Urease-mediated room-temperature synthesis of nanocrystalline titanium dioxide.

Enzymes are an important class of biological molecules whose specific functionalities can be exploited to perform tasks beyond the reach of conventional chemistry. Because they are operational under environmentally friendly, ambient conditions, the adaptation of these biomacromolecules can potentially be used to replace current energy-intensive and environmentally harsh synthesis methods for materials. Here we used a hydrolytic enzyme, urease, to modify the solution environment around a water-soluble and stable TiO(2) precursor to synthesize nanocrystalline titanium dioxide under environmentally benign conditions. This urease-mediated synthesis yields nearly monodisperse TiO(2) nanostructures with high surface area that can be utilized for numerous energy-based applications such as low-cost photovoltaics and photocatalysts.

Plasma hyperosmolality elevates the internal temperature threshold for active thermoregulatory vasodilation during heat stress in humans.

Plasma hyperosmolality delays the response in skin blood flow to heat stress by elevating the internal temperature threshold for cutaneous vasodilation. This elevation could be because of a delayed onset of cutaneous active vasodilation and/or to persistent cutaneous active vasoconstriction. Seven healthy men were infused with either hypertonic (3% NaCl) or isotonic (0.9% NaCl) saline and passively heated by immersing their lower legs in 42 degrees C water for 60 min (room temperature, 28 degrees C; relative humidity, 40%). Skin blood flow was monitored via laser-Doppler flowmetry at sites pretreated with bretylium tosylate (BT) to block sympathetic vasoconstriction selectively and at adjacent control sites. Plasma osmolality was increased by approximately 13 mosmol/kgH(2)O following hypertonic saline infusion and was unchanged following isotonic saline infusion. The esophageal temperature (T(es)) threshold for cutaneous vasodilation at untreated sites was significantly elevated in the hyperosmotic state (37.73 +/- 0.11 degrees C) relative to the isosmotic state (36.63 +/- 0.12 degrees C, P < 0.001). A similar elevation of the T(es) threshold for cutaneous vasodilation was observed between osmotic conditions at the BT-treated sites (37.74 +/- 0.18 vs. 36.67 +/- 0.07 degrees C, P < 0.001) as well as sweating. These results suggest that the hyperosmotically induced elevation of the internal temperature threshold for cutaneous vasodilation is due primarily to an elevation in the internal temperature threshold for the onset of active vasodilation, and not to an enhancement of vasoconstrictor activity.

Neuropeptide Y and neurovascular control in skeletal muscle and skin.

Neuropeptide Y (NPY) is a ubiquitous peptide with multiple effects on energy metabolism, reproduction, neurogenesis, and emotion. In addition, NPY is an important sympathetic neurotransmitter involved in neurovascular regulation. Although early studies suggested that the vasoactive effects of NPY were limited to periods of high stress, there is growing evidence for the involvement of NPY on baseline vasomotor tone and sympathetically evoked vasoconstriction in vivo in both skeletal muscle and the cutaneous circulation. In Sprague-Dawley rat skeletal muscle, Y(1)-receptor activation appears to play an important role in the regulation of basal vascular conductance, and this effect is similar in magnitude to the alpha(1)-receptor contribution. Furthermore, under baseline conditions, agonist and receptor-based mechanisms for Y(1)-receptor-dependent control of vascular conductance in skeletal muscle are greater in male than female rats. In skin, there is Y(1)-receptor-mediated vasoconstriction during whole body, but not local, cooling. As with the NPY system in muscle, this neural effect in skin differs between males and females and in addition, declines with aging. Intriguingly, skin vasodilation to local heating also requires NPY and is currently thought to be acting via a nitric oxide pathway. These studies are establishing further interest in the role of NPY as an important vasoactive agent in muscle and skin, adding to the complexity of neurovascular regulation in these tissues. In this review, we focus on the role of NPY on baseline vasomotor tone in skeletal muscle and skin and how NPY modulates vasomotor tone in response to stress, with the aim of compiling what is currently known, while highlighting some of the more pertinent questions yet to be answered.

The effect of microdialysis needle trauma on cutaneous vascular responses in humans.

Microdialysis enables in-depth mechanistic study of the cutaneous circulation in humans. However, whether the insertion or presence of the microdialysis fiber (MDF) affects the skin circulation or its responses is unknown. We tested whether the cutaneous vascular response to whole body heating (WBH) was affected by MDF or by pretreatment with ice (part 1) or local anesthesia (LA; part 2). Eleven subjects participated, 9 in part 1 and 8 in part 2 (5 participated in both). In both parts, four sites on the forearm were selected, providing untreated control, MDF only, ice or LA only, and combined MDF plus ice or LA. A tube-lined suit controlled whole body skin temperature, which was raised to approximately 38 degrees C for WBH. Skin sites were instrumented with laser-Doppler flow probes. Data were expressed as cutaneous vascular conductance (CVC). Baseline levels were not different among sites (P > 0.05). In part 1, the internal temperature for the onset of vasodilation was higher (P > 0.05) with MDF with or without ice pretreatment than at untreated control sites (control 36.6 +/- 0.1 degrees C, Ice 36.5 +/- 0.1, MDF 36.8 +/- 0.1 degrees C, and Ice+MDF 36.8 +/- 0.1 degrees C). Peak CVC during WBH was decreased (P < 0.05) by MDF (control 73 +/- 7 vs. MDF 59 +/- 6% of maximal CVC). Ice (73 +/- 6% of maximal CVC) or Ice+MDF (69 +/- 6% of maximal CVC) did not affect (P > 0.05) peak CVC compared with control. In part 2, the temperature threshold for the onset of vasodilation was increased by MDF with or without LA treatment and by LA alone (P < 0.05; control 36.6 +/- 0.1 degrees C, MDF 36.7 +/- 0.1 degrees C, LA 36.8 +/- 0.1 degrees C, and LA+MDF 36.8 +/- 0.1 degrees C). Peak CVC was decreased by MDF (control 69 +/- 6% of maximal CVC vs. MDF 58 +/- 8% of maximal CVC; P < 0.05). LA only (65 +/- 10% of maximal CVC) or MDF in the presence of LA (73 +/- 12% of maximal CVC) did not affect (P > 0.05) peak CVC compared with control. Thus LA or MDF increases the temperature threshold for the onset of vasodilation. MDF alone decreases the peak vasodilator response in CVC to WBH; however, this attenuation did not occur if ice or LA is used before MDF placement. Ice or LA alone do not affect the peak response in CVC to WBH. How those treatments prevent or reverse the effect of MDF placement is presently unclear.

The involvement of norepinephrine, neuropeptide Y, and nitric oxide in the cutaneous vasodilator response to local heating in humans.

Presynaptic blockade of cutaneous vasoconstrictor nerves (VCN) abolishes the axon reflex (AR) during slow local heating (SLH) and reduces the vasodilator response. In a two-part study, forearm sites were instrumented with microdialysis fibers, local heaters, and laser-Doppler flow probes. Sites were locally heated from 33 to 40 degrees C over 70 min. In part 1, we tested whether this effect of VCN acted via nitric oxide synthase (NOS). In five subjects, treatments were as follows: 1) untreated; 2) bretylium, preventing neurotransmitter release; 3) N(G)-nitro-L-arginine methyl ester (L-NAME) to inhibit NOS; and 4) combined bretylium + L-NAME. At treated sites, the AR was absent, and there was an attenuation of the ultimate vasodilation (P < 0.05), which was not different among those sites (P > 0.05). In part 2, we tested whether norepinephrine and/or neuropeptide Y is involved in the cutaneous vasodilator response to SLH. In seven subjects, treatments were as follows: 1) untreated; 2) propranolol and yohimbine to antagonize alpha- and beta-receptors; 3) BIBP-3226 to antagonize Y(1) receptors; and 4) combined propranolol + yohimbine + BIBP-3226. Treatment with propranolol + yohimbine or BIBP-3226 significantly increased the temperature at which AR occurred (n = 4) or abolished it (n = 3). The combination treatment consistently eliminated it. Importantly, ultimate vasodilation with SLH at the treated sites was significantly (P < 0.05) less than at the control. These data suggest that norepinephrine and neuropeptide Y are important in the initiation of the AR and for achieving a complete vasodilator response. Since VCN and NOS blockade in combination do not have an inhibition greater than either alone, these data suggest that VCN promote heat-induced vasodilation via a nitric oxide-dependent mechanism.

Exogenous melatonin administration modifies cutaneous vasoconstrictor response to whole body skin cooling in humans.

Humans and other diurnal species experience a fall in internal temperature (T(int)) at night, accompanied by increased melatonin and altered thermoregulatory control of skin blood flow (SkBF). Also, exogenous melatonin induces a fall in T(int), an increase in distal skin temperatures and altered control of the cutaneous active vasodilator system, suggesting an effect of melatonin on the control of SkBF. To test whether exogenous melatonin also affects the more tonically active vasoconstrictor system in glabrous and nonglabrous skin during cooling, healthy males (n = 9) underwent afternoon sessions of whole body skin temperature (T(sk)) cooling (water-perfused suits) after oral melatonin (Mel; 3 mg) or placebo (Cont). Cutaneous vascular conductance (CVC) was calculated from SkBF (laser Doppler flowmetry) and non-invasive blood pressure. Baseline T(int) was lower in Mel than in Cont (P < 0.01). During progressive reduction of T(sk) from 35 degrees C to 32 degrees C, forearm CVC was first significantly reduced at T(sk) of 34.33 +/- 0.01 degrees C (P < 0.05) in Cont. In contrast, CVC in Mel was not significantly reduced until T(sk) reached 33.33 +/- 0.01 degrees C (P < 0.01). The decrease in forearm CVC in Mel was significantly less than in Cont at T(sk) of 32.66 +/- 0.01 degrees C and lower (P < 0.05). In Mel, palmar CVC was significantly higher than in Cont above T(sk) of 33.33 +/- 0.01 degrees C, but not below. Thus exogenous melatonin blunts reflex vasoconstriction in nonglabrous skin and shifts vasoconstrictor system control to lower T(int). It provokes vasodilation in glabrous skin but does not suppress the sensitivity to falling T(sk). These findings suggest that by affecting the vasoconstrictor system, melatonin has a causal role in the nocturnal changes in body temperature and its control.

Skin vasoconstriction as a heat conservation thermoeffector.

Cold exposure stimulates heat production and conservation to protect internal temperature. Heat conservation is brought about via reductions in skin blood flow. The focus, here, is an exploration of the mechanisms, particularly in humans, leading to that cutaneous vasoconstriction. Local skin cooling has several effects: (1) reduction of tonic nitric oxide formation by inhibiting nitric oxide synthase and element(s) downstream of the enzyme, which removes tonic vasodilator effects, yielding a relative vasoconstriction; (2) translocation of intracellular alpha-2c adrenoceptors to the vascular smooth-muscle cell membrane, enhancing adrenergic vasoconstriction; (3) increased norepinephrine release from vasoconstrictor nerves; and (4) cold-induced vasodilation, seen more clearly in anastomoses-rich glabrous skin. Cold-induced vasodilation occurs in nonglabrous skin when nitric oxide synthase or sympathetic function is blocked. Reflex responses to general body cooling complement these local effects. Sympathetic excitation leads to the increased release of norepinephrine and its cotransmitter neuropeptide Y, each of which contributes significantly to the vasoconstriction. The contributions of these two transmitters vary with aging, disease and, in women, reproductive hormone status. Interaction between local and reflex mechanisms is in part through effects on baseline and in part through removal of the inhibitory effects of nitric oxide on adrenergic vasoconstriction.

Influence of hyperoxia on skin vasomotor control in normothermic and heat-stressed humans.

Hyperoxia induces skin vasoconstriction in humans, but the mechanism is still unclear. In the present study we examined whether the vasoconstrictor response to hyperoxia is through activated adrenergic function (protocol 1) or through inhibitory effects on nitric oxide synthase (NOS) and/or cyclooxygenase (COX) (protocol 2). We also tested whether any such vasoconstrictor effect is altered by body heating. In protocol 1 (n = 11 male subjects), release of norepinephrine from adrenergic terminals in the forearm skin was blocked locally by iontophoresis of bretylium (BT). In protocol 2, the NOS inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) and the nonselective COX antagonist ketorolac (Keto) were separately administered by intradermal microdialysis in 11 male subjects. In the two protocols, subjects breathed 21% (room air) or 100% O(2) in both normothermia and hyperthermia. Skin blood flow (SkBF) was monitored by laser-Doppler flowmetry. Cutaneous vascular conductance (CVC) was calculated as the ratio of SkBF to blood pressure measured by Finapres. In protocol 1, breathing 100% O(2) decreased (P < 0.05) CVC at the BT-treated and at untreated sites from the levels of CVC during 21% O(2) breathing both in normothermia and hyperthermia. In protocol 2, the administration of l-NAME inhibited (P < 0.05) the reduction of CVC during 100% O(2) breathing in both thermal conditions. The administration of Keto inhibited (P < 0.05) the reduction of CVC during 100% O(2) breathing in hyperthermia but not in normothermia. These results suggest that skin vasoconstriction with hyperoxia is partly due to the decreased activity of functional NOS in normothermia and hyperthermia. We found no significant role for adrenergic mechanisms in hyperoxic vasoconstriction. Decreased production of vasodilator prostaglandins may play a role in hyperoxia-induced cutaneous vasoconstriction in heat-stressed humans.

Relative roles of local and reflex components in cutaneous vasoconstriction during skin cooling in humans.

The reduction in skin blood flow (SkBF) with cold exposure is partly due to the reflex vasoconstrictor response from whole body cooling (WBC) and partly to the direct effects of local cooling (LC). Although these have been examined independently, little is known regarding their roles when acting together, as occurs in environmental cooling. We tested the hypothesis that the vasoconstrictor response to combined LC and WBC would be additive, i.e., would equal the sum of their independent effects. We further hypothesized that LC would attenuate the reflex vasoconstrictor response to WBC. We studied 16 (7 women, 9 men) young (30.5+/-2 yr) healthy volunteers. LC and WBC were accomplished with metal Peltier cooler-heater probe holders and water-perfused suits, respectively. Forearm SkBF was monitored by laser-Doppler flowmetry (LDF). Cutaneous vascular conductance (CVC) was calculated as LDF/blood pressure. Subjects underwent 15 min of LC alone or 15 min of WBC with and without simultaneous LC, either at equal levels (34-31 degrees C) or as equipotent stimuli (34-28 degrees C LC; 34-31 degrees C WBC). The fall in CVC with combined WBC and LC was greater (P<0.05) than for either alone (57.0+/-5% combined vs. 39.2+/-6% WBC; 34.4+/-4% LC) with equipotent cooling, but it was only significantly greater than for LC alone with equal levels of cooling (51.3+/-8% combined vs. 29.5+/-4% LC). The sum of the independent effects of WBC and LC was greater than their combined effects (74.9+/-4 vs. 51.3+/-8% equal and 73.6+/-7 vs. 57.0+/-5% equipotent; P<0.05). The fall in CVC with WBC at LC sites was reduced compared with control sites (17.6+/-2 vs. 42.4+/-8%; P<0.05). Hence, LC contributes importantly to the reduction in SkBF with body cooling, but also suppresses the reflex response, resulting in a nonadditive effect of these two components.

Rate dependency and role of nitric oxide in the vascular response to direct cooling in human skin.

Local cooling of nonglabrous skin without functional sympathetic nerves causes an initial vasodilation followed by vasoconstriction. To further characterize these responses to local cooling, we examined the importance of the rate of local cooling and the effect of nitric oxide synthase (NOS) inhibition in intact skin and in skin with vasoconstrictor function inhibited. Release of norepinephrine was blocked locally (iontophoresis) with bretylium tosylate (BT). Skin blood flow was monitored from the forearm by laser-Doppler flowmetry (LDF). Cutaneous vascular conductance (CVC) was calculated as the ratio of LDF to blood pressure. Local temperature was controlled over 6.3 cm2 around the sites of LDF measurement. Local cooling was applied at -0.33 or -4 degrees C/min. At -4 degrees C/min, CVC increased (P < 0.05) at BT sites in the early phase. At -0.33 degrees C/min, there was no early vasodilator response, but there was a delay in the onset of vasoconstriction relative to intact skin. The NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) (intradermal microdialysis) decreased (P < 0.05) CVC by 28.3 +/- 3.8% at untreated sites and by 46.9 +/- 6.3% at BT-treated sites from the value before infusion. Rapid local cooling (-4 degrees C/min) to 24 degrees C decreased (P < 0.05) CVC at both untreated (saline) sites and L-NAME only sites from the precooling levels, but it transiently increased (P < 0.05) CVC at both BT + saline sites and BT + L-NAME sites in the early phase. After 35-45 min of local cooling, CVC decreased at BT + saline sites relative to the precooling levels (P < 0.05), but at BT + L-NAME sites CVC was not reduced below the precooling level (P = 0.29). These findings suggest that the rate of local cooling, but not functional NOS, is an important determinant of the early non-adrenergic vasodilator response to local cooling and that functional NOS, adrenergic nerves, as well as other mechanisms play roles in vasoconstriction during prolonged local cooling of skin.

Responses to hyperthermia. Optimizing heat dissipation by convection and evaporation: Neural control of skin blood flow and sweating in humans.

Under normothermic, resting conditions, humans dissipate heat from the body at a rate approximately equal to heat production. Small discrepancies between heat production and heat elimination would, over time, lead to significant changes in heat storage and body temperature. When heat production or environmental temperature is high the challenge of maintaining heat balance is much greater. This matching of heat elimination with heat production is a function of the skin circulation facilitating heat transport to the body surface and sweating, enabling evaporative heat loss. These processes are manifestations of the autonomic control of cutaneous vasomotor and sudomotor functions and form the basis of this review. We focus on these systems in the responses to hyperthermia. In particular, the cutaneous vascular responses to heat stress and the current understanding of the neurovascular mechanisms involved. The available research regarding cutaneous active vasodilation and vasoconstriction is highlighted, with emphasis on active vasodilation as a major responder to heat stress. Involvement of the vasoconstrictor and active vasodilator controls of the skin circulation in the context of heat stress and nonthermoregulatory reflexes (blood pressure, exercise) are also considered. Autonomic involvement in the cutaneous vascular responses to direct heating and cooling of the skin are also discussed. We examine the autonomic control of sweating, including cholinergic and noncholinergic mechanisms, the local control of sweating, thermoregulatory and nonthermoregulatory reflex control and the possible relationship between sudomotor and cutaneous vasodilator function. Finally, we comment on the clinical relevance of these control schemes in conditions of autonomic dysfunction.

Effect of skin temperature on cutaneous vasodilator response to the ß-adrenergic agonist isoproterenol.

The vascular response to local skin cooling is dependent in part on a cold-induced translocation of α2C-receptors and an increased α-adrenoreceptor function. To discover whether ß-adrenergic function might contribute, we examined whether ß-receptor sensitivity to the ß-agonist isoproterenol was affected by local skin temperature. In seven healthy volunteers, skin blood flow was measured from the forearm by laser-Doppler flowmetry and blood pressure was measured by finger photoplethysmography. Data were expressed as cutaneous vascular conductance (CVC; laser-Doppler flux/mean arterial blood pressure). Pharmacological agents were administered via intradermal microdialysis. We prepared four skin sites: one site was maintained at a thermoneutral temperature of 34°C (32 ± 10%CVCmax) one site was heated to 39°C (38 ± 11%CVCmax); and two sites were cooled, one to 29°C (22 ± 7%CVCmax) and the other 24°C (16 ± 4%CVCmax). After 20 min at these temperatures to allow stabilization of skin blood flow, isoproterenol was perfused in concentrations of 10, 30, 100, and 300 µM. Each concentration was perfused for 15 min. Relative to the CVC responses to isoproterenol at the thermoneutral skin temperature (34°C) (+21 ± 10%max), low skin temperatures reduced (at 29°C) (+17 ± 6%max) or abolished (at 24°C) (+1 ± 5%max) the vasodilator response, and warm (39°C) skin temperatures enhanced the vasodilator response (+40 ± 9%max) to isoproterenol. These data indicate that ß-adrenergic function was influenced by local skin temperature. This finding raises the possibility that a part of the vasoconstrictor response to direct skin cooling could include reduced background ß-receptor mediated vasodilation.

Body temperature regulation during hemodialysis in long-term patients: is it time to change dialysate temperature prescription?

During hemodialysis procedures, changes in the dialysate temperature can raise or lower body temperature because the blood is returned to the patient in thermal equilibrium with the dialysate. Even a dialysate temperature equal to the patient's body temperature as measured from the tympanic membrane, oral cavity, or axilla can result in an increase in the patient's body temperature, leading to cutaneous vasodilation and the potential for cardiovascular instability and hypotension. This deleterious cycle of events can be prevented by suitably adjusting the dialysate temperature. Lowering the dialysate temperature from 37 degrees C to 34-35.5 degrees C has improved the cardiovascular stability of many hemodialysis patients. Continuous monitoring of blood temperature allows the practitioner to make preemptive changes in dialysate temperature because a small change in body temperature can have enormous cardiovascular implications. For example, only 0.3 degrees C to 0.8 degrees C separates the thresholds for skin vasodilation from that for shivering. A suggested improvement in the hemodialysis procedure is to use devices that allow continuous monitoring of arterial and venous blood temperatures and adjust the dialysate temperature automatically, keeping the patient, not the dialysate, isothermic. Less optimal solutions appear to be (1) to monitor arterial and venous temperatures while manually adjusting the dialysate temperature to maintain arterial (and hence body) temperature stability; (2) to monitor peripheral temperatures (oral, tympanic) at regular intervals and adjust dialysate temperature to maintain the body temperature constant; (3) routinely use a dialysate temperature <37.0 degrees C in all patients unless contraindicated.

Cutaneous vasoconstrictor response to whole body skin cooling is altered by time of day.

To test for a diurnal difference in the vasoconstrictor control of the cutaneous circulation, we performed whole body skin cooling (water-perfused suits) at 0600 (AM) and 1600 (PM). After whole body skin temperature (T(sk)) was controlled at 35 degrees C for 10 min, it was progressively lowered to 32 degrees C over 18-20 min. Skin blood flow (SkBF) was monitored by laser-Doppler flowmetry at three control sites and at a site that had been pretreated with bretylium by iontophoresis to block noradrenergic vasoconstriction. After whole body skin cooling, maximal cutaneous vascular conductance (CVC) was measured by locally warming the sites of SkBF measurement to 42 degrees C for 30 min. Before whole body skin cooling, sublingual temperature (T(or)) in the PM was significantly higher than that in the AM (P < 0.05), but CVC, expressed as a percentage of maximal CVC (%CVC(max)), was not statistically different between AM and PM. During whole body skin cooling, %CVC(max) levels at bretylium-treated sites in AM or PM were not significantly reduced from baseline. In the PM, %CVC(max) at control sites fell significantly at T(sk) of 34.3 +/- 0.01 degrees C and lower (P < 0.05). In contrast, in the AM %CVC(max) at control sites was not significantly reduced from baseline until T(sk) reached 32.3 +/- 0.01 degrees C and lower (P < 0.05). Furthermore, the decrease in %CVC(max) in the PM was significantly greater than that in AM at T(sk) of 33.3 +/- 0.01 degrees C and lower (P < 0.05). Integrative analysis of the CVC response with respect to both T(or) and T(sk) showed that the cutaneous vasoconstrictor response was shifted to higher internal temperatures in the PM. These findings suggest that during whole body skin cooling the reflex control of the cutaneous vasoconstrictor system is shifted to a higher internal temperature in the PM. Furthermore, the slope of the relationship between CVC and T(sk) is steeper in the PM compared with that in the AM.

Cutaneous vasodilator and vasoconstrictor mechanisms in temperature regulation.

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.

Nitric oxide and receptors for VIP and PACAP in cutaneous active vasodilation during heat stress in humans.

VPAC2 receptors sensitive to vasoactive intestinal polypeptide (VIP) and pituitary adenylyl cyclase activating polypeptide (PACAP), PAC1 receptors sensitive to PACAP, and nitric oxide (NO) generation by NO synthase (NOS) are all implicated in cutaneous active vasodilation (AVD) through incompletely defined mechanisms. We hypothesized that VPAC2/PAC1 receptor activation and NO are synergistic and interdependent in AVD and tested our hypothesis by examining the effects of VPAC2/PAC1 receptor blockade with and without NOS inhibition during heat stress. The VPAC2/PAC1 antagonist, pituitary adenylate cyclase activating peptide 6-38 (PACAP6-38) and the NOS inhibitor, N(G)-nitro-l-arginine methyl ester (l-NAME) were administered by intradermal microdialysis. PACAP6-38, l-NAME, a combination of PACAP6-38 and l-NAME, or Ringer's solution alone were perfused at four separate sites. Skin blood flow was monitored by laser-Doppler flowmetry at each site. Body temperature was controlled with water-perfused suits. Blood pressure was monitored by Finapres, and cutaneous vascular conductance (CVC) calculated (CVC = laser-Doppler flowmetry/mean arterial pressure). The protocol began with a 5- to 10-min baseline period without antagonist perfusion, followed by perfusion of PACAP6-38, l-NAME, or combined PACAP6-38 and l-NAME at the different sites in normothermia (45 min), followed by 3 min of whole body cooling. Whole body heating was then performed to induce heat stress and activate AVD. Finally, 58 mM sodium nitroprusside were perfused at all sites to effect maximal vasodilation for normalization of blood flow data. No significant differences in CVC (normalized to maximum) were found among Ringer's PACAP6-38, l-NAME, or combined antagonist sites during normothermia (P > 0.05 among sites) or cold stress (P > 0.05 among sites). CVC responses at all treated sites were attenuated during AVD (P < 0.05 vs. Ringer's). Attenuation was greater at l-NAME and combined PACAP6-38- and l-NAME-treated sites than at PACAP6-38 sites (P > 0.05). Because responses did not differ between l-NAME and combined treatment sites (P > 0.05), we conclude that VPAC2/PAC1 receptors require NO in series to effect AVD.

Antagonism of soluble guanylyl cyclase attenuates cutaneous vasodilation during whole body heat stress and local warming in humans.

We hypothesized that nitric oxide activation of soluble guanylyl cyclase (sGC) participates in cutaneous vasodilation during whole body heat stress and local skin warming. We examined the effects of the sGC inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), on reflex skin blood flow responses to whole body heat stress and on nonreflex responses to increased local skin temperature. Blood flow was monitored by laser-Doppler flowmetry, and blood pressure by Finapres to calculate cutaneous vascular conductance (CVC). Intradermal microdialysis was used to treat one site with 1 mM ODQ in 2% DMSO and Ringer, a second site with 2% DMSO in Ringer, and a third site received Ringer. In protocol 1, after a period of normothermia, whole body heat stress was induced. In protocol 2, local heating units warmed local skin temperature from 34 to 41°C to cause local vasodilation. In protocol 1, in normothermia, CVC did not differ among sites [ODQ, 15 ± 3% maximum CVC (CVC(max)); DMSO, 14 ± 3% CVC(max); Ringer, 17 ± 6% CVC(max); P > 0.05]. During heat stress, ODQ attenuated CVC increases (ODQ, 54 ± 4% CVC(max); DMSO, 64 ± 4% CVC(max); Ringer, 63 ± 4% CVC(max); P < 0.05, ODQ vs. DMSO or Ringer). In protocol 2, at 34°C local temperature, CVC did not differ among sites (ODQ, 17 ± 2% CVC(max); DMSO, 18 ± 4% CVC(max); Ringer, 18 ± 3% CVC(max); P > 0.05). ODQ attenuated CVC increases at 41°C local temperature (ODQ, 54 ± 5% CVC(max); DMSO, 86 ± 4% CVC(max); Ringer, 90 ± 2% CVC(max); P < 0.05 ODQ vs. DMSO or Ringer). sGC participates in neurogenic active vasodilation during heat stress and in the local response to direct skin warming.

Local thermal control of the human cutaneous circulation.

The level of skin blood flow is subject to both reflex thermoregulatory control and influences from the direct effects of warming and cooling the skin. The effects of local changes in temperature are capable of maximally vasoconstricting or vasodilating the skin. They are brought about by a combination of mechanisms involving endothelial, adrenergic, and sensory systems. Local warming initiates a transient vasodilation through an axon reflex, succeeded by a plateau phase due largely to nitric oxide. Both phases are supported by sympathetic transmitters. The plateau phase is followed by the die-away phenomenon, a slow reversal of the vasodilation that is dependent on intact sympathetic vasoconstrictor nerves. The vasoconstriction with local skin cooling is brought about, in part, by a postsynaptic upregulation of α(2c)-adrenoceptors and, in part, by inhibition of the nitric oxide system at at least two points. There is also an early vasodilator response to local cooling, dependent on the rate of cooling. The mechanism for that transient vasodilation is not known, but it is inhibited by intact sympathetic vasoconstrictor nerve function and by intact sensory nerve function.

Thermoregulatory and thermal control in the human cutaneous circulation.

The past 10-15 years has been a time of focus on the mechanisms of control in the human cutaneous circulation. Methodological developments have provided powerful means for resolving the important contributors to the reflex control of skin blood flow (thermoregulatory control) and also for the equally impressive effects of direct heating and cooling of the skin (thermal control). This review is devoted largely to that recent literature. We treat the sympathetic vasoconstrictor system and its transmitters and modulatory factors and the sympathetic active vasodilator system and its abundant mysteries, with focus on the putative transmitters and cotransmitters, the involvement of nitric oxide and the relationship to sweating and modulatory factors. We also deal with the current understanding of the mechanisms of vasoconstriction and vasodilation that accompany direct skin cooling and heating, noting that adrenergic function, afferent nerve function and the nitric oxide system are involved in the vascular responses to both thermal stimuli.