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.