Shastry, Shubha

We sought to examine further the potential role of nitric oxide (NO) in the neurally mediated cutaneous vasodilation in nonacral skin during body heating in humans. Six subjects were heated with a water-perfused suit while cutaneous blood flow was measured by using laser-Doppler flowmeters placed on both forearms. The NO synthase inhibitor NG-monomethyl-l-arginine (l-NMMA) was given selectively to one forearm via a brachial artery catheter after marked cutaneous vasodilation had been established. During body heating, oral temperature increased by 1.1 ± 0.1°C while heart rate increased by 30 ± 6 beats/min. Mean arterial pressure stayed constant at 84 ± 2 mmHg. In the experimental forearm, cutaneous vascular conductance (CVC; laser-Doppler) decreased to 86 ± 5% of the peak response to heating ( P < 0.05 vs. pre-l-NMMA values) afterl-NMMA infusion. In some subjects, l-NMMA caused CVC to fall by ∼30%; in others, it had little impact on the cutaneous circulation. CVC in the control arm showed a similar increase with heating, then stayed constant whilel-NMMA was given to the contralateral side. These results demonstrate that NO contributes modestly, but not consistently, to cutaneous vasodilation during body heating in humans. They also indicate that NO is not the only factor responsible for the dilation.

The binding of heat shock protein 90 (HSP90) to endothelial nitric oxide (NO) synthase (eNOS) can enhance eNOS activation. Studies have shown that the HSP90-specific inhibitor geldanamycin (GA) can cause attenuation of NO-mediated processes. Twenty subjects participated in one of two protocols. In each protocol, one forearm of each subject was instrumented with two intradermal microdialysis probes for drug delivery. Laser Doppler flowmeters were used to measure cutaneous blood flow. Skin sites were either treated with the endothelial agonist acetylcholine or locally heated to 42°C, a maneuver that evokes NO-mediated dilation. Interventions were performed with and without GA. In the presence of GA, maximal cutaneous vascular conductance (CVC) to ACh was 20 ± 3% lower than with ACh alone ( P < 0.001). During local heating, maximal CVC in the presence of GA was 22 ± 6% lower than during heating alone ( P < 0.01). The results show that GA can attenuate NO-mediated dilation in human skin, suggesting a potential role for HSP90 in activation of eNOS in the microcirculation.

We sought to investigate further the roles of sweating, ACh spillover, and nitric oxide (NO) in the neurally mediated cutaneous vasodilation during body heating in humans. Six subjects were heated with a water-perfused suit while cutaneous blood flow was measured with a laser-Doppler flowmeter. After a rise in core temperature (1.0 ± 0.1°C) and the establishment of cutaneous vasodilation, atropine and subsequently the NO synthase inhibitor N G-nitro-l-arginine methyl ester (l-NAME) were given to the forearm via a brachial artery catheter. After atropine infusion, cutaneous vascular conductance (CVC) remained constant in five of six subjects, whereasl-NAME administration blunted the rise in CVC in three of six subjects. A subsequent set of studies using intradermal microdialysis probes to selectively deliver drugs into forearm skin confirmed that atropine did not affect CVC. However, perfusion ofl-NAME resulted in a significant decrease in CVC (37 ± 4%, P < 0.05). The results indicate that neither sweating nor NO release via muscarinic receptor activation is essential to sustain cutaneous dilation during heating in humans.