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Cutaneous Vasodilator and Vasoconstrictor Mechanisms in Temperature Regulation

John M. Johnson, Christopher T. Minson, Dean L. Kellogg

10.1002/cphy.c130015

Source: Volume 4, Issue 1, January 2014

Published online: January 2014

Full Article on Wiley Online Library



Abstract

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. © 2014 American Physiological Society. Compr Physiol 4:33‐89, 2014.

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Figure 1. Figure 1. Summary of the changes in cardiac output and its distribution during whole body heat stress in resting subjects. Note that the blood flow to the major visceral circulations is reduced at a time cardiac output is significantly increased, indicating the average increase in blood flow to skin equaled or exceeded 7.8 L·min−1. Adapted, with permission, from Rowell (331).
Figure 2. Figure 2. Edholm et al. (92) demonstrated that thermoregulatory reflex vasodilation was dependent on neural activation by anaesthetizing the cutaneous nerves after activating the heat stress response by whole body heating. Forearm blood flow was measured in each forearm under normothermic conditions. Heat stress was then induced and when forearm blood flow had increased and stabilized, the skin of one forearm was anesthetized with lidocaine injections and forearm blood flow measurements continued. The upper three figures show the effect of cutaneous nerve block performed during whole body heating after forearm blood flow has increased. Control experiments were performed with saline in lieu of lidocaine. The results of this substitution are shown in the lower three figures.
Figure 3. Figure 3. Response in forearm skin blood flow to local and combined local and whole body heating, as functions of internal temperature (Tes). The filled symbols are from the arm initially warmed to 42°C. The open symbols are from the arm maintained at 34°C throughout. While the arms were at those temperatures, the subject underwent whole body heat stress. Note that the blood flow in the two arms reached the same level, indicating that either local warming to 42°C or the reflex response to whole body heat stress can maximally vasodilate the skin. Adapted, with permission, from Taylor et al. (399).
Figure 4. Figure 4. Responses in forearm blood flow and esophageal temperature to small cycles in whole body skin temperature. The data in the upper panel are from a forearm that was maintained at a neutral temperature throughout and the data in the second panel are from a forearm that had the surface temperature cycle with skin temperature. The vasoconstrictor response to the approximately 2°C reductions in skin temperature was sufficient to limit heat loss and cause internal temperature to increase. In this range, the response was almost entirely due to reflex vasoconstriction, as the variation in local temperature did not notably affect the response. Adapted, with permission, from Savage and Brengelmann (342).
Figure 5. Figure 5. Responses in cutaneous vascular conductance (CVC) to changes in internal temperature caused by mild exercise. Whole body skin temperature (Tsk) and local temperature at the site of blood flow measurement (Tloc) were independently controlled in a series of four experiments in which one or the other was cooled. The open symbols are data from control skin sites and the filled symbols are from skin sites pretreated with the antiadrenergic compound bretylium. Note that a cool Tsk shifts the relationship to a higher threshold and that shift is unaffected by vasoconstrictor nerve blockade (panels A vs. C). Note also that local cooling does not have any obvious effect on the threshold, but does reduce the sensitivity of the CVC‐esophageal temperature relationship and that reduction in sensitivity is reversed by vasoconstrictor nerve blockade. Adapted, with permission, from Pérgola et al. (308).
Figure 6. Figure 6. (A) Example of the effects of NOS blockade with L‐NAME on responses to cold stress (CS1 and CS2), whole body heating, and sodium nitroprusside infusion (SNP). Cutaneous vascular responses to cold stress were unaltered by L‐NAME treatment; however, the increase in cutaneous vascular conductance during whole body heating was attenuated. Sweat rate response was unaltered by L‐NAME. Adapted, with permission, from Kellogg et al. (216). (B) Example of cutaneous vascular conductance responses to intra‐arterial infusion of Ach, L‐NMMA, and nitroprusside (NTP) during whole body heating. Cutaneous vascular responses to whole body heating were attenuated by L‐NMMA infusion indicating that NO participates in cutaneous active vasodilation. Adapted, with permission, from Shastry et al. (351).
Figure 7. Figure 7. Influence of antagonism of nNOS via intradermal 7‐NI on the vasodilator response to whole body heating and (top panel) and to direct skin warming (lower panel). Note that the reflex effects were significantly reduced, whereas the response to direct local warming was unaffected. Adapted, with permission, from Kellogg et al. (231).
Figure 8. Figure 8. Effect of intradermal botulinum toxin on cutaneous active vasodilation, vasoconstriction, and sweating from one subject. The top panel shows sweating responses at an untreated site and at a botulinum toxin‐treated site. The lower panel shows cutaneous vascular conductance responses recorded simultaneously from the same sites as sweating. Periods of whole‐body cold stress (min 10‐13), whole‐body heating (min 26‐63), and local warming of the LDF sites (min 72‐112) are indicated. During cold stress, there was a fall in CVC at both sites, demonstrating cutaneous vasoconstriction. During heat stress, the untreated site showed a typical cutaneous vasodilation. No vasodilation occurred at the site pretreated with botulinum toxin. Sweating occurred at the untreated site, but not at the botulinum toxin‐treated site. These results indicate that cholinergic nerves mediate cutaneous active vasodilation. Given the results from atropinization above, this result demonstrates that mediation is via release of a cotransmitter. Adapted, with permission, from Kellogg et al. (227).
Figure 9. Figure 9. Evidence that VIP may affect a portion of cutaneous active vasodilation. Forearm sites were treated with atropine, the antagonist VIP(10‐28), both antagonists, or Ringer solution only. (A) The magnitude of the change in cutaneous vascular conductance during the last 2 min of whole body heating was not statistically different among treatment sites (‡p = 0.08); however, one subject displayed a dramatic, unexplained vasodilatation during the last 7 min of heat stress at the VIP(10‐28)‐treatment site only. (B) With this subject removed, VIP(10‐28) reduced the vasodilator response significantly Atropine did not significantly affect the magnitude of the vasodilation (15).
Figure 10. Figure 10. The effect of NK1 receptor desensitization on the plateau in skin blood flow achieved during whole‐body heating. The vasodilator response to whole body heating was significantly reduced in sites where substance P pretreatment was given when compared to untreated control sites. NOS inhibited sites that received L‐NAME only were attenuated compared to both untreated control sites and substance P desensitized sites. Responses at sites pretreated with substance P and L‐NAME were significantly reduced compared to all other sites. Adapted, with permission, from Wong and Minson (448).
Figure 11. Figure 11. Effect of TRPV1 channel antagonism with capsazepine, NOS blockade with L‐NAME, and combined TRPV1 and NOS during whole body heating as a function of increasing oral temperature (Tor). Cutaneous vascular conductance increases at sites treated capsazepine, L‐NAME, and combined capsazepine/L‐NAME sites were attenuated compared to untreated control sites. L‐NAME treatment whether with or without capsazepine produced similar degrees of attenuation. These results indicate that TRPV‐1 channels affect a portion of cutaneous active vasodilation and involve NO generation by NOS. Adapted, with permission, from Wong and Fieger (447).
Figure 12. Figure 12. An example of the effect of cyclooxygenase antagonism by ketorolac (KETO) with and without NOS blockade by L‐NAME on cutaneous vascular conductance responses to whole body heating. In normothermia, cutaneous vascular conductance did not differ among sites. In response to whole body heating cutaneous vascular conductance at all treated sites was significantly attenuated when compared to untreated control sites. Cutaneous vascular conductance at the combined KETO and L‐NAME site was significantly attenuated when compared to sites treated with KETO or L‐NAME alone. These results are consistent with involvement of the cyclooxygenase pathway in cutaneous active vasodilation through NO‐independent mechanisms. Adapted, with permission, from McCord et al. (279).
Figure 13. Figure 13. Summary of the Mechanisms Contributing to Active Vasodilation. In the left panel, a typical tracing of the skin blood flow response to whole body heating is presented, displaying baseline skin blood flow (expressed as percent of maximal cutaneous vascular conductance), the initial rise in skin blood flow representing release of tonic vasoconstrictor tone, and the subsequent rise in skin blood flow attributed to active vasodilation by sympathetic cholinergic nerves. In the right panel, a schematic of the current theory of cutaneous active vasodilation is presented. Acetylcholine (Ach) is released and contributes to the early rise in cutaneous active vasodilation and causes a simultaneous activation of sweat glands. The purported cotransmitters with Ach include vasoactive intestinal peptide (VIP) and/or pituitary adenylate cyclase‐activating peptide (PACAP). These will then bind to the pituitary adenylate cyclase‐activating peptide 1 receptor (PAC1) or the vasoactive intestinal peptide receptor 1 or 2 (VPAC1 or VPAC2). Evidence suggests a potential role for histamine acting via histamine‐1 receptors (H1), as well as activation of transient receptor potential vanilloid receptor 1 (TRPV‐1). These two pathways [and Ach via muscarinic receptor‐ 3 (M3)] appear to work through nitric oxide (NO) to contribute up to 40% to 50% of active vasodilation. Recent evidence demonstrates it is the neural NO synthase (nNOS) isoform. In addition, prostacyclin (PGI2) contributes to active vasodilation via the cyclooxygenase pathway (COX). A role for substance P via the neurokinin‐1 receptor (NK1) has also been described, although the specific mechanisms of this pathway have not been determined.
Figure 14. Figure 14. (A) Vasoconstrictor responses to reductions in whole body skin temperature from skin sites treated with the Y1 NPY receptor antagonist BIBP‐3226 (upper curve) or with Ringer's solution (lower curve), both by microdialysis. The NPY receptor antagonist inhibited the vasoconstrictor response. (B) Response to reduced whole body skin temperature at skin sites treated with Ringer's (control), Yohimbine and Propranolol (adrenergic antagonism) and Yohimbine, Propranolol plus BIBP‐3226 for adrenergic and NPY Y1 receptor blockade. Note that either adrenergic receptor blockade or NPY receptor blockade reduced the vasoconstrictor response to cooling, and that the combination eliminated the response, indicating a cotransmitter role for NPY in reflex cutaneous vasoconstriction. Adapted, with permission, from Stephens et al. (372).
Figure 15. Figure 15. Summary of the Mechanisms Contributing to Thermal Hyperemia. In the top left of the figure, a typical tracing of the skin blood flow response to rapid local heating to 42°C is presented, displaying an Initial Peak, a subsequent drop to a Nadir, and a further vasodilation to a sustained Plateau. This is often followed by an attenuation of the Plateau phase during the “die‐away” phenomenon. The middle figure displays the current theory behind the vasodilation to local heating during the Initial Peak, and the bottom figure displays the current theory behind vasodilation during the Plateau Phase. In both figures, pathways in the endothelium and the smooth muscle are presented. Roles for both sensory/nociceptive nerves releasing substance P (SP) and calcitonin gene‐related peptide (CGRP) and adrenergic nerves releasing norepinephrine (NE) and neuropeptide Y (NPY) are also shown. In both phases, vasodilation occurs through complex pathways that lead to the production of NO and smooth muscle relaxation via hyperpolarization from endothelial derived hyperpolarization factors (EDHFs). Potential sources of endothelial derived NO identified to date include the transient receptor peptide TRPV1, the adenosine receptors (A1 and A2), NK1‐receptor activation by SP, CGRP, and β2 receptor activation. Potential EDHFs include the epoxyeicosatrienoic acids (EETs), the lipoxygenase (LOX) derivatives 12‐(S)‐hydroxyeicosatetraenoic acid (12‐S‐HETE) and 11,12,15‐trihydroxyeicosatrienoic acid (11,12,15‐THETA), and H2O2.
Figure 16. Figure 16. Responses in CVC to slow local heating (panel A) and rapid local heating (panel B) from control sites and sites pretreated with bretylium (BT). Slow local heating causes an axon reflex (*). Under conditions of adrenergic blockade with BT, the axon reflex was abolished and a lower peak vasodilator response achieved. Rapid local heating caused a more pronounced axon reflex and a greater peak vasodilator response at the untreated site. Pretreatment with BT reduced (p < 0.05) but did not abolish the axon reflex to rapid heating. BT also causes an attenuated peak vasodilator response to local heating. The untreated sites showed a decline in CVC following rapid heating. This “die away” phenomenon was abolished by pretreatment with BT. †p < 0.05, CVC at these points is significantly higher at the untreated sites compared with that at the BT treated sites for that heating protocol. From Hodges et al. (157).
Figure 17. Figure 17. NOS isoforms and the responses to local skin warming. At a local skin temperature (Tloc) of 34°C, CVC values, normalized to their respective maxima, did not differ significantly among untreated, LNAA treated (eNOS antagonist), NPLA treated (nNOS antagonist) or their combination. CVC increased in response to local skin warming at all sites but that increase was significantly inhibited at the site with eNOS antagonism (228).
Figure 18. Figure 18. Representative tracing during local heating to 42°C from one subject from Brunt and Minson (41). Four microdialysis sites were infused with Ringer solution (Control), tetraethylammonium (TEA), NG‐nitro‐l‐arginine methyl ester (L‐NAME), and TEA+L‐NAME. Data are expressed as a percent of maximal CVC obtained from infusion of 56 mmol/L sodium nitroprusside. Initial Peak, Nadir, and Plateau phase responses were all reduced with TEA (to block calcium‐activated potassium channels; KCa). Combined blockade with TEA and L‐NAME nearly abolished all vasodilation during local heating, demonstrating that KCa channels have a profound role in the Initial Peak response to local heating, and account for the remaining ∼40% of vasodilation during the Plateau phase not inhibited by NO‐synthase inhibition alone (41).
Figure 19. Figure 19. (A) Effects of blockade of adrenergic receptors with yohimbine and propranolol (Y + P), the rho kinase inhibitor fasudil and their combination on the vasoconstrictor response to locally applied norepinephrine. (B) The effects of the same antagonists on the vasoconstrictor response to local skin cooling. Either antagonist reduced, but did not eliminate the response. Importantly, the combination of Y+P+ fasudil did not have an effect greater than that by fasudil alone, suggesting the adrenergic portion of the response to local skin cooling was through the rho kinase system. Adapted, with permission, from Thompson‐Torgerson et al. (407).
Figure 20. Figure 20. Effect of local treatment of skin with ascorbic acid on the vasoconstrictor response to local cooling (reduced Tloc at 0 min) and to reduced whole body skin temperature (Mean Tsk). Note that the vasoconstrictor response to local skin cooling was reduced by ascorbic acid treatment, suggesting a role for reactive oxygen species in the control response. Adapted, with permission, From Yamazaki (456).
Figure 21. Figure 21. Role of adrenergic nerves and NOS in the cutaneous vascular response to local skin cooling from 34 to 24°C. Sites were pretreated with bretylium to eliminate transmitter release from vasoconstrictor nerve terminals. NOS were inhibited at both sites, beginning at min 20, causing a vasoconstriction to develop over the next 35 min. At one site, NO and basely e CVC were restored via exogenous sodium nitroprusside (SNP; filled symbols). Local cooling was then applied to both sites between min 85 and 115. Note that in the site without exogenous SNP (open symbols), there was no vasoconstrictor response to local cooling, indicating the normal vasoconstrictor response to be dependent on a combination of NOS inhibition and adrenergic activation. At the site with NO and baseline blood flow restored, there was a “rescue” vasoconstriction, indicating that elements of the NOS system, downstream from the enzyme itself, are also inhibited by local cooling. Adapted, with permission, From Hodges et al. (159).
Figure 22. Figure 22. Summary of the mechanisms currently thought to participate in the cutaneous vascular response to local skin cooling. Included in this synthesis are a transient vasodilator response via an unknown mechanism, alpha2c receptor translocation from the Golgi to the smooth cell membrane via a Rho/Rho kinase stimulation, an inhibition of NOS and elements on that system downstream from NOS and an unknown involvement of cold sensitive afferents.
Figure 23. Figure 23. Illustration of threshold shifts in the skin blood flow‐internal temperature relationship. (A) During the development of reflex changes in skin blood flow during whole body heating under control conditions, there is an abrupt increase in skin blood flow after internal temperature reaches a threshold of approximately 37°C. (B) The internal temperature threshold for vasodilation is increased. This occurs during the luteal phase of the menstrual cycle or with oral contraceptive use. (C) The internal temperature threshold for vasodilation is decreased. This is observed during estrogen replacement therapy). The postthreshold sensitivity of responses A through C, that is, the slope of the skin blood flow‐internal temperature relationship, does not change. Adapted, with permission, From Charkoudian (48).
Figure 24. Figure 24. Increase in ΔSkBF from baseline to limits of thermal tolerance during direct passive heating, calculated as sum of increase in cardiac output ( Q · c ) from baseline and total blood flow redistributed from splanchnic (SBF) and renal (RBF) circulations: ΔSkBF = Δ Q · c + ΔSBF + ΔRBF. Numerical values are means ± SE for total ΔSkBF; n = 7/group. *Significantly different from young men (p < 0.01); (289).
Figure 25. Figure 25. Cutaneous vascular conductance responses during the plateau in skin blood flow heat stress in young and older persons. Cutaneous vasodilation was attenuated at untreated control sites and NOS‐inhibited sites in older subjects. Arginase inhibition, L‐arginine supplementation, and arginase inhibition with L‐arginine supplementation augmented in older but not young persons. Adapted, with permission, from Holowatz et al. (170).
Figure 26. Figure 26. Vasoconstrictor responses to LBNP in normothermic and hyperthermic conditions. The upper panel shows CVC responses from a site pretreated with bretylium to block vasoconstrictor nerve function. The middle panel shows data from an unblocked, control site. Three bouts of LBNP were performed (upper line, bottom panel). Cold stress was used to test for the adequacy of vasoconstrictor nerve block (solid squares and rectangles). The key features are that bretylium blocked the vasoconstrictor responses to body cooling and to LBNP in normothermia, but did not block the response to LBNP in hyperthermia. This finding indicates the cutaneous vasoconstriction (reduced CVC) with LBNP in hyperthermia is via inhibition of the active vasodilator system. Adapted, with permission, from Kellogg et al. (220).
Figure 27. Figure 27. Role of the active vasodilator system in the increased threshold internal temperature with dynamic exercise. CVC data are from rest (left two collections of square symbols) and exercise (right collections of circle symbols). Filled symbols indicate pretreatment with bretylium to block vasoconstrictor nerve function. Threshold was determined as the internal temperature (Tes) at which CVC began to increase. Both at rest and with exercise, the threshold for vasodilation did not differ between untreated control sites and sites pretreated with bretylium. However, the threshold for vasodilation was increased in both cases by exercise. This indicates the increased threshold to be an influence of exercise on the control of the vasodilator system. Adapted, with permission, from Kellogg et al. (222).
Figure 28. Figure 28. Responses in CVC measure from glabrous (palm and sole) and nonglabrous (forearm and leg) to isometric handgrip exercise (IHG) and isometric leg extension (ILE). Either form of isometric exercise caused a prompt and significant vasoconstriction in glabrous skin but no significant responses were seen in nonglabrous skin. Adapted, with permission, from Saad et al. (336).


Figure 1. Summary of the changes in cardiac output and its distribution during whole body heat stress in resting subjects. Note that the blood flow to the major visceral circulations is reduced at a time cardiac output is significantly increased, indicating the average increase in blood flow to skin equaled or exceeded 7.8 L·min−1. Adapted, with permission, from Rowell (331).


Figure 2. Edholm et al. (92) demonstrated that thermoregulatory reflex vasodilation was dependent on neural activation by anaesthetizing the cutaneous nerves after activating the heat stress response by whole body heating. Forearm blood flow was measured in each forearm under normothermic conditions. Heat stress was then induced and when forearm blood flow had increased and stabilized, the skin of one forearm was anesthetized with lidocaine injections and forearm blood flow measurements continued. The upper three figures show the effect of cutaneous nerve block performed during whole body heating after forearm blood flow has increased. Control experiments were performed with saline in lieu of lidocaine. The results of this substitution are shown in the lower three figures.


Figure 3. Response in forearm skin blood flow to local and combined local and whole body heating, as functions of internal temperature (Tes). The filled symbols are from the arm initially warmed to 42°C. The open symbols are from the arm maintained at 34°C throughout. While the arms were at those temperatures, the subject underwent whole body heat stress. Note that the blood flow in the two arms reached the same level, indicating that either local warming to 42°C or the reflex response to whole body heat stress can maximally vasodilate the skin. Adapted, with permission, from Taylor et al. (399).


Figure 4. Responses in forearm blood flow and esophageal temperature to small cycles in whole body skin temperature. The data in the upper panel are from a forearm that was maintained at a neutral temperature throughout and the data in the second panel are from a forearm that had the surface temperature cycle with skin temperature. The vasoconstrictor response to the approximately 2°C reductions in skin temperature was sufficient to limit heat loss and cause internal temperature to increase. In this range, the response was almost entirely due to reflex vasoconstriction, as the variation in local temperature did not notably affect the response. Adapted, with permission, from Savage and Brengelmann (342).


Figure 5. Responses in cutaneous vascular conductance (CVC) to changes in internal temperature caused by mild exercise. Whole body skin temperature (Tsk) and local temperature at the site of blood flow measurement (Tloc) were independently controlled in a series of four experiments in which one or the other was cooled. The open symbols are data from control skin sites and the filled symbols are from skin sites pretreated with the antiadrenergic compound bretylium. Note that a cool Tsk shifts the relationship to a higher threshold and that shift is unaffected by vasoconstrictor nerve blockade (panels A vs. C). Note also that local cooling does not have any obvious effect on the threshold, but does reduce the sensitivity of the CVC‐esophageal temperature relationship and that reduction in sensitivity is reversed by vasoconstrictor nerve blockade. Adapted, with permission, from Pérgola et al. (308).


Figure 6. (A) Example of the effects of NOS blockade with L‐NAME on responses to cold stress (CS1 and CS2), whole body heating, and sodium nitroprusside infusion (SNP). Cutaneous vascular responses to cold stress were unaltered by L‐NAME treatment; however, the increase in cutaneous vascular conductance during whole body heating was attenuated. Sweat rate response was unaltered by L‐NAME. Adapted, with permission, from Kellogg et al. (216). (B) Example of cutaneous vascular conductance responses to intra‐arterial infusion of Ach, L‐NMMA, and nitroprusside (NTP) during whole body heating. Cutaneous vascular responses to whole body heating were attenuated by L‐NMMA infusion indicating that NO participates in cutaneous active vasodilation. Adapted, with permission, from Shastry et al. (351).


Figure 7. Influence of antagonism of nNOS via intradermal 7‐NI on the vasodilator response to whole body heating and (top panel) and to direct skin warming (lower panel). Note that the reflex effects were significantly reduced, whereas the response to direct local warming was unaffected. Adapted, with permission, from Kellogg et al. (231).


Figure 8. Effect of intradermal botulinum toxin on cutaneous active vasodilation, vasoconstriction, and sweating from one subject. The top panel shows sweating responses at an untreated site and at a botulinum toxin‐treated site. The lower panel shows cutaneous vascular conductance responses recorded simultaneously from the same sites as sweating. Periods of whole‐body cold stress (min 10‐13), whole‐body heating (min 26‐63), and local warming of the LDF sites (min 72‐112) are indicated. During cold stress, there was a fall in CVC at both sites, demonstrating cutaneous vasoconstriction. During heat stress, the untreated site showed a typical cutaneous vasodilation. No vasodilation occurred at the site pretreated with botulinum toxin. Sweating occurred at the untreated site, but not at the botulinum toxin‐treated site. These results indicate that cholinergic nerves mediate cutaneous active vasodilation. Given the results from atropinization above, this result demonstrates that mediation is via release of a cotransmitter. Adapted, with permission, from Kellogg et al. (227).


Figure 9. Evidence that VIP may affect a portion of cutaneous active vasodilation. Forearm sites were treated with atropine, the antagonist VIP(10‐28), both antagonists, or Ringer solution only. (A) The magnitude of the change in cutaneous vascular conductance during the last 2 min of whole body heating was not statistically different among treatment sites (‡p = 0.08); however, one subject displayed a dramatic, unexplained vasodilatation during the last 7 min of heat stress at the VIP(10‐28)‐treatment site only. (B) With this subject removed, VIP(10‐28) reduced the vasodilator response significantly Atropine did not significantly affect the magnitude of the vasodilation (15).


Figure 10. The effect of NK1 receptor desensitization on the plateau in skin blood flow achieved during whole‐body heating. The vasodilator response to whole body heating was significantly reduced in sites where substance P pretreatment was given when compared to untreated control sites. NOS inhibited sites that received L‐NAME only were attenuated compared to both untreated control sites and substance P desensitized sites. Responses at sites pretreated with substance P and L‐NAME were significantly reduced compared to all other sites. Adapted, with permission, from Wong and Minson (448).


Figure 11. Effect of TRPV1 channel antagonism with capsazepine, NOS blockade with L‐NAME, and combined TRPV1 and NOS during whole body heating as a function of increasing oral temperature (Tor). Cutaneous vascular conductance increases at sites treated capsazepine, L‐NAME, and combined capsazepine/L‐NAME sites were attenuated compared to untreated control sites. L‐NAME treatment whether with or without capsazepine produced similar degrees of attenuation. These results indicate that TRPV‐1 channels affect a portion of cutaneous active vasodilation and involve NO generation by NOS. Adapted, with permission, from Wong and Fieger (447).


Figure 12. An example of the effect of cyclooxygenase antagonism by ketorolac (KETO) with and without NOS blockade by L‐NAME on cutaneous vascular conductance responses to whole body heating. In normothermia, cutaneous vascular conductance did not differ among sites. In response to whole body heating cutaneous vascular conductance at all treated sites was significantly attenuated when compared to untreated control sites. Cutaneous vascular conductance at the combined KETO and L‐NAME site was significantly attenuated when compared to sites treated with KETO or L‐NAME alone. These results are consistent with involvement of the cyclooxygenase pathway in cutaneous active vasodilation through NO‐independent mechanisms. Adapted, with permission, from McCord et al. (279).


Figure 13. Summary of the Mechanisms Contributing to Active Vasodilation. In the left panel, a typical tracing of the skin blood flow response to whole body heating is presented, displaying baseline skin blood flow (expressed as percent of maximal cutaneous vascular conductance), the initial rise in skin blood flow representing release of tonic vasoconstrictor tone, and the subsequent rise in skin blood flow attributed to active vasodilation by sympathetic cholinergic nerves. In the right panel, a schematic of the current theory of cutaneous active vasodilation is presented. Acetylcholine (Ach) is released and contributes to the early rise in cutaneous active vasodilation and causes a simultaneous activation of sweat glands. The purported cotransmitters with Ach include vasoactive intestinal peptide (VIP) and/or pituitary adenylate cyclase‐activating peptide (PACAP). These will then bind to the pituitary adenylate cyclase‐activating peptide 1 receptor (PAC1) or the vasoactive intestinal peptide receptor 1 or 2 (VPAC1 or VPAC2). Evidence suggests a potential role for histamine acting via histamine‐1 receptors (H1), as well as activation of transient receptor potential vanilloid receptor 1 (TRPV‐1). These two pathways [and Ach via muscarinic receptor‐ 3 (M3)] appear to work through nitric oxide (NO) to contribute up to 40% to 50% of active vasodilation. Recent evidence demonstrates it is the neural NO synthase (nNOS) isoform. In addition, prostacyclin (PGI2) contributes to active vasodilation via the cyclooxygenase pathway (COX). A role for substance P via the neurokinin‐1 receptor (NK1) has also been described, although the specific mechanisms of this pathway have not been determined.


Figure 14. (A) Vasoconstrictor responses to reductions in whole body skin temperature from skin sites treated with the Y1 NPY receptor antagonist BIBP‐3226 (upper curve) or with Ringer's solution (lower curve), both by microdialysis. The NPY receptor antagonist inhibited the vasoconstrictor response. (B) Response to reduced whole body skin temperature at skin sites treated with Ringer's (control), Yohimbine and Propranolol (adrenergic antagonism) and Yohimbine, Propranolol plus BIBP‐3226 for adrenergic and NPY Y1 receptor blockade. Note that either adrenergic receptor blockade or NPY receptor blockade reduced the vasoconstrictor response to cooling, and that the combination eliminated the response, indicating a cotransmitter role for NPY in reflex cutaneous vasoconstriction. Adapted, with permission, from Stephens et al. (372).


Figure 15. Summary of the Mechanisms Contributing to Thermal Hyperemia. In the top left of the figure, a typical tracing of the skin blood flow response to rapid local heating to 42°C is presented, displaying an Initial Peak, a subsequent drop to a Nadir, and a further vasodilation to a sustained Plateau. This is often followed by an attenuation of the Plateau phase during the “die‐away” phenomenon. The middle figure displays the current theory behind the vasodilation to local heating during the Initial Peak, and the bottom figure displays the current theory behind vasodilation during the Plateau Phase. In both figures, pathways in the endothelium and the smooth muscle are presented. Roles for both sensory/nociceptive nerves releasing substance P (SP) and calcitonin gene‐related peptide (CGRP) and adrenergic nerves releasing norepinephrine (NE) and neuropeptide Y (NPY) are also shown. In both phases, vasodilation occurs through complex pathways that lead to the production of NO and smooth muscle relaxation via hyperpolarization from endothelial derived hyperpolarization factors (EDHFs). Potential sources of endothelial derived NO identified to date include the transient receptor peptide TRPV1, the adenosine receptors (A1 and A2), NK1‐receptor activation by SP, CGRP, and β2 receptor activation. Potential EDHFs include the epoxyeicosatrienoic acids (EETs), the lipoxygenase (LOX) derivatives 12‐(S)‐hydroxyeicosatetraenoic acid (12‐S‐HETE) and 11,12,15‐trihydroxyeicosatrienoic acid (11,12,15‐THETA), and H2O2.


Figure 16. Responses in CVC to slow local heating (panel A) and rapid local heating (panel B) from control sites and sites pretreated with bretylium (BT). Slow local heating causes an axon reflex (*). Under conditions of adrenergic blockade with BT, the axon reflex was abolished and a lower peak vasodilator response achieved. Rapid local heating caused a more pronounced axon reflex and a greater peak vasodilator response at the untreated site. Pretreatment with BT reduced (p < 0.05) but did not abolish the axon reflex to rapid heating. BT also causes an attenuated peak vasodilator response to local heating. The untreated sites showed a decline in CVC following rapid heating. This “die away” phenomenon was abolished by pretreatment with BT. †p < 0.05, CVC at these points is significantly higher at the untreated sites compared with that at the BT treated sites for that heating protocol. From Hodges et al. (157).


Figure 17. NOS isoforms and the responses to local skin warming. At a local skin temperature (Tloc) of 34°C, CVC values, normalized to their respective maxima, did not differ significantly among untreated, LNAA treated (eNOS antagonist), NPLA treated (nNOS antagonist) or their combination. CVC increased in response to local skin warming at all sites but that increase was significantly inhibited at the site with eNOS antagonism (228).


Figure 18. Representative tracing during local heating to 42°C from one subject from Brunt and Minson (41). Four microdialysis sites were infused with Ringer solution (Control), tetraethylammonium (TEA), NG‐nitro‐l‐arginine methyl ester (L‐NAME), and TEA+L‐NAME. Data are expressed as a percent of maximal CVC obtained from infusion of 56 mmol/L sodium nitroprusside. Initial Peak, Nadir, and Plateau phase responses were all reduced with TEA (to block calcium‐activated potassium channels; KCa). Combined blockade with TEA and L‐NAME nearly abolished all vasodilation during local heating, demonstrating that KCa channels have a profound role in the Initial Peak response to local heating, and account for the remaining ∼40% of vasodilation during the Plateau phase not inhibited by NO‐synthase inhibition alone (41).


Figure 19. (A) Effects of blockade of adrenergic receptors with yohimbine and propranolol (Y + P), the rho kinase inhibitor fasudil and their combination on the vasoconstrictor response to locally applied norepinephrine. (B) The effects of the same antagonists on the vasoconstrictor response to local skin cooling. Either antagonist reduced, but did not eliminate the response. Importantly, the combination of Y+P+ fasudil did not have an effect greater than that by fasudil alone, suggesting the adrenergic portion of the response to local skin cooling was through the rho kinase system. Adapted, with permission, from Thompson‐Torgerson et al. (407).


Figure 20. Effect of local treatment of skin with ascorbic acid on the vasoconstrictor response to local cooling (reduced Tloc at 0 min) and to reduced whole body skin temperature (Mean Tsk). Note that the vasoconstrictor response to local skin cooling was reduced by ascorbic acid treatment, suggesting a role for reactive oxygen species in the control response. Adapted, with permission, From Yamazaki (456).


Figure 21. Role of adrenergic nerves and NOS in the cutaneous vascular response to local skin cooling from 34 to 24°C. Sites were pretreated with bretylium to eliminate transmitter release from vasoconstrictor nerve terminals. NOS were inhibited at both sites, beginning at min 20, causing a vasoconstriction to develop over the next 35 min. At one site, NO and basely e CVC were restored via exogenous sodium nitroprusside (SNP; filled symbols). Local cooling was then applied to both sites between min 85 and 115. Note that in the site without exogenous SNP (open symbols), there was no vasoconstrictor response to local cooling, indicating the normal vasoconstrictor response to be dependent on a combination of NOS inhibition and adrenergic activation. At the site with NO and baseline blood flow restored, there was a “rescue” vasoconstriction, indicating that elements of the NOS system, downstream from the enzyme itself, are also inhibited by local cooling. Adapted, with permission, From Hodges et al. (159).


Figure 22. Summary of the mechanisms currently thought to participate in the cutaneous vascular response to local skin cooling. Included in this synthesis are a transient vasodilator response via an unknown mechanism, alpha2c receptor translocation from the Golgi to the smooth cell membrane via a Rho/Rho kinase stimulation, an inhibition of NOS and elements on that system downstream from NOS and an unknown involvement of cold sensitive afferents.


Figure 23. Illustration of threshold shifts in the skin blood flow‐internal temperature relationship. (A) During the development of reflex changes in skin blood flow during whole body heating under control conditions, there is an abrupt increase in skin blood flow after internal temperature reaches a threshold of approximately 37°C. (B) The internal temperature threshold for vasodilation is increased. This occurs during the luteal phase of the menstrual cycle or with oral contraceptive use. (C) The internal temperature threshold for vasodilation is decreased. This is observed during estrogen replacement therapy). The postthreshold sensitivity of responses A through C, that is, the slope of the skin blood flow‐internal temperature relationship, does not change. Adapted, with permission, From Charkoudian (48).


Figure 24. Increase in ΔSkBF from baseline to limits of thermal tolerance during direct passive heating, calculated as sum of increase in cardiac output ( Q · c ) from baseline and total blood flow redistributed from splanchnic (SBF) and renal (RBF) circulations: ΔSkBF = Δ Q · c + ΔSBF + ΔRBF. Numerical values are means ± SE for total ΔSkBF; n = 7/group. *Significantly different from young men (p < 0.01); (289).


Figure 25. Cutaneous vascular conductance responses during the plateau in skin blood flow heat stress in young and older persons. Cutaneous vasodilation was attenuated at untreated control sites and NOS‐inhibited sites in older subjects. Arginase inhibition, L‐arginine supplementation, and arginase inhibition with L‐arginine supplementation augmented in older but not young persons. Adapted, with permission, from Holowatz et al. (170).


Figure 26. Vasoconstrictor responses to LBNP in normothermic and hyperthermic conditions. The upper panel shows CVC responses from a site pretreated with bretylium to block vasoconstrictor nerve function. The middle panel shows data from an unblocked, control site. Three bouts of LBNP were performed (upper line, bottom panel). Cold stress was used to test for the adequacy of vasoconstrictor nerve block (solid squares and rectangles). The key features are that bretylium blocked the vasoconstrictor responses to body cooling and to LBNP in normothermia, but did not block the response to LBNP in hyperthermia. This finding indicates the cutaneous vasoconstriction (reduced CVC) with LBNP in hyperthermia is via inhibition of the active vasodilator system. Adapted, with permission, from Kellogg et al. (220).


Figure 27. Role of the active vasodilator system in the increased threshold internal temperature with dynamic exercise. CVC data are from rest (left two collections of square symbols) and exercise (right collections of circle symbols). Filled symbols indicate pretreatment with bretylium to block vasoconstrictor nerve function. Threshold was determined as the internal temperature (Tes) at which CVC began to increase. Both at rest and with exercise, the threshold for vasodilation did not differ between untreated control sites and sites pretreated with bretylium. However, the threshold for vasodilation was increased in both cases by exercise. This indicates the increased threshold to be an influence of exercise on the control of the vasodilator system. Adapted, with permission, from Kellogg et al. (222).


Figure 28. Responses in CVC measure from glabrous (palm and sole) and nonglabrous (forearm and leg) to isometric handgrip exercise (IHG) and isometric leg extension (ILE). Either form of isometric exercise caused a prompt and significant vasoconstriction in glabrous skin but no significant responses were seen in nonglabrous skin. Adapted, with permission, from Saad et al. (336).
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Article Title: Cutaneous Vasodilator and Vasoconstrictor Mechanisms in Temperature Regulation
 

How to Cite

John M. Johnson, Christopher T. Minson, Dean L. Kellogg. Cutaneous Vasodilator and Vasoconstrictor Mechanisms in Temperature Regulation. Compr Physiol 2014, 4: 33-89. doi: 10.1002/cphy.c130015