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.

Whether nitric oxide (NO) is involved in cutaneous active vasodilation during hyperthermia in humans is unclear. We tested for a role of NO in this process during heat stress (water-perfused suits) in seven healthy subjects. Two forearm sites were instrumented with intradermal microdialysis probes. One site was perfused with the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) dissolved in Ringer solution to abolish NO production. The other site was perfused with Ringer solution only. At those sites, skin blood flow (laser-Doppler flowmetry) and sweat rate were simultaneously and continuously monitored. Cutaneous vascular conductance, calculated from laser-Doppler flowmetry and mean arterial pressure, was normalized to maximal levels as achieved by perfusion with the NO donor nitroprusside through the microdialysis probes. Under normothermic conditions, L-NAME did not significantly reduce cutaneous vascular conductance. During hyperthermia, with skin temperature held at 38-38.5 degreesC, internal temperature rose from 36.66 +/- 0.10 to 37.34 +/- 0.06 degreesC (P < 0.01). Cutaneous vascular conductance at untreated sites increased from 12 +/- 2 to 44 +/- 5% of maximum, but only rose from 13 +/- 2 to 30 +/- 5% of maximum at L-NAME-treated sites (P < 0.05 between sites) during heat stress. L-NAME had no effect on sweat rate (P > 0.05). Thus cutaneous active vasodilation requires functional NO synthase to achieve full expression.

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In this review, we focus on significant developments in our understanding of the mechanisms that control the cutaneous vasculature in humans, with emphasis on the literature of the last half-century. To provide a background for subsequent sections, we review methods of measurement and techniques of importance in elucidating control mechanisms for studying skin blood flow. In addition, the anatomy of the skin relevant to its thermoregulatory function is outlined. The mechanisms by which sympathetic nerves mediate cutaneous active vasodilation during whole body heating and cutaneous vasoconstriction during whole body cooling are reviewed, including discussions of mechanisms involving cotransmission, NO, and other effectors. Current concepts for the mechanisms that effect local cutaneous vascular responses to local skin warming and cooling are examined, including the roles of temperature sensitive afferent neurons as well as NO and other mediators. Factors that can modulate control mechanisms of the cutaneous vasculature, such as gender, aging, and clinical conditions, are discussed, as are nonthermoregulatory reflex modifiers of thermoregulatory cutaneous vascular responses.

Exercise in the heat can pose a severe challenge to human cardiovascular control, and thus the provision of oxygen to exercising muscles and vital organs, because of enhanced thermoregulatory demand for skin blood flow coupled with dehydration and hyperthermia. Cardiovascular strain, typified by reductions in cardiac output, skin and locomotor muscle blood flow and systemic and muscle oxygen delivery accompanies marked dehydration and hyperthermia during prolonged and intense exercise characteristic of many summer Olympic events. This review focuses on how the cardiovascular system is regulated when exercising in the heat and how restrictions in locomotor skeletal muscle and/or skin perfusion might limit athletic performance in hot environments. Exercise in the heatThe demands of dynamic exercise at intensities up to maximum oxygen consumption (V O 2 ,max ) distill down to demands for blood flow. Blood flow to active muscle (and the myocardium) is required to meet the energetic demands for muscular activity (principally the demand for oxygen), while blood flow to skin is required to meet the demands of temperature regulation. These combined demands for blood flow can result in a competition for the available cardiac output (Rowell, 1974), which has, as a bottom line, a limit to the ability to meet the dual demands of exercise per se and of temperature regulation, particularly during intense dynamic exercise. The focus of this review pertains to how this limitation becomes manifest during exercise in the heat: reduced muscle blood flow, limited skin blood flow or both? Reduced muscle blood flow will limit the intensity and duration of exercise, while reduced skin blood flow will limit the disposal of heat resulting in adverse effects of elevated internal temperature, including that of the central nervous system. This topic, which has been periodically reviewed over the past 35 years or more (e.g.

Regional vascular responses to gradual reductions in right atrial pressure and aortic pressure were investigated in nine men. In each study, lower body negative pressure was applied in a ramp of -1 mm Hg/min for 40-50 minutes. During the range from control to -20 mm Hg, right atrial pressure (4 studies) fell from 4.2 mm Hg to -0.6 mm Hg; heart rate was slightly reduced (2 beats/min), and aortic mean pressure and pulse pressure (6 studies) were unchanged. The maximal rate of rise of aortic pressure showed no consistent trends. Forearm blood flow (30 studies) fell with the onset of lower body negative pressure and reached 67% of the control value by -20 mm Hg. Splanchnic blood flow (14 studies) was significantly reduced by -7 mm Hg and fell to 89% of control by -20 mm Hg. During the range from -20 to -50 mm Hg, right atrial pressure continued to fall. Aortic mean pressure fell slightly or was unchanged in four subjects and fell dramatically at -35 mm Hg in two subjects. Aortic pulse pressure began to fall at about -20 mm Hg and fell linearly thereafter. Heart rate paralleled aortic pulse pressure (r=-0.86 to -0.93). Forearm blood flow fell to 55% and splanchnic blood flow fell to 65% of control at -50 mm Hg. Thus, significant vasoconstriction occurred without measurable change in arterial blood pressure. We concluded that low-pressure baroreceptors, presumably in the cardiopulmonary region, initiate splanchnic and forearm vasoconstriction with more pronounced vasoconstriction occurring in the forearm.KEYS WORDS peripheral circulation heart rate lower body negative pressure blood pressure regulation forearm blood flow splanchnic blood flow low-pressure baroreceptors • A major cardiovascular adjustment to moderate hemorrhage is increased sympathetic outflow to the heart and various vascular beds. Traditionally this adjustment has been associated with carotid sinus and aortic baroreceptors (1) which clearly play important roles in regulating arterial blood pressure. More recently, however, stretch receptors in the cardiopulmonary region (low-pressure baroreceptors) have been implicated in the mediation of reflex responses to hemorrhage in dogs, cats, and rabbits (2-4). In humans, simulation of hemorrhage by mild degrees of lower body negative pressure can evoke marked forearm vasoconstriction without significant changes in heart rate, aortic mean pressure, aortic pulse pressure, or maximal rate of rise of aortic blood pressure (dP/dt max) (5). It appears that reduced pressures in the cardiopulmonary region accompanying lower body negative pressure must be the stimulus for the reflex vasoconstriction. Previous studies in man (6, 7) have implicated low-pressure baroreceptors in the reflex release of forearm vasoconstrictor tone accompanying increases in thoracic blood volume induced by postural or respiratory maneuvers.We attempted to determine whether the vasoconstriction seen in forearms during a mild degree of lower body negative pressure, which was insufficient to measurably affect arterial blood pressure, was evide...

The role of adrenergic nerve function in the cutaneous vascular response to changes in local skin temperature in the human forearm was examined using three protocols: 1) blocking release of norepinephrine presynaptically by local iontophoresis of bretylium (BT), 2) altering background adrenergic tone by changing whole body skin temperature, and 3) blocking cutaneous nerves by proximal infiltration of local anesthetic. Forearm skin blood flow was measured by laser-Doppler flowmetry (LDF) and cutaneous vascular conductance (CVC) was calculated as LDF/blood pressure. In protocol 1, local cooling (29 degrees C) elicited a rapid and sustained fall in CVC at control sites (-43 +/- 8%) in contrast to a biphasic response at BT-treated sites, consisting of an initial vasodilation followed by a vasoconstriction (percent change CVC = 28 +/- 13 and -34 +/- 18, respectively). Local warming (39 degrees C) increased CVC at control and at BT-treated sites by 331 +/- 46 and 139 +/- 31%, respectively. In protocol 2, at a neutral, cool, or warm whole body skin temperature, local cooling (29 degrees C) elicited similar reductions in CVC (-34 +/- 8, -29 +/- 5, and -30 +/- 4%, respectively), and local warming (38 degrees C) produced similar increases in CVC (89 +/- 15, 85 +/- 21, and 74 +/- 22%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Sympathetic, sensory, and nonneuronal contributions to the cutaneous vasoconstrictor response to local cooling. Am J Physiol Heart Circ Physiol 288: H1573-H1579, 2005. First published December 2, 2004; doi:10.1152/ajpheart.00849.2004.-Previous work indicates that sympathetic nerves participate in the vascular responses to direct cooling of the skin in humans. We evaluated this hypothesis further in a four-part series by measuring changes in cutaneous vascular conductance (CVC) from forearm skin locally cooled from 34 to 29°C for 30 min. In part 1, bretylium tosylate reversed the initial vasoconstriction (Ϫ14 Ϯ 6.6% control CVC, first 5 min) to one of vasodilation (ϩ19.7 Ϯ 7.7%) but did not affect the response at 30 min (Ϫ30.6 Ϯ 9% control, Ϫ38.9 Ϯ 6.9% bretylium; both P Ͻ 0.05, P Ͼ 0.05 between treatments). In part 2, yohimbine and propranolol (YP) also reversed the initial vasoconstriction (Ϫ14.3 Ϯ 4.2% control) to vasodilation (ϩ26.3 Ϯ 12.1% YP), without a significant effect on the 30-min response (Ϫ26.7 Ϯ 6.1% YP, Ϫ43.2 Ϯ 6.5% control; both P Ͻ 0.05, P Ͼ 0.05 between sites). In part 3, the NPY Y1 receptor antagonist BIBP 3226 had no significant effect on either phase of vasoconstriction (P Ͼ 0.05 between sites both times). In part 4, sensory nerve blockade by anesthetic cream (Emla) also reversed the initial vasoconstriction (Ϫ20.1 Ϯ 6.4% control) to one of vasodilation (ϩ213.4 Ϯ 87.0% Emla), whereas the final levels did not differ significantly (Ϫ37.7 Ϯ 10.1% control, Ϫ37.2 Ϯ 8.7% Emla; both P Ͻ 0.05, P Ͼ 0.05 between treatments). These results indicate that local cooling causes cold-sensitive afferents to activate sympathetic nerves to release norepinephrine, leading to a local cutaneous vasoconstriction that masks a nonneurogenic vasodilation. Later, a vasoconstriction develops with or without functional sensory or sympathetic nerves.human; peripheral circulation; local control of blood flow; skin circulation; microdialysis; iontophoresis; neuropeptide Y; norepinephrine; axon reflex THE CONTROL OF SKIN BLOOD FLOW in humans involves several mechanisms. Reflex control occurs through a vasoconstrictor pathway and through an independent active vasodilator system (18, 33). These systems are both known to be sympathetic in origin. 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).Local thermal control of skin blood flow has also been the subject of considerable attention. Direct local warming of the skin leads to a vasodilation that involves nitric oxide and sensory nerves (20,25,38). With respect to direct local cooling, several lines of evidence point to an involvement of the sympathetic vasoconstrictor system in the reduction of skin blood flow. Postsynaptic ␣ 2 -adrenergic receptors have an enhanced affinity for norepinephrine, perhaps mediated th...