1420

Baroreflex Control of the Cutaneous Active Vasodilator System in Humans

Dean L. Kellogg Jr., John M. Johnson, and W.A. Kosiba

Cutaneous arterioles are controlled by vasoconstrictor and active vasodilator sympathetic nerves. To find out whether the active vasodilator system is under control, laser-Doppler velocimetry and the local iontophoresis of bretylium were combined to allow selective study of the active vasodilator system. Each of six subjects had two forearm sites (0.64 cm2) treated with bretylium to abolish adrenergic vasoconstrictor control. Laser-Doppler

Downloaded from velocimetry was monitored at those sites and at two adjacent untreated sites. Subjects underwent 3 minutes of lower-body negative pressure (LBNP) and 3 minutes of cold stress to verify blockade of vasoconstrictor nerves. They were then subjected to whole-body heat stress (water-perfused suits), and the 3 minutes of LBNP was repeated. Finally, subjects were returned to normothermia, and LBNP and cold stress were repeated to verify the persistence of blockade. During the application of LBNP in normothermia, cutaneous vascular conductance http://circres.ahajournals.org/ (CVC) fell at untreated sites by 22.7+4.7% (p<0.01) but was unaffected at bretylium-treated sites (p >0.20). During cold stress, CVC at untreated sites fell by 30.2±1.7% (p<0.01) and at treated sites rose by 0.7+±4.6% (p>0.10). Both control and bretylium-treated sites reflexly vasodilated in response to hyperthermia. With LBNP during hyperthermia, CVC at untreated sites fell by 23.3±7.1% (p<0.05) and at treated sites by 17.9±9.2% (p<0.05) with no significant difference between sites (p>0.10). After return to normothermia, neither LBNP application nor cold stress caused CVC to fall at treated sites (p>0.10). Thus, the vasoconstrictor system was blocked by bretylium treatment throughout the study, whereas the active vasodilator response

by guest on November 4, 2017 to heat stress was intact. Because LBNP in hyperthermia induced similar falls in CVC at both sites, we conclude that baroreceptor unloading elicits a withdrawal of active vasodilator tone and that the baroreflex has control of the active vasodilator system. (Circulation Research 1990;66:1420-1426)

T he participation of the human cutaneous cir- Despite some skepticism, it does appear that the culation in thermoregulatory and nonther- cutaneous circulation is on the efferent limb of moregulatory has been the subject of several nonthermoregulatory reflexes, including the much research over the last 30 years. Investigations baroreceptor . During baroreceptor unloading of thermoregulatory reflexes have clearly demon- in normothermic conditions, cutaneous vasoconstric- strated the neural mechanisms responsible for tion has been documented.5,7"1',14'18 Further, the effecting changes in skin blood flow in response to cutaneous vascular responses to nonthermoregula- heat and cold stresses.'-4 However, such clarity of tory reflexes can be modified by thermal status. understanding has not been achieved for nonther- During periods of heat stress, the absolute decrease moregulatory reflexes. Though much evidence from in cutaneous vascular conductance (CVC) is usually studies measuring skin blood flow supports the con- clusion that the cutaneous circulation participates in greater than in normothermia; however, the vasocon- reflexes of nonthermoregulatory origin,3 14 some striction induced by the baroreflex does not com- doubts have persisted in the literature.15-17 Given pletely overwhelm the induced by heat that debate, it is not surprising that the neural stress.6,8 9 Thus, the baroreflex competes with simul- mechanisms involved are also uncertain. taneous thermoregulatory reflex drives to produce an integrated cutaneous vascular response.6-9 From the Department of Physiology, The University of Texas The integration of neural control mechanisms for Health Science Center at San Antonio. the cutaneous circulation in nonapical areas (limbs Supported by National Institutes of Health grant HL-20663. and trunk) is not well understood. Arterioles in these Address for correspondence: John M. Johnson, PhD, Depart- ment of Physiology, The University of Texas Health Science skin areas receive efferent sympathetic active vasodi- Center at San Antonio, San Antonio, TX 78284. lator innervation in addition to noradrenergic vaso- Received July 25, 1989; accepted January 9, 1990. constrictor nerves.' Thus, alterations of CVC during Kellogg et al Baroreflex-Induced Vasodilator Withdrawal 1421

simultaneous thermoregulatory and nonthermoregu- as an average from six thermocouples placed at latory reflexes could be effected by changes in either representative sites over the body surface. Subjects one of these dual vasomotor systems or perhaps by wore two sets of impermeable garments with a water- simultaneous changes in both. The neurotransmitter perfused suit between them. T,k was controlled by of the vasodilator nerves is unknown, although an perfusing the tube-lined suit with water of different indirect relation to sudomotor nerve activity is temperatures.26'27 The suits and garments covered postulated.1"19-21 The active vasodilator system is the entire body with the exception of the head, arms, responsible for 85-95% of the cutaneous vasodila- and feet. Cold stress was induced by perfusing the tion occurring with heat stress.48 Because whole- suit with cold water to lower TSk from 34°-35° C to body skin blood flow can achieve levels approaching 30°-32°C. Similarly, heat stress was induced by 8 1/min, or 60% of during heat stress,8 with warm water to raise Tsk to 38°-38.5° C it is clear that this vasodilator system is important and Tes by 1°-1.5° C. both to thermoregulatory responses and to systemic rate was continuously recorded from the . ECG. LDV was measured at each of four forearm How the dual neural systems that control the non- sites (Blood Perfusion Monitor, TSI, St. Paul, Min- apical cutaneous circulation interact to produce inte- nesota). was recorded approximately grated cutaneous vascular responses to simultaneously once per minute with an electrosphygmomanometer occurring thermoregulatory and nonthermoregulatory applied to the arm contralateral to the LDV probes drives is unknown.3,8'9 Are nonthermoregulatory (PE-300, Narco Bio-Systems, Houston, Texas). Sys- Downloaded from reflexes that exert control over cutaneous arterioles tolic and diastolic pressures were ascertained by mediated by both efferent neural pathways? Alterna- analysis of Korotkoff sounds superimposed on the tively, are nonthermoregulatory reflexes mediated cuff pressure tracing.28 was solely by alterations in vasoconstrictor tone? At which computed from the blood pressure measurements as site or sites are simultaneous thermoregulatory and the diastolic pressure plus one third of the http://circres.ahajournals.org/ nonthermoregulatory reflexes integrated? pressure. CVC was calculated as LDV (volts)/mean If active vasoconstrictor control could be abolished arterial pressure (mm Hg). without altering the vasodilator system, the reflexes In all experiments, iontophoresis was accom- responsible for controlling the latter could be directly plished with Plexiglas chambers (0.64 cm2) mounted studied. Recently, a method based on a similar on the forearm and filled with a 10 mM solution of approach by Lindblad and Ekenvall22 for such a selec- bretylium tosylate dissolved in propylene glycol. tive abolition has been accomplished.23 Local ionto- Total current density for iontophoresis procedures phoresis of bretylium tosylate in combination with was 400 ,gA/cm2 for a duration of 10 minutes. Details laser-Doppler velocimetry (LDV) has been shown to and experimental verification of this procedure have by guest on November 4, 2017 give reliable pharmacological abolition of responses been reported previously.23 caused by the cutaneous active vasoconstrictor system Lower-body negative pressure (LBNP) was accom- without significant effect on the vasodilator system.23 plished by enclosing the body below the iliac crests in Bretylium is an antiadrenergic agent that is taken up by a chamber attached to a vacuum source to reduce the adrenergic nerve terminals and blocks the release of air pressure within the LBNP chamber.29 This drop norepinephrine.24 The combination of bretylium ionto- in pressure increases the transmural pressure gradi- phoresis with LDV appears to be an ideal technique to ent across lower-body blood vessels. This, in turn, study directly the active vasodilator system without the leads to the pooling of blood in the lower body, confounding effects of the active vasoconstrictor sys- causing unloading of cardiopulmonary and, possibly, tem. Hence, the use of this technique could reveal arterial . LBNP was applied at -40 whether the cutaneous vasodilator system is under mm Hg (relative to atmospheric pressure) for a dura- baroreceptor reflex control. tion of 3 minutes. The protocol followed in these experiments began Subjects and Methods with the iontophoresis of bretylium at two experi- Experiments were performed in six supine male mental sites on the right forearm. There were also subjects (ages 26-44). Their average age was 32.5± two adjacent untreated control sites. Subjects were 2.55 years, average height was 179.07+2.30 cm, and instrumented and placed in a supine position approx- average weight was 75.75 + 3.16 kg. Physical examina- imately 1.5 hours after the completion of iontophore- tions, including 12-lead ECG, showed all subjects to sis. During this period the antiadrenergic effects of be in good health. The informed consent of each the drug developed. subject was obtained before participation in this The entire protocol subsequent to the iontophore- institutionally approved study. sis procedure is shown for one subject in Figure 1. Esophageal temperature (Tes) was monitored as an Data collection began with a 5-minute, normother- index of internal temperature with a catheter con- mic control period followed by a 3-minute applica- taining a thermocouple swallowed to left atrial level. tion of -40 mm Hg LBNP. After 10-12 minutes of Placement of the Tes catheter was verified by P wave recovery, a 3-minute cold stress period was per- configuration of the ECG as recorded from the formed, after which the subject was returned to catheter tip.25 Skin temperature (TJk) was recorded normothermia for a 5-minute period of recovery. 1422 Circulation Research Vol 66, No 5, May 1990

800-

600- cvc - U 400 - z < 100 -

200- z RETYLIUM 0 TREATED u 75- 0- R 0 800 z o 50- U 600 QC cvc

400 -

200- MINUTES 0 2. the cutaneous vascular conductance 100- FIGURE Example of (CVC) responses in one subject to lower-body negative pres- sure (LBNP) under normothermic conditions. CVC values

Downloaded from MAP - mm Hg have been normalized to the initial 5-minute controlperiod of the study. Note the prompt and sustained decrease in CVC at the untreated site during LBNP. No such CVCfall waspresent

0 4 at the bretylium-treated site. 38 Tes http://circres.ahajournals.org/ observing reflex cutaneous .13 T10c 36.5* was controlled by a heating element that surrounded °C. the LDV probe and was monitored by a thermocou- ple placed between the skin surface and the heating

-50 0o _20 r 40 60 80, 100_ 120 element.12 In one study, local warming was not used MINUTES in conjunction with the verification of blockade. FIGURE 1. Illustration of entire protocol and results from Because bretylium acts presynaptically to block nor- one subject. Upper panels show cutaneous vascular conduc- epinephrine release, cold stresses and LBNP periods tance (CVC) at untreated and bretylium-treated sites as

by guest on November 4, 2017 were kept brief to avoid a-receptor activation by percentages of initial control levels. The bottom panel shows circulating catecholamines.24 periods of lower-body negative pressure (LBNP) (continuous LDV, Tes, TSk, , and LBNP levels were line), cold stress (black squares at 15 and 102 minutes), recorded by a laboratory computer equipped with an whole-body heat stress (open rectangle between 26 and 58 analog-to-digital converter. Each variable was sam- minutes), and local warming of sites of blood flow measure- once per and average values for each ment (shaded rectangle between 70 and 111 minutes). Also pled second, shown are mean arterial pressure (MAP) and esophageal 20-second period were calculated. temperature (TeJ. Note that CVC at bretylium-treated sites is For data analysis, responses from the two bretylium- not reduced by cold stress or by LBNP in nornothermia but is treated and two untreated sites were averaged to yield reduced by LBNP when cutaneous active vasodilator activity treated and untreated average responses for each sub- has been increased by whole-body heat stress. ject. Effects of bretylium were analyzed by paired t test, which compared the responses at control sites with those at the bretylium-treated sites. Percent changes These manipulations served to confirm the presence were calculated from a 5-minute control period to the of vasoconstrictor blockade. A 35-45 -minute period last minute of LBNP or cold stress. of heat stress (Tsk, 38°-38.5° C) was then performed. After Te, had increased by approximately 05-1° C Results and LDV measurements stabilized, the 3-minute Initial blockade of the vasoconstrictor system by period of -40 mm Hg LBNP was repeated. After bretylium iontophoresis was shown by the failure of recovery, subjects were cooled to normothermia. This CVC at treated sites to respond to either LBNP or was followed by a final LBNP period and a second cold stress in the first period of normothermia. cold stress to verify that the cutaneous vasoconstric- Figure 2 shows responses in CVC from both tor blockade was sustained. In five studies, including bretylium-treated and untreated sites to the initial the study depicted in Figure 1, the verification LBNP period of LBNP for one subject. On the average, periods and cold stresses were done after the skin CVC fell by 22.7+4.7% at untreated sites (p<0.01), at both the treated and untreated sites was locally but did not change significantly at sites treated with warmed to 390 C (Tloc) because it has been shown bretylium (p>0.20) (see Table 1). The results of that a local temperature of 39° C is optimal for LBNP application during normothermia are summa- Kellogg et al Baroreflex-Induced Vasodilator Withdrawal 1423

TABLE 1. Responses in Cutaneous Vascular Conductance to Cold 800 1 Stress and Lower-Body Negative Pressure Control site Bretylium site Condition (%) (%) LLI Initial cold stress -30.2±1.7* 0.8±4.5t z LBNP normothermia -22.7±4.7* -1.9±2.5t doU z LBNP hyperthermia -23.3±7.1* - 17.9 ± 9.2t 0 _i LBNP blockade verification -14.6±10.6 3.3±3.7 0 Cold stress verification -34.9±10.7i 1.6±1.9t z 0 Ui Values are mean±SEM. be Percent changes in cutaneous vascular conductance (CVC) at control (untreated) and bretylium-treated sites in response to cold stress, lower-body negative pressure (LBNP) in normothermia and hyperthermia, and cold stress and LBNP after hyperthermia (verification). Note that vasoconstrictor responses at the bret- ylium-treated sites were successfully blocked except in response to MINUTES LBNP during hyperthermia. FIGURE 4. An example of the cutaneous vascular conduc- *p<0.01 reduction from rest. tance (CVC) response to lower-body negative pressure tp<0.01 treated vs. untreated sites. tp<0.05 reduction from rest. (LBNP) in one subject under hyperthermic conditions. This Downloaded from example is takenfrom the same study and sites as shown under rized in Figure 3. As also shown by Table 1, similar normothermic conditions in Figure 1 and is again normalized findings were made for the initial period of cold to thefirst 5-minute controlperiod ofthe study. Note that CVC stress. Bretylium-treated sites again showed no sig- before LBNP had increased dramatically with heat stress (compare with Figure 1). With LBNP application there was a nificant change in CVC (p>0.30), whereas CVC at dramatic and http://circres.ahajournals.org/ untreated sites fell significantly (p<0.01). Paired com- sustained fall in CVC at both the treated and parisons revealed a highly significant difference in untreated sites. After termination of LBNP, both sites recov- responses between sites (p<0.005 for both cold stress ered to or above pre-LBNP control levels. and LBNP). Heart rate rose slightly, but significantly, during the initial period of LBNP (60.9+3.7 beats/min Heat stress caused significant vasodilation at all control to 65.9±3.6 beats/min LBNP, p<0.05). Mean sites, regardless of treatment. At control sites, CVC arterial pressure was not significantly affected by rose by an average of 497+82% (p<0.001) and at LBNP. sites treated with bretylium by 361+57% (p<

by guest on November 4, 2017 0.005). There was no significant difference in the 20 degree of vasodilation between untreated and 10 bretylium-treated sites (p>0.10). The internal tem- perature at which vasodilation began was not dif- L 0' ferent between untreated and bretylium-treated cc -10 _ sites (36.97±+0.070 C and 37.12±+0.100 C, respec- tively, p>0.05 between sites). The failure of Z> -20- Lu -4 - bretylium iontophoresis to alter these vasodilator -30 parameters, despite blockade of vasoconstriction, is Lu consistent with earlier findings.23 COl -40 The period of LBNP during hyperthermia was U associated with a significant reduction in CVC at (~) -50 both untreated sites and at sites treated by bretylium iontophoresis. Figure 4 shows responses from one subject to the period of LBNP in hyperthermia. The

-70 -60 -50 -40 -30 -20 -10 0 10 20 results of LBNP application during hyperthermia are %X CVC UNTREATED summarized in Figure 5 and Table 1. At untreated sites, CVC fell by while at FIGURE 3. Identity plot summarizing results of initial lower- 23.3±+7.1% (p<0.05), treated fall body negative pressure (LBNP) application in normothernia. sites this averaged 17.9±9.2% (p<0.05). Note that all points are shifted above the line of identity and Comparison of responses between sites revealed no cluster around zero on the bretylium-treated axis. Overall, significant difference (p>0.10). Also, during the sec- untreated sites fell by 22.73+4.71% (p<0.001) from the ond period of LBNP, heart rate rose from 79.7±3.9 5-minute pre-LBNP controlperiod to the last minute ofLBNP to 92.0+6.8 beats/min (p<0.05). There was no sig- application. Bretylium-treated sites fell by 1.91±2.51% nificant change in mean arterial pressure. (p>0.20). The difference between these responses was highly After heat stress, subjects were returned to nor- significant (p<0.005), indicating that vasoconstrictor block- mothermia, and LBNP was repeated to verify that ade was present. vasoconstrictor blockade had persisted through the 1424 Circulation Research Vol 66, No 5, May 1990

of heat stress. This conclusion is also supported by the lack of responses in CVC at treated sites during the initial LBNP application in normothermia. Again, a reflex known to be mediated by increased vasoconstrictor tone was abolished by bretylium cz -10 iontophoresis. Why LBNP application after heat

-20 stress caused no significant falls at either treated or D untreated sites is unclear. Nevertheless, it is safe to -30 conclude that bretylium iontophoresis had blocked Lii the vasoconstrictor system for the duration of these -40 studies. Thus, responses in CVC recorded from

U~ -50 bretylium-treated sites were due exclusively to the active vasodilator system. However, had bretylium -60 / also affected vasodilator responses?

-70 Two pieces of evidence support the conclusion that -70 -60 -50 -40 -30 -20 -10 0 10 20 the active vasodilator system was unaltered by the

?A CVC UNTREATED drug. First, the internal temperature thresholds for FIGURE 5. Identity plot summarizing data for lower-body the onset of cutaneous vasodilation were not dif- ferent between treated and untreated sites. Second, Downloaded from negative pressure (LBNP) application during heat stress. Note the clustering ofpoints along the line ofidentity, unlike that in there was no significant difference in the extent of normothermia (compare with Figure 2). Overall, during vasodilation induced by heat stress between sites. LBNP application in hyperthermia, cutaneous vascular con- Both observations are in keeping with an earlier ductance (CVC) at untreated sites fell by 23.30±7.12% study from this laboratory.23 This leads to the con- (p<0.05) and at bretylium-treated sites by 17.90±9.21% clusion that the responses in CVC at bretylium- http://circres.ahajournals.org/ (p<0.05). The treated and untreated responses were not treated sites were entirely due to an intact vasodila- significantly different from each other (p>0.10), indicating tor system. Thus, baroreceptor unloading directly that bretylium treatment did not alter the vasoconstriction reduced active vasodilator tone and thereby effected induced by baroreceptor unloading during heat stress. Vaso- vasoconstriction. constriction must have occurred because of withdrawal of What of the active vasoconstrictor system? Did it active vasodilator tone. play a role in the baroreflex-mediated vasoconstric- tion during heat stress? Untreated sites, with both vasomotor systems intact, showed CVC reductions study. In the five studies in which local temperature that were statistically identical to those at treated by guest on November 4, 2017 was raised to 390 C, LBNP application for verification sites during LBNP application in hyperthermia. of blockade elicited no statistically significant alter- Because the treated sites (with only vasodilator con- ations in CVC at either treated or untreated sites trol) and the untreated sites (with dual control) (p>0.10 for both sites) (see Table 1). However, when showed statistically identical responses, all of the cold stress verification was performed, CVC at decrease in CVC may have been due to vasodilator untreated sites fell by 34.9+10.8% (p<0.05), where- withdrawal. However, we cannot rule out some minor as at treated sites CVC was unchanged (p>0.30). participation by the vasoconstrictor system. Nonethe- These responses were significantly different between less, the integrated cutaneous vascular response to sites (p<0.05), indicating vasoconstrictor blockade simultaneous thermoregulatory and baroreceptor was still present at treated sites. reflexes is due largely to reduction in active vasodi- lator tone. What can be concluded about the site of Discussion this integration? The major result of this study was the clear dem- Before this study, some authors had speculated onstration of baroreceptor reflex control of the active about the mechanisms and sites of integration of ther- vasodilator system in skin and hence the cutaneous moregulatory and nonthermoregulatory reflexes.348,21 circulation. This conclusion is based on reductions in One proposal, based on the assumption that vasodilator CVC observed during LBNP in hyperthermia in the systems do not participate in baroreflexes,30 was that presence of selective cutaneous vasoconstrictor integration occurred at the cutaneous arterioles blockade. Was such blockade present? through enhanced vasoconstrictor tone.348 According Vasoconstrictor blockade by bretylium was dem- to this view, heat stress induced increases in vasodilator onstrated both by cold stress and by LBNP in tone. This high vasodilator activity would compete with normothermia. Both of these manipulations acti- baroreceptor-mediated increases in active vasoconstric- vate the vasoconstrictor system and thus elicit falls tor tone at the cutaneous arterioles. The arterioles in CVC.5,7,11,14,21 Because bretylium treatment abol- would summate these competing neural tones. The ished the responses in CVC attendant to cold stress outcome of the summation would be an active cutane- both before and after heat stress, vasoconstrictor ous vasoconstriction tempered by the vasodilator sys- blockade was present at the initiation and conclu- tem. The arterioles would therefore be the site of sion of the study, including the intervening period integration in this scheme. Kellogg et al Baroreflex-Induced Vasodilator Withdrawal 1425

The results of the present study indicate that, sponse was secondary to reduced release of norepi- instead, an alternative mechanism of direct vasodila- nephrine and is not similar, in that respect, to the tor withdrawal is responsible for integration of the participation by the cutaneous active vasodilator baroreflex and thermoregulatory reflexes. This system in the baroreceptor reflex as identified here. implies that, during heart stress, integration must The finding that the cutaneous active vasodilator have occurred within the nervous system, proximal to system responds to baroreceptor unloading indicates the cutaneous arterioles. Further, because untreated that vasodilator systems can participate in barorecep- sites and those with local vasoconstrictor blockade tor reflexes. If baroreceptor loading during hyper- responded quite similarly to baroreceptor unloading thermia elicits a cutaneous vasodilation by enhancing during hyperthermia, one can rule out a major role active vasodilator tone, then baroreceptor reflexes for the vasoconstrictor system in that setting. could buffer blood pressure challenges over all ther- While the results of the direct approach of LDV moregulatory conditions. This question requires fur- combined with bretylium iontophoresis are unques- ther experimental work. tionably clear, it is reasonable to ask why these results were not obtained from studies in which sweat References rate was used as an index of cutaneous vasodilator 1. Fox RH, Edholm OG: Nervous control of the cutaneous system activity. Solack et a12' found a reduction in the circulation. Br Med Bull 1963;19:110-114 unload- 2. Grant RT, Holling HE: Further observations on the vascular rate of rise of sweat rate during baroreceptor responses of the human limb to body warming: Evidence for ing in heat-stressed humans; however, sweat rate, per sympathetic vasodilator nerves in the normal subject. Clin Sci Downloaded from se, did not decline. In the present study, direct 1938;3:273-285 reductions in active vasodilator tone were found with 3. Johnson JM, Brengelmann GL, Hales JRS, Vanhoutte PM, baroreceptor unloading in hyperthermia. It appears Wenger CB: Regulation of the cutaneous circulation. Fed Proc 1986;45:2841-2850 that the assumption that sweat rate is a reliable index 4. Rowell LB: Reflex control of the cutaneous vasculature. J Invest of active vasodilator tone during brief vasoconstrictor Dermatol 1977;69:154-166 http://circres.ahajournals.org/ reflexes in hyperthermia is invalid. One may specu- 5. Beiser GD, Zelis R, Epstein SE, Mason DT, Braunwald E: late that sweat rate does not respond quickly to The role of skin and muscle resistance vessels in reflexes mediated by the baroreceptor system. J Clin Invest 1970; nonthermoregulatory reflexes because of a long half- 49:225-231 life of the sudomotor neurotransmitter or its effects 6. Crossley RJ, Greenfield ADM, Plassaras GC, Stevens D: The at sweat glands. Alternatively, completely different interrelation of thermoregulatory and baroreceptor reflexes in efferent nerves could be responsible for active vaso- the control of the blood vessels in the human forearm. JPhysiol dilation and for sweating. The latter alternative could (Lond) 1966;183:628-636 7. Heistad DD, Abboud FM, Mark AL, Schmid PS: Interaction also explain the ability of atropine to block sweating, of thermal and baroreceptor reflexes in man. J Appl Physiol but to leave active vasodilation unaltered or only 1973;35:581-586 by guest on November 4, 2017 temporally delayed.20,31 8. Johnson JM: Non-thermoregulatory control of human skin It is interesting that studies with sympathetic nerve blood flow. JAppl Physiol 1986;61:1613-1622 9. Johnson JM, Niederberger M, Rowell LB, Eisman MM, recordings have not found evidence for baroreceptor Brengelmann GL: Competition between cutaneous vasodila- control of either active vasodilation or vasoconstric- tor and vasoconstrictor reflexes in man. J Appl Physiol 1973; tion in the cutaneous vasculature.32-34 This disparity 35:798-803 of findings has not gone unrecognized. It has been 10. Johnson JM, Rowell LB, Niederberger M, Eisman MM: proposed that the complexity of cutaneous Human splanchnic and forearm vasoconstrictor responses to nerves, reductions in right atrial and aortic pressures. Circ Res 1974; containing separate afferent, active vasoconstrictor, 34:515-524 and sudomotor fibers, may be the cause of this 11. Rowell LB, Wyss CR, Brengelmann GL: Sustained human discrepancy.34 If separate vasodilator efferents are skin and muscle vasoconstriction with reduced baroreceptor also present, skin sympathetic nerve studies would be activity. J Appl Physiol 1973;34:639-643 12. Taylor WF, Johnson JM, Kosiba WA, Kwan CM: Graded even more difficult to interpret. Further refinement cutaneous vascular responses to dynamic leg exercise. J Appl and combination of single fiber sympathetic nerve Physiol 1988;64:1803-1809 recordings with functional measurements such as 13. Taylor WF, Johnson JM, O'Leary DS, Park MK: Modification LDV may help corroborate conclusions based on of the cutaneous vascular response to exercise by local skin measurements of skin blood flow. temperature. J Appl Physiol 1984;57:1878-1884 14. Tripathi A, Nadel ER: Forearm skin and muscle vasoconstric- Brody3O concluded that the active cholinergic vaso- tion during lower body negative pressure. J Appl Physiol 1986; dilator system in skeletal muscle is unaffected by 60:1535-1541 baroreceptor loading. This was based on studies in 15. Essandoh LK, Houston DS, Vanhoutte PM, Shepherd JT: which atropinization, sufficient to block the effects of Differential effects of lower body negative pressure on forearm and calf blood flow. JAppl Physiol 1986;61:994-998 acetylcholine, had no effect on the reflex vasodilation 16. Mancia G, Grassi G, Ferrari A, Zanchetti A: Reflex cardio- of the skeletal muscle vasculature in response to vascular regulation in humans. J Cardiovasc Pharmacol 1985; increased blood pressure. This proposal is at variance 7:S152-S159 with the finding by Ito and Feigl35 of active parasym- 17. Shepherd JT, Mancia G: Reflex control of the cardiovascular vasodilation in arteries system. Rev Physiol Biochem Pharmacol 1986;105:1-99 pathetic dog coronary during 18. Mosley JG: A reduction in some vasodilator responses in baroreceptor loading. Participation by histamine free-standing man. Cardiovasc Res 1969;3:14-21 release in the vasodilator response to increased 19. Brengelmann GL, Freund PR, Rowell LB, Olerud JE, Kran- baroreceptor activity has been noted.30 That re- ing KK: Absence of active vasodilation associated with con- 1426 Circulation Research Vol 66, No 5, May 1990

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Circ Res. 1990;66:1420-1426 doi: 10.1161/01.RES.66.5.1420 Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1990 American Heart Association, Inc. All rights reserved. http://circres.ahajournals.org/ Print ISSN: 0009-7330. Online ISSN: 1524-4571

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