Transient receptor potential vanilloid type-1 (TRPV-1) channels contribute to cutaneous thermal hyperaemia in humans

Abstract

The initial, rapid increase in skin blood flow in response to direct application of heat is thought to be mediated by an axon reflex, which is dependent on intact cutaneous sensory nerves. We tested the hypothesis that inhibition of transient receptor potential vanilloid type 1 (TRPV-1) channels, which are putative channels located on sensory nerves, would attenuate the skin blood flow response to local heating in humans. Ten subjects were equipped with four microdialysis fibres which were randomly assigned one of four treatments: (1) vehicle control (90% propylene glycol + 10% lactated Ringer solution); (2) 20 mm capsazepine to inhibit TRPV-1 channels; (3) 10 mm l-NAME to inhibit NO synthase; and (4) combined 20 mm capsazepine + 10 mm l-NAME. Following baseline measurements, the temperature of skin heaters was increased from 33°C to 42°C at a rate of 1.0°C every 10 s and local temperature was held at 42°C for 20-30 min until a stable plateau in skin blood flow was achieved. An index of skin blood flow was measured directly over each microdialysis site via laser-Doppler flowmetry (LDF). Beat-by-beat blood pressure was measured via photoplethysmography and verified via automated brachial auscultation. At the end of the local heating protocol, temperature of the heaters was increased to 43°C and 28 mm nitroprusside was infused to achieve maximal vasodilatation. Cutaneous vascular conductance (CVC) was calculated as LDF/mean arterial pressure and normalized to maximal values (%CVCmax). Initial peak in capsazepine (44 ± 4%CVCmax), l-NAME (56 ± 4%CVCmax) and capsazepine + l-NAME (32 ± 6%CVCmax) sites was significantly attenuated compared to control (87 ± 5%CVCmax; P < 0.001 for all conditions). The plateau phase of thermal hyperaemia was significantly attenuated in capsazepine (73 ± 6%CVCmax), l-NAME (47 ± 5%CVCmax) and capsazepine + l-NAME (31 ± 7%CVCmax) sites compared to control (92 ± 5%CVCmax; P < 0.001 for all conditions). These data suggest TRPV-1 channels contribute substantially to the initial peak and modestly to the plateau phases of thermal hyperaemia. These data further suggest a portion of the NO component of thermal hyperaemia may be due to activation of TRPV-1 channels.

Figures

Figure 1. Representative tracing of the skin blood flow response in the four treatment sites

A, vehicle control (90% propylene glycol + 10% lactated Ringer solution); B, capsazepine (TRPV-1 inhibition); C, l-NAME (NO synthase inhibition); D, combined capsazepine +l-NAME. Data are from one subject.

Figure 2. Comparison of baseline CVC between treatment sites

Post-drug infusion baseline CVC values were not significantly different between treatment sites. Values are mean ±s.e.m.

Figure 3. Effect of TRPV-1 channel and NO synthase inhibiton on the initial peak response to local heating

Inhibition of TRPV-1 channels and NO synthase significantly attenuated the initial peak compared to control. The effect of TRPV-1 inhibition was greater than the effect of NO synthase inhibition. Combined inhibition of TRPV-1 channels and NO synthase further attenuated the initial peak. *P < 0.05 vs. control; #P < 0.05 vs.l-NAME; +P < 0.05 vs. capsazepine. CPZ, capsazepine (TRPV-1 inhibition); l-NAME, NO synthase inhibition.

Figure 4. Effect of TRPV-1 channel and NO synthase inhibiton on the nadir response to local heating

Inhibition of TRPV-1 channels and NO synthase significantly attenuated the nadir compared to control. The effect of NO synthase inhibition was greater than the effect of TRPV-1 inhibition. Combined inhibition of TRPV-1 channels and NO synthase further attenuated the initial peak. *P < 0.05 vs. control; #P < 0.05 vs.l-NAME; +P < 0.05 vs. capsazepine. CPZ, capsazepine (TRPV-1 inhibition); l-NAME, NO synthase inhibition.

Figure 5. Effect of TRPV-1 channel and NO synthase inhibiton on the plateau response to local heating

Inhibition of TRPV-1 channels and NO synthase significantly attenuated the plateau compared to control. The effect of NO synthase inhibition was greater than the effect of TRPV-1 inhibition. Combined inhibition of TRPV-1 channels and NO synthase further attenuated the initial peak. *P < 0.05 vs. control; #P < 0.05 vs.l-NAME; +P < 0.05 vs. capsazepine. CPZ, capsazepine (TRPV-1 inhibition); l-NAME, NO synthase inhibition.

Figure 6. Per cent contribution of TRPV-1 channels, NO, and combined TRPV-1 channels + NO to cutaneous thermal hyperaemia

A, per cent contrtibution of TRPV-1 channels and NO to the initial peak; B, per cent contribution of TRPV-1 channels and NO to the nadir; C, per cent contribution of TRPV-1 channels and NO to the plateau. *P < 0.05 vs. nitric oxide + TRPV-1 channels; #P < 0.05 vs. TRPV-1 channels.