0.4 μM) stimulation of VO2 (92%) (P < .05) and vasoconstriction (64%), but this returned to normal after 7 days. The inhibition of VO2 by 1 μM capsaicin was significantly (P < .05) enhanced 7 and 14 days after pretreatment (66% and 140%, respectively), as was the maximum vasoconstriction (64% and 68%, respectively). These data suggest that capsaicin-sensitive neurons, presumably via release of SP and NKA, are involved in VN1 responses and that capsaicin pretreatment potentiates VN2 responses, either by depletion of CGRP reserves or by upregulation of putative VN2 receptors.

Item Details

Item Type:Refereed Article
Research Division:Medical and Health Sciences
Research Group:Medical Biochemistry and Metabolomics
Research Field:Medical Biochemistry and Metabolomics not elsewhere classified
Objective Division:Health
Objective Group:Other Health
Objective Field:Health not elsewhere classified
Author:Griffiths, CD (Mr Griffiths)
Author:Geraghty, DP (Professor Dominic Geraghty)
Author:Colquhoun, EQ (Dr Eric Colquhoun)
ID Code:12995
Year Published:1998
Web of Science® Times Cited:6
Deposited By:Health Sciences A
Deposited On:1998-08-01
Last Modified:2011-08-05
Downloads:0

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