Vol. 287, Issue 2, 697-704, November 1998

Acute and Chronic Effects of Capsaicin in Perfused Rat Muscle: The Role of Tachykinins and Calcitonin Gene-Related Peptide¹

Cory D. Griffiths, Dominic P. Geraghty², Tristram P.D. Eldershaw and Eric Q. Colquhoun

Division of Biochemistry, University of Tasmania, Hobart, Australia

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) (; ). 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 g¹ h¹) 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 g¹ h¹) 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 g¹ h¹, 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.