Cutaneous Active Vasodilation in Humans Is Mediated by Cholinergic Nerve Cotransmission

Abstract

During heat stress, increases in blood flow in nonglabrous skin in humans are mediated through active vasodilation by an unknown neurotransmitter mechanism. To investigate this mechanism, a three-part study was performed to determine the following: (1) Is muscarinic receptor activation necessary for active cutaneous vasodilation? We iontophoretically applied atropine to a small area of forearm skin. At that site and an untreated control site, we measured the vasomotor (laser-Doppler blood flow [LDF]) and sudomotor (relative humidity) responses to whole-body heat stress. Blood pressure was monitored. Cutaneous vascular conductance (CVC) was calculated (LDF divided by mean arterial pressure). Sweating was blocked at treated sites only. CVC rose at both sites (P < .05 at each site); thus, cutaneous active vasodilation is not effected through muscarinic receptors. (2) Are nonmuscarinic cholinergic receptors present on cutaneous arterioles? Acetylcholine (ACh) was iontophoretically applied to forearm skin at sites pretreated by atropine iontophoresis and at untreated sites. ACh increased CVC at untreated sites (P < .05) but not at atropinized sites. Thus, the only functional cholinergic receptors on cutaneous vessels are muscarinic. (3) Does cutaneous active vasodilation involve cholinergic nerve cotransmission? Botulinum toxin was injected intradermally in the forearm to block release of ACh and any coreleased neurotransmitters. Heat stress was performed as in part 1 of the study. At treated sites, CVC and relative humidity remained at baseline levels during heat stress (P > .05). Active vasodilator and sudomotor responses to heat stress were abolished by botulinum toxin. We conclude that cholinergic nerve activation mediates cutaneous active vasodilation through release of an unknown cotransmitter, not through ACh.

Transient receptor potential melastatin 8 channel involvement in the regulation of vascular tone

“…A further possibility to consider is that menthol activated TRPM8 channels in sympathetic vasodilator fibers that are known to innervate the human forearm cutaneous circulation, mediated by release of ACh (17,19). This would be consistent with our observation that both L-NAME and atropine markedly reduced the dilatation induced by menthol.…”

“…In contrast, control of the human forearm cutaneous circulation is more complex, having all of these elements active, in addition to sympathetic vasoconstrictor tone (15,17,19,25,33). It is possible that neuronal activation by TRPM8 channels may result in a vasodilatation.…”

Mechanisms of nicotine-induced cutaneous vasodilation and sweating in young adults: roles for KCa, KATP, and KVchannels, nitric oxide, and prostanoids

“…Since previous studies reported that muscarinic receptors are essential in mediating the sweating response during heat stress (Kellogg et al 1995;Shibasaki et al 2002), one might conclude that the observed NOS-and COX-dependent sweating during exercise in the heat is associated with muscarinic receptors. However, we previously reported that muscarinic receptor activation by methacholine did not exhibit NOS-and COX-dependent sweating under a normothermic state (Fujii et al 2014b).…”

“…While muscarinic receptor activation by acetylcholine is thought to be a major mechanism for cholinergic cutaneous vasodilation and sweating during heat stress (Kellogg et al 1995;Shibasaki et al 2002), it is well accepted that acetylcholine can also activate nicotinic receptors. Hence, nicotinic receptors may also contribute to the regulation of the heat loss responses.…”

Sympathetic, sensory, and nonneuronal contributions to the cutaneous vasoconstrictor response to local cooling

“…In the case of the vasoconstrictor system, the transmitters appear to be norepinephrine and one or more cotransmitters (26 -27, 36, 37, 39 -40). The active vasodilator mechanism is less well defined but appears to be cholinergic and also to involve a cotransmitter, perhaps vasoactive intestinal polypeptide (3,21).…”