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Research ArticleArticle

Acute and Chronic Effects of Capsaicin in Perfused Rat Muscle: The Role of Tachykinins and Calcitonin Gene-Related Peptide

Cory D. Griffiths, Dominic P. Geraghty, Tristram P.D. Eldershaw and Eric Q. Colquhoun
Journal of Pharmacology and Experimental Therapeutics November 1998, 287 (2) 697-704;
Cory D. Griffiths
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Dominic P. Geraghty
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Tristram P.D. Eldershaw
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Eric Q. Colquhoun
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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; ΔVO2, 1.35 ± 0.14 μmol g−1 h−1) was accompanied by mild vasoconstriction (ΔPP, 5.8 ± 0.6 mm Hg). In contrast, 2 μM capsaicin produced strong inhibition of VO2(ΔVO2, −2.25 ± 0.23 μmol g−1h−1) with pronounced vasoconstriction (ΔPP, 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 ΔVO2, 0.52 ± 0.06 and 0.53 ± 0.08 μmol g−1 h−1, respectively; EC50values, 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 ΔPP, 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.

Footnotes

  • Send reprint requests to: D.P. Geraghty, Department of Biomedical Science, University of Tasmania, Launceston, Australia 7250.

  • ↵1 This work was supported in part by the National Health and Medical Research Council of Australia and the Australian Research Council.

  • ↵2 Present address: Department of Biomedical Science, University of Tasmania, Launceston, Australia 7250.

  • Abbreviations:
    SP
    substance P
    NKA
    neurokinin A
    NKB
    neurokinin B
    CGRP
    calcitonin gene-related peptide
    VO2
    oxygen consumption
    PO2
    partial pressure of oxygen
    PP
    perfusion pressure
    BSA
    bovine serum albumin
    EC50
    50% of maximum response
    • Received December 19, 1997.
    • Accepted June 10, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 2
1 Nov 1998
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Research ArticleArticle

Acute and Chronic Effects of Capsaicin in Perfused Rat Muscle: The Role of Tachykinins and Calcitonin Gene-Related Peptide

Cory D. Griffiths, Dominic P. Geraghty, Tristram P.D. Eldershaw and Eric Q. Colquhoun
Journal of Pharmacology and Experimental Therapeutics November 1, 1998, 287 (2) 697-704;

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Research ArticleArticle

Acute and Chronic Effects of Capsaicin in Perfused Rat Muscle: The Role of Tachykinins and Calcitonin Gene-Related Peptide

Cory D. Griffiths, Dominic P. Geraghty, Tristram P.D. Eldershaw and Eric Q. Colquhoun
Journal of Pharmacology and Experimental Therapeutics November 1, 1998, 287 (2) 697-704;
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