TRPV₁ channels in human skeletal muscle feed arteries: implications for vascular function

New Findings: What is the central question of this study? We sought to determine whether human skeletal muscle feed arteries (SFMAs) express TRPV₁ channels and what role they play in modulating vascular function. What is the main finding and its importance? Human SMFAs do express functional TRPV₁ channels that modulate vascular function, specifically opposing α-adrenergic receptor-mediated vasocontraction and potentiating vasorelaxation, in an endothelium-dependent manner, as evidenced by the α₁-receptor-mediated responses. Thus, the vasodilatory role of TRPV₁ channels, and their ligand capsaicin, could be a potential therapeutic target for improving vascular function. Additionally, given the ‘sympatholytic’ effect of TRPV₁ activation and known endogenous activators (anandamide, reactive oxygen species, H⁺, etc.), TRPV₁ channels might contribute to functional sympatholysis during exercise. To examine the role of the transient receptor potential vanilloid type 1 (TRPV₁) ion channel in the vascular function of human skeletal muscle feed arteries (SMFAs) and whether activation of this heat-sensitive receptor could be involved in modulating vascular function, SMFAs from 16 humans (63 ± 5 years old, range 41–89 years) were studied using wire myography with capsaicin (TRPV₁ agonist) and without (control). Specifically, phenylephrine (α₁-adrenergic receptor agonist), dexmedetomidine (α₂-adrenergic receptor agonist), ACh and sodium nitroprusside concentration–response curves were established to assess the role of TRPV₁ channels in α-receptor-mediated vasocontraction as well as endothelium-dependent and -independent vasorelaxation, respectively. Compared with control conditions, capsaicin significantly attenuated maximal vasocontraction in response to phenylephrine [control, 52 ± 8% length–tension_max (LT_max) and capsaicin, 21 ± 5%LT_max] and dexmedetomidine (control, 29 ± 12%LT_max and capsaicin, 2 ± 3%LT_max), while robustly enhancing maximal vasorelaxation with ACh (control, 78 ± 8% vasorelaxation and capsaicin, 108 ± 13% vasorelaxation) and less clearly enhancing the sodium nitroprusside response. Denudation of the endothelium greatly attenuated the maximal ACh-induced vasorelaxation equally in the control and capsaicin conditions (∼17% vasorelaxation) and abolished the attenuating effect of capsaicin on the maximal phenylephrine response (denuded + capsaicin, 61 ± 20%LT_max). Immunohistochemistry identified a relatively high density of TRPV₁ channels in the endothelium compared with the smooth muscle of the SMFAs, but because of the far greater volume of smooth muscle, total TRPV₁ protein content was not significantly attenuated by denudation. Thus, SMFAs ubiquitously express functional TRPV₁ channels, which alter vascular function, in terms of α₁-receptors, in a predominantly endothelium-dependent manner, conceivably contributing to the functional sympatholysis and unveiling a therapeutic target.