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Am J Physiol Regul Integr Comp Physiol 275: R1703-R1711, 1998;
0363-6119/98 $5.00
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Vol. 275, Issue 5, R1703-R1711, November 1998

Plasma hyperosmolality and arterial pressure regulation during heating in dehydrated and awake rats

Yasufumi Nakajima, Hiroshi Nose, and Akira Takamata

Departments of Anesthesiology and Physiology, Kyoto Prefectural University of Medicine, Kyoto 602-0841; and Department of Sports Medicine, Shinshu University School of Medicine, Matsumoto 390-8621, Japan

    ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

To gain better insights into the effect of dehydration on thermal and cardiovascular regulation during hyperthermia, we examined these regulatory responses during body heating in rats under isosmotic hypovolemia and hyperosmotic hypovolemia. Rats were divided into four groups: normovolemic and isosmotic (C), hypovolemic and isosmotic [L, plasma volume loss (Delta PV) = -20% of control], hypovolemic and less hyperosmotic [HL1, increase in plasma osmolality (Delta Posm) = 23 mosmol/kgH2O, Delta PV = -16%], and hypovolemic and more hyperosmotic (HL2, Delta Posm = 52 mosmol/kgH2O, Delta PV = -17%). Hyperosmolality was attained by subcutaneous injection of hypertonic saline and hypovolemia by intra-arterial injection of furosemide before heating. Then rats were placed in a thermocontrolled box (35°C air temperature, ~20% relative humidity) for 1-2 h until rectal temperatures (Tre) reached 40.0°C. Mean arterial pressure in L decreased with rise in Tre (P < 0.001), whereas mean arterial pressure remained constant in the other groups. Maximal tail skin blood flow in L, HL1, and HL2 was decreased to ~30% of that in C (P < 0.001). Tre threshold for tail skin vasodilation (TVD) was not changed in L, whereas the threshold shifted higher in the HL groups. Tre threshold for TVD was highly correlated with Posm (r = 0.94, P < 0.001). Heart rate in the HL groups increased with rise in Tre (P < 0.001), whereas it remained unchanged in C and L. Cardiovascular responses to heating were not influenced by V1 antagonist in C, L, and HL2. Thus isotonic hypovolemia attenuates maximal tail skin blood flow, whereas hypertonic hypovolemia causes an upward shift of Tre threshold for TVD and an increase in heart rate during hyperthermia. These results suggest that plasma hyperosmolality stimulates pressor responses in the hypovolemic condition that subsequently contribute to arterial pressure regulation during heat stress.

plasma osmolality; thermal dehydration; cardiovascular control; tail skin blood flow

    INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

IT IS WELL KNOWN THAT dehydration attenuates the increase in skin blood flow (SkBF) during heat stress in humans (15, 23) and experimental animals (21, 43). In humans, blood pooling in cutaneous vessels and/or hypovolemia due to sweating reduces venous return to the heart, making it difficult to maintain arterial blood pressure during heat stress (33). As feedback mechanisms to maintain arterial blood pressure, the increase in SkBF in response to increased esophageal temperature (Tes) was attenuated above a certain level of Tes (3), and the maximal SkBF is reduced in hypohydrated subjects (15, 23). Because the attenuation was partially prevented by blood volume expansion (10, 23, 26), a supine position (16), or head-out water immersion (25), baroreflexes are likely to be involved in the regulation of SkBF in humans. In animals, O'Leary and Johnson (29) studied the baroreflex control of tail SkBF in awake and anesthetized rats and reported that acute blood shedding suppressed thermogenic tail skin vasodilation by enhancing sympathetic nervous activity (SNA). Takamata et al. (42) reported in passively heated anesthetized rats that the decrease in central venous pressure with the increase in body temperature was highly correlated with the increase in total peripheral resistance. Thus it is likely that hypovolemia in dehydration attenuates the increase in SkBF to maintain arterial blood pressure in rats as well as in humans.

The effects of hyperosmolality on thermoregulatory responses have also been reported (2, 24, 37). Fortney et al. (11) reported in humans exercising in a hot environment that hyperosmolality, with blood volume remaining unchanged, caused an upward shift in the Tes threshold for cutaneous vasodilation. Recently, Takamata et al. (41) performed a more quantitative study in resting humans to determine the relationship between plasma osmolality (Posm) and the Tes threshold for cutaneous vasodilation and reported that the threshold moved toward a higher Tes parallel to the increase in Posm. Turlejska and Baker (44) reported that application of hypertonic artificial cerebrospinal fluid into the lateral ventricle in hyperthermic rabbits produces vasoconstriction in the skin of the ear as well as inhibition of thermal panting. However, the suppression of thermoregulatory responses by hyperosmolity has been studied with regard to the competition between body fluid and thermal regulations (2), and no one has attempted to analyze it in relation to the regulation of arterial blood pressure during heating as reported in hypovolemia.

Plasma vasopressin has been reported to contribute to the maintenance of arterial pressure in dehydrated rats (32, 47). Plasma hyperosmolality and hypovolemia stimulate vasopressin secretion, and osmotic vasopressin secretion was augmented by increased body temperature at Posm >295 mosmol/kgH2O in humans (40). Thus increased body temperature should augment vasopressin secretion in the hyperosmotic hypovolemic condition, and this can play a role in the regulation of arterial pressure.

In the present study we assess the effects of hyperosmolality on arterial pressure regulation and analyze it in relation to the effects on tail SkBF in hypovolemic and hyperthermic rats. In addition, to elucidate the involvement of vasopressin in the regulation of arterial pressure during heat stress, we examine the effect of vasopressin V1-receptor antagonism on cardiovascular and thermal responses to heat stress.

    MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

Experimental Animals

The study was approved by the Committee for Animal Research, Kyoto Prefectural University of Medicine. Male Wistar rats (280-340 g body wt) were housed in mesh cages in a room maintained at 23-25°C and illuminated from 0700 to 1800; they were given laboratory rat chow (Oriental, Osaka, Japan) and tap water ad libitum. All experiments were performed between 0900 and 1800.

Surgical and Experimental Procedures

Rats were anesthetized with sevoflurane (inhaled anesthetics), and then catheters (PE-50) were placed into the right femoral artery. The catheters were filled with heparinized saline (100 U/ml) and tunneled subcutaneously to the back. Lidocaine jelly was liberally applied to the area of the closed incisions to minimize postoperative discomfort. All rats regained consciousness within 5 min postoperatively, but >= 6-24 h were allowed for postoperative recovery. All experimental protocols were carried out in conscious rats gently restrained by a plastic holder to prevent free movement, to which the rats were acclimatized beforehand to avoid any effects of their discomfort on cardiovascular function. The heating protocol was performed in a thermocontrolled box maintained at an air temperature of 35°C and ~20% relative humidity, while the tail extended out a window (12 cm diameter) in the wall of the box and was exposed to the room temperature of 23-24°C. Wires and tubing for measurements also extended through the window.

Tail SkBF was measured by venous occlusion plethysmograhy (31, 46). A venous occlusion cuff (2 cm wide) was placed at the base of the tail. Approximately 4 cm distal to the cuff, a mercury-in-Silastic circumference gauge was wrapped around the tail. The gauge was connected to a strain amplifier, and the voltage output was displayed on a linear potentiometric recorder. Tail SkBF was measured by inflating the venous occlusion cuff to 40-50 mmHg, with the tail being held slightly above heart level to allow for adequate venous drainage. The initial slope of the volume increase was used to calculate tail SkBF as milliliters per minute per 100 g. The accuracy of venous occlusion plethysmography was confirmed in anesthetized rats by simultaneous measurement of tail arterial blood flow under laparotomy with an ultrasonic blood flowmeter (model T106, Transonic Systems). The change in tail SkBF by ultrasonic flowmeter (y, ml/min) was highly correlated with that by plethysmography (x), with a regression equation as follows: y = 0.15x + 0.04 (r = 0.95, n = 30, P < 0.001). The threshold of body core temperature for tail vasodilation was determined as the rectal temperature (Tre) required to cause a significant increase in tail SkBF from the baseline.

Arterial pressure was monitored continuously through the femoral arterial catheter with a strain gauge transducer (model TP400T, Nihon Kohden, Tokyo, Japan), and mean arterial pressure (MAP) was determined by passing the output signal through a low-pass filter (time constant 3.3 s) and recorded in the computer (model PC9801n, NEC, Tokyo, Japan) every 15 s on an average of samples at a second interval. The reference level of the transducer was held at the level of the right atrium. Heart rate (HR) was determined from the pulsations of the arterial pressure recording (model 1321 tachometer, Sanei, Tokyo, Japan). Tail vascular conductance (TVC) was calculated as 100 × tail SkBF/MAP. Tre was monitored continuously by a thermistor placed 7 cm past the anal sphincter. MAP, HR, and TVC were noted at each 0.1°C increase in Tre to 40.0°C.

Protocol

First series. The hypovolemic and isosmotic group (L, n = 7) was injected intra-arterially with furosemide (3 mg/100 g body wt) and subcutaneously with 150 mM NaCl solution (1 ml/100 g body wt). The hypovolemic and less hyperosmotic group (HL1, n = 7) was subcutaneously injected with 1 ml of 1,000 mM NaCl solution per 100 g body wt and the hypovolemic and more hyperosmotic group (HL2, n = 7) with 1 ml of 2,000 mM NaCl solution per 100 g body wt after induction of hypovolemia by intra-arterial injection of furosemide in both groups. The control group (C, n = 7) was injected intra-arterially and subcutaneously with 150 mM NaCl solution. Furosemide was injected 4 h before heating, because urine output was reported to return to the baseline of 0.01-0.02 ml/min in 1 h (42). Hypertonic saline was injected 2 h before heating, because a preliminary study confirmed that Posm reached a steady state 1-2 h after subcutaneous injection of hypertonic saline and lasted for >= 4 h. Baseline measurements were taken at the Tre of 37.0°C, which was attained by adjusting the air temperature of the thermocontrolled box in which the rats were placed. After these measurements were taken, the air temperature in the box was increased to 35°C.

Second series. V1 antagonist was administered in three groups of rats pretreated in the same way as C, L, and HL2 in the first series of experiments; these groups were named C + V1, L + V1, and HL2 + V1, respectively (n = 6/group). The V1 antagonist [Pmp1,Tyr(Me)2]-Arg8-vasopressin was administered intra-arterially at 7 µg/100 g body wt 30 min before heating. After baseline measurements of MAP, HR, and TVC, rats were passively heated at 35°C in a thermocontrolled box until Tre rose to 40.0°C. The action of the V1 antagonist was verified at the end of heating by injection of vasopressin at 10 ng/100 g body wt, a dose that resulted in a 40- to 50-mmHg rise in MAP in euhydrated rats in a preliminary experiment.

Blood Chemicals

We measured hematocrit (Hct) by microcentrifugation, plasma protein concentration (PPC) by refractometry, and Posm by freezing-point depression (Fiske one-ten osmometer) in 0.3 ml of blood sampled from a catheter in the femoral artery before the treatment to modify plasma volume (PV) and Posm. Samples for measurement were also obtained before heating (after the treatment) and after heating. An aliquot for measurement of Posm was immediately transferred to a small plastic tube and centrifuged. The separated plasma was stored in the freezer (Medicool, Sanyo, Tokyo, Japan) at -20°C until assay. Blood for the determination of Hct and PPC was immediately processed. The change in PV was calculated from the change in Hct values (45).

Statistics

Data were analyzed by a general linear regression models procedure for an ANOVA with repeated measures followed by a multiple-comparison test with Fisher's least significant difference test (38). Regression equations for the relationships (see Figs. 4 and 8) were calculated using least-squares linear regression. P < 0.05 was considered significant.

    RESULTS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

First Series

Table 1 shows Hct, PPC, and Posm before PV and Posm modification (before treatment), after treatment (before heating), and after heating in C, L, HL1, and HL2. After treatment, PV decreased significantly from baseline by -19.5 ± 2.0% in L, -15.9 ± 1.3% in HL1, and -16.5 ± 2.3% in HL2, with the reduced levels maintained until the end of heating, whereas PV in C remained unchanged throughout the experiment. The administration of V1 antagonist had no effect on PV in the corresponding groups. After treatment, PV tended to decrease more in L than in HL1 and HL2, but no significant difference was observed (P > 0.05). The increases in PPC for L, HL1, and HL2 were almost entirely explained by the decreases in plasma water. The baseline of PPC was slightly but significantly lower in L than in C (P < 0.05), and after treatment the increase in PPC was significantly greater in L than in HL1 and HL2 (P < 0.05). Posm increased by 23 and 52 mosmol/kgH2O in HL1 and HL2, respectively, after treatment, whereas it remained unchanged in C and L. There were no changes in Hct, PPC, and Posm in any group after heating, except for a slight but significant increase in Posm in HL1.

                              
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  		Table 1.   Changes in Hct, PPC, and Posm during experiment

Figure 1, top, shows MAP during heating in L compared with C as a function of Tre. MAP in HL1 and HL2 are also presented in Fig. 1, middle and bottom, respectively. MAP in C did not change during heating, whereas MAP in L slowly decreased above 37.9°C, and significant decreases compared with C were observed from 38.2 to 38.3°C and at Tre >38.7°C (P < 0.05). MAP at 37.0°C in HL1 was 120 ± 3 mmHg, which was significantly higher than 109 ± 2 mmHg in C (P < 0.05). During heating, MAP in HL1 did not change but remained significantly higher than in C (P < 0.05). MAP in HL2 was similar to that in HL1 during heating and remained significantly higher than in C (P < 0.05).


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  		Fig. 1.   Mean arterial pressure (MAP) during heating as a function of rectal temperature (Tre) in hypovolemic and isosmotic group (L), hypovolemic and less hyperosmotic group (HL1), and hypovolemic and more hyperosmotic group (HL2). Each condition was compared with normovolemic and isosmotic group (C) group. Values are means ± SE; n = 7 in each group. * Significantly different from C.

Figure 2, top, shows HR during heating in C and L as a function of Tre. HR in HL1 and HL2 are also presented in Fig. 2, middle and bottom, respectively. HR at 37°C in L was 426 ± 8 beats/min, which is significantly higher than 384 ± 7 beats/min in C (P < 0.05). HR in C and L remained constant during heating, but HR remained significantly higher in L than in C (P < 0.05). During heating, HR in HL1 slowly increased at >37.7°C, and significant increases compared with C were observed from 39.0 to 39.2°C and at >39.6°C (P < 0.05). HR in HL2 was similar to that in HL1, and significant increases compared with C were observed at 38.2 and >38.4°C (P < 0.05).


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  		Fig. 2.   Heart rate (HR) during heating as a function of Tre in L, HL1, and HL2. Each condition was compared with C. Values are means ± SE; n = 7 in each group. * Significantly different from C.

Figure 3, top, shows TVC during heating in C and L as a function of Tre. TVC in HL1 and HL2 are also presented compared with TVC in C in Fig. 3, middle and bottom, respectively. TVC at 37.0°C was 0.7 ± 0.1 ml · min-1 · 100 g-1 · 100 mmHg-1 in C, L, and HL2 and 0.6 ± 0.1 ml · min-1 · 100 g-1 · 100 mmHg-1 in HL1 but not significantly different among the groups. After the beginning of heating, TVC in C increased sharply at >38.1°C, reached the maximal level of 33.1 ± 1.2 ml · min-1 · 100 g-1 · 100 mmHg-1 at 38.6°C, and remained at this elevated level until 40°C. On the other hand, TVC in L began to increase at 37.9°C, the same Tre as in C, but the maximal level was remarkably reduced to 11.2 ± 1.8 ml · min-1 · 100 g-1 · 100 mmHg-1, ~30% of that in C. The increase in TVC for HL1 was delayed compared with that for C and L and began to increase at Tre of 38.8°C, then reached the maximal level of 9.9 ± 1.6 ml · min-1 · 100 g-1 · 100 mmHg-1 at 39.2°C, and remained at that level thereafter. The increase in TVC was more delayed in HL2 than in HL1. TVC began to increase at Tre of 39.4°C, reached the maximal level of 7.4 ± 1.5 ml · min-1 · 100 g-1 · 100 mmHg-1 at 39.6°C, and remained at that elevated level thereafter. There was no significant difference in the maximal TVC between L and HL1, but in HL2 it was significantly reduced compared with the other dehydrated groups of L and HL1 (P < 0.05).


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  		Fig. 3.   Tail vascular conductance (TVC) during heating as a function of Tre in L, HL1, and HL2. Each condition was compared with C. Values are means ± SE; n = 7 in each group. * Significantly different from C.

Figure 4 shows the relationship between changes in TVC (Delta TVC) and MAP (Delta MAP) during heating in L. Data for every 0.5°C increase in Tre from 37.0 to 40.0°C demonstrate a highly negative correlation between the two parameters, with a regression equation as follows: Delta MAP = -1.1 × Delta TVC - 0.6 (r = 0.99, P < 0.001).


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  		Fig. 4.   Relationship between change in MAP (Delta MAP) and change in TVC (Delta TVC) in L. Values are means ± SE of 7 rats for every 0.5°C increase in Tre.

Second Series

There were no significant differences in Hct, PPC, and Posm between the groups administered a V1 antagonist and the corresponding control groups: C vs. C + V1, L vs. L + V1, and HL2 vs. HL2 + V1 (Table 1).

Figure 5 shows the effects of V1 antagonist on MAP during heating in each group. There was no effect of V1 antagonist on MAP in C at 37°C or during heating (Fig. 5, top). MAP in L + V1 declined as in L, and there was no significant difference between the two groups except at Tre of 38.5-38.6°C (Fig. 5, middle). MAP at 37.0°C tended to be lower in HL2 + V1 than in HL2, and the difference became significant at a Tre of 38.4°C and thereafter (Fig. 5, bottom).


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  		Fig. 5.   MAP during heating as a function of Tre in C, L, and HL2 injected with V1 antagonist before heating (C + V1, L + V1, and HL2 + V1, respectively). Values are means ± SE; n = 6 in each group. * Significantly different from corresponding group.

Figure 6 shows the effects of V1 antagonist on HR at 37°C and during heating in each group. In C there was no difference in HR during heating due to the antagonist. HR tended to be lower in L + V1 than in L, and differences were significant at Tre between 39.2 and 39.4°C (P < 0.05). HR in HL2 + V1 was 466 ± 13 beats/min at 37°C, which is significantly higher than 380 ± 14 beats/min in HL2 (P < 0.05). During heating the difference became insignificant at Tre of >39.5°C, because HR in HL2 increased with the rise in Tre at a higher rate than in HL2 + V1.


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  		Fig. 6.   HR during heating as a function of Tre in C, L, and HL2 injected with V1 antagonist before heating (C + V1, L + V1, and HL2 + V1, respectively). Values are means ± SE; n = 6 in each group. * Significantly different from corresponding group.

Figure 7 shows the effects of V1 antagonist on TVC during heating in each group. The response of TVC to increased Tre was almost the same in the groups with and without the antagonist, although there was a slight statistical difference (P < 0.05).


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  		Fig. 7.   TVC during heating as a function of Tre in C, L, and HL2 injected with V1 antagonist before heating (C + V1, L + V1, and HL2 + V1, respectively). Values are means ± SE; n = 6 in each group. * Significantly different from corresponding group.

Posm and Tre Threshold for Tail Skin Vasodilation

Figure 8 shows the relationship between Posm and Tre threshold for tail skin vasodilation (TVD) in each group. Because V1 antagonist caused no significant differences in Posm and TVD in each group, the data were pooled to determine the relationship between the two parameters. These data were highly correlated with a regression equation: Tre for TVD = 0.023 × Posm + 31.2 (r = 0.94, P < 0.001).


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  		Fig. 8.   Tre thresholds for tail vasodilation (TVD) as a function of plasma osmolality (Posm). open circle , Data from individual rats; , means and SE bars of each group (C, L, HL1, HL2, C + V1, L + V1, and HL2 + V1).

Time to Reach 40°C Tre

The time to reach Tre of 40°C was 108 ± 6, 66 ± 5, 55 ± 2, and 43 ± 4 min in C, L, HL1, and HL2, respectively, with significant differences (P < 0.05). There was no significant effect of V1 antagonist on the time between corresponding groups.

    DISCUSSION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

The increase in SkBF in hyperthermia is attenuated in dehydration in humans (15, 23) and in experimental animals (21, 43). The relative importance of baroreflexes in the attenuation of SkBF is well known. However, the role of hyperosmolality in regulation of SkBF and the effects on arterial blood pressure under dehydration have not been elucidated. To accomplish this, we assessed the combined effects of hypovolemia and hyperosmolality on tail SkBF and arterial pressure regulation in awake rats and compared the results with those in isosmotic and hypovolemic rats. It was suggested that hyperosmolality contributes significantly to arterial pressure regulation during heating in hypovolemic rats, probably by enhanced SNA.

As shown in Table 1, PV in L, HL1, and HL2 decreased by ~20% compared with C. Posm in HL1 and HL2 increased by 23 and 52 mosmol/kgH2O, respectively. We previously reported a 40% loss of PV and an increase in Posm of 20 mosmol/kgH2O in rats thermally dehydrated by 10% body weight (27). A similar dehydration level was attained by maintaining rats at room temperature without water for 72 h (47). Thornton and Proppe (43) also examined the effects of severe dehydration on thermoregulation in baboons after 68-72 h of water deprivation: a 16% loss of PV and an increase in Posm of 50 mosmol/kgH2O. The present study was designed to cover the ranges of PV and Posm after dehydration previously reported.

The reduction in PV for the HL groups tended to be slightly attenuated compared with that for L. The fluid shift from intra- to extracellular fluid space by plasma hyperosmolality may cause higher retention of water in intravascular fluid space, resulting in the significantly attenuated increases in PPC for the HL groups. The difference in PV decrease between L and HL was only 3% of control, which is too small to cause any significant effect on cardiovascular function. Posm in the HL groups tended to be higher after than before heating. However, similarly, the increase was only ~3 mosmol/kgH2O, which is equivalent to 13 and 6% increases in Posm in the HL groups, a change too small to cause any significant effects on the results in this study.

All experiments were performed 6-24 h after surgical preparation. The action of sevoflurane anesthesia after the cessation of inhalation is very short, and, indeed, all rats regained consciousness within 5 min after the cessation of anesthesia (9). We considered that rats were sufficiently recovered from the surgical preparation, because the time required for surgical preparation was <= 30 min and surgery is minor. It was confirmed that the baseline level of MAP and HR and thermal responses of these variables were not significantly different from those of rats receiving the similar preparation 2 days before the experiment in our preliminary experiment and in the experiment reported elsewhere (5, 19, 34).

MAP and HR at 37.0°C

MAP at 37°C in L was maintained, despite a 20% loss of PV (Fig. 1). Takamata et al. (42) reported in alpha -chloralose-anesthetized and isotonic hypovolemic rats that MAP was maintained, despite a 20% loss of PV, because a 40% decrease in cardiac output (CO) was compensated for by the increase in total peripheral resistance. Proppe (30) reported in unanesthetized and isotonic hypovolemic baboons that a 20% loss of PV did not reduce MAP, accompanied by 10-fold increase in plasma renin activity. Because V1 antagonist had no effect on MAP in L (Fig. 5), vasopressin was not involved in the maintenance of MAP in this case. Because vasopressin is not secreted until 20% of PV is lost isotonically (8), plasma vasopressin in L may not be sufficient to cause pressor responses. The maintenance of MAP in L was achieved by increased SNA as well as an enhanced renin-anigiotensin system, considering that HR at 37°C was 12% higher in L than in C (Fig. 2).

Despite a 16-17% loss of PV, MAP at 37°C was 10 mmHg higher in HL1 and HL2 than in C while HR remained unchanged (Fig. 1). The V1 antagonist injection in HL2 (HL2 + V1) reduced MAP to the level in C (Fig. 5) but increased the baseline HR to 124% of that in HL2 (Fig. 6). Several studies reported the importance of vasopressin in maintaining arterial blood pressure in normothermic and dehydrated animals (32, 35, 36, 47). Rascher et al. (32) reported in carotid sinus-denervated and dehydrated rats that V1 antagonist reduced MAP by decreasing total peripheral resistance, whereas in innervated and dehydrated rats it did not decrease MAP, despite the reduction in total peripheral resistance that was caused by a compensatory increase in CO by stimulated baroreflexes. Woods and Johnston (47) also reported that in Brattleboro rats, which are genetically deficient in vasopressin, MAP was significantly decreased after dehydration, although it remained constant in control rats. These results suggest that V1 antagonist in HL2 decreased total peripheral resistance, but compensatory increases in HR and CO by activated SNA prevent hypotension. Thus we reconfirmed that vasopressin is more important for arterial pressure regulation than SNA in normothermic and dehydrated rats.

MAP and HR During Heating

MAP and HR in C remained constant during heating. Kregel et al. (20) reported that MAP and HR increased with the rise in Tre in euhydrated and conscious rats heated at 46°C with an infrared lamp. They ascribed the increase in MAP during heating to splanchnic vasoconstriction, counteracting the pressor effect against TVD. Recently, they examined the role of SNA in splanchnic vasoconstriction by placing conscious rats in a small chamber maintained at 42°C and reported that plasma catecholamine levels increased with rises in MAP and HR, and the increase was significant at Tre >40.0°C, when splanchnic blood flow was decreased (19). Recently, Kenney et al. (18) measured the change in splanchnic sympathetic nervous discharge during heating in baroreceptor-denervated rats and compared the results with those in innervated rats. They reported that the sympathetic nervous discharge in both groups slowly increased with the rise in Tre, and the increase was significant at >40.0°C. They concluded that the increase in sympathetic nervous discharge was increased not by unloading the baroreceptors but by direct effects of increased body temperature. The reason for no change in MAP and HR in C during heating in the present study is not clear. However, the environmental temperature of 35°C, which is much lower than that in the previous reports, may be too mild to cause pressor responses. Alternatively, Tre in the present study did not rise beyond 40.0°C, above which MAP, HR, and SNA were previously reported to increase in euhydrated rats (12, 18, 19, 42).

MAP in L decreased with the rise in Tre (Fig. 1), and the decrease was highly correlated with the increase in TVC (Fig. 4). There was no effect of V1 antagonist on MAP during heating in L + V1 (Fig. 5). Takamata et al. (42) reported in anesthetized and hyperthermic rats that a 20% loss of PV reduced CO to 60% of that in C, and the reduced level persisted until Tre rose to 40°C. Although the maximal increase in TVC during heating was only 30% of that in C, a small reduction in total peripheral resistance by TVD might be sufficient to reduce MAP in the condition of decreased CO. Massett et al. (21) reported that splanchnic vasoconstriction during heating was attenuated in water-deprived rats. Gisolfi et al. (12) reported in anesthetized rats that splanchnic vasoconstriction in hyperthermia was attenuated not by decreased SNA but by accumulation of metabolites: lactate and K+ in plasma in severe hyperthermia. These results suggest that the reduction in MAP during heating in L may be caused by attenuated splanchnic vasoconstriction as well as TVD. In addition, we found that vasopressin was not involved in MAP regulation during heating in the isotonic hypovolemic condition.

HR in L remained unchanged, despite the gradual decrease in MAP during heating. Similar results were reported by Massett et al. (21): the increase in HR responding to hyperthermia was significantly attenuated in 48-h water-deprived rats, despite decreased MAP. The precise reason for the blunted response of HR to hypotension during heating is not clear. However, Massett et al. (22) recently reported that the operating range and slope of the baroreflex curve relating HR to MAP were reduced in hyperthermic rats. Alternatively, HR in L was 425 beats/min at Tre of 37°C, which is ~50 beats/min higher than in C, which may be the maximum level caused by increased SNA through baroreflexes. Chen and Dicarlo (5) reported in conscious rats that HR reached the maximum and plateau of 440 beats/min, which is ~40 beats/min higher than baseline, when MAP was reduced by 20 mmHg. Thus, HR in L already attained the maximum level elicited by unloading of baroreceptors at Tre of 37.0°C and did not increase further in response to reduction in MAP during heating. Finally, it was also plausible that acute adaptation or resetting of baroreceptors was caused by gradual reduction in MAP during heating (7, 39).

Despite hypovolemia, MAP during heating remained 10 mmHg higher in HL1 and HL2 than in C. Although MAP in HL2 + V1 was reduced to the baseline in C, it remained constant during heating. These results suggest that the maintenance of MAP in HL1 and HL2 was not achieved by vasopressin but by the other pressor responses to hyperosmolality. The administration of hypertonic saline into the cerebroventricle has been reported to increase MAP by enhancing SNA (1, 4). Recently, Chen (6) reported that MAP was reduced by injection of hypotonic saline into the lateral ventricle of dehydrated rats, and the reduction in MAP was highly correlated with the decrease in Na+ concentration in cerebrospinal fluid. They also reported that the decrease in MAP was caused by the reductions in CO and total peripheral resistance. Recently, Hirose et al. (14) suggested that osmosensitive sites related to arterial pressure regulation were close to the third ventricle. Kannan et al. (17) reported that electrostimulation to the paraventricular nucleus increased renal SNA to increase MAP in awake rats. These results suggest that MAP in thermal dehydration was maintained by enhanced SNA, which was caused by stimulation of the osmoreceptors in periventricular brain tissue.

In contrast to L and L + V1, the gradual increase in HR occurred in HL and HL2 + V1 during heating. Russ et al. (34) reported in 48 water-deprived rats a significant increase in baroreceptor sensitivity, determined from the Delta MAP vs. Delta HR slope, which was, in addition, augmented by administration of V1 antagonist. In contrast, they reported that the baroreflex sensitivity was not influenced by acute hypertonic saline infusion alone. Thus simultaneous exposure to hypovolemia and hyperosmolality may enhance baroreflex sensitivity. Another explanation for the increased HR in HL and HL + V1 during heating is that increased body temperature might depolarize the pacemaker potential of the heart. This idea may be supported by the reports that the baroreflex curve of the MAP vs. HR slope shifts to higher HR in hyperthermic rats (22) and baboons (13). Alternatively, HR at 37°C in the HL groups was ~375 beats/min, which is significantly lower than in L and L + V1, and was in the operating range of the baroreflex curve (5), leading to a more sensitive HR response to a small reduction in MAP during heating (Fig. 2, middle and bottom).

HR at 37°C was 80 beats/min higher in HL2 + V1 than in HL2 and slowly increased during heating (Fig. 6, bottom). Because HR in HL2 increased with the rise in Tre at a higher rate than in HL2 + V1, the significant difference between the two groups disappeared at >39.5°C. The diminished increase in HR during heating in HL2 + V1 compared with that in HL2 could be attributable to the higher baseline caused by enhanced SNA after elimination of the pressor effect of vasopressin.

TVC During Heating

The maximal TVC in L, HL1, and HL2 was reduced to 30% of that in C. These results suggest that maximal TVC was determined mainly by hypovolemia regardless of Posm. Nadel et al. (23) reported in exercising subjects in a hot environment that maximal forearm blood flow in the isotonic hypovolemic condition was reduced to 50% of that in the euhydrated condition. Proppe (30) reported in hyperthermic baboons that iliac vascular conductance was reduced by isotonic PV loss, whereas it was not changed by hypertonic infusion. O'Leary and Johnson (29) studied the baroreflex control of TVC by blood volume shedding in conscious rats and reported that tail vasoconstriction was enhanced in hyperthermic rats at a given decrease in MAP. They also reported that TVC was regulated solely by the sympathetic vasoconstrictor (28). Thus the reduction in maximal TVC in hypovolemic rats is likely to be caused by increased SNA by stimulated baroreflexes.

The threshold of Tre for TVD did not depend on PV loss but on Posm, and a high correlation between Posm and Tre threshold for TVD was observed (Fig. 8). Suppression of thermoregulation by hyperosmolality has been reported in several studies (2). Fortney et al. (11) reported in exercising subjects an upward shift of the Tes threshold for forearm vascular dilation by hyperosmolality. Takamata et al. (41) reported the linear relationship between the Tes threshold for cutaneous vasodilation and Posm in human subjects at rest. In the present study we reconfirmed the relationship in awake rats. Because V1 antagonist has no major effects on TVC in any groups, vasopressin was not involved in TVC regulation in hyperthermia.

Heating Time to Raise Tre to 40.0°C

Heating time to raise Tre to 40.0°C became shorter depending on the maximal TVC and the Tre threshold for TVD. This result was reasonable, in that there is no difference in metabolic rate among the groups, because heat dissipation from tail blood flow was reported to be proportional to tail SkBF below an environmental temperature of 30°C (31).

In summary, these results indicate that hyperosmolality prevents the reduction in MAP during heating in hypovolemic rats, which was partially achieved by an upward shift of the Tre threshold for TVD and by increased HR. In addition, vasopressin plays a relatively minor role in the cardiovascular adjustments to heating in hypovolemic and hyperosmotic rats.

Perspectives

Previous studies have reported the importance of vasopressin, rather than SNA, in arterial pressure regulation in normothermic and dehydrated rats. In the present study, however, we found that SNA enhanced by hyperosmolality contributes more to the arterial pressure regulation than vasopressin in hyperthermic and dehydrated rats. In addition, we found that the Tre threshold for TVD increased in parallel with the increase in Posm, whereas isotonic hypovolemia did not change the threshold. In contrast, the reduction in maximum vasodilation was not influenced by osmolality but by blood volume. These results suggest that the tail SkBF may be controlled by at least two nonthermal regulatory systems via SNA: baroreflexes and commands from the higher central nervous system, which may integrate vasodilatory commands from the thermoregulatory system and vasoconstrictive commands from the osmoregulatory system. Thus tail SkBF during heating is controlled by multiple feedback systems in the body, the final goal of which seems to be arterial pressure regulation under hyperthermic and dehydrated conditions.

    ACKNOWLEDGEMENTS

The authors are grateful to Prof. Yoshifumi Tanaka and Prof. Taketoshi Morimoto for help with the present study.

    FOOTNOTES

This work was partially supported by grants from the Ministry of Education, Science, Sports, and Culture, in Japan.

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Address for reprint requests: Y. Nakajima, Dept. of Anesthesiology, Kyoto Prefectural University of Medicine, Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-0841, Japan.

Received 24 February 1998; accepted in final form 27 July 1998.

    REFERENCES
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

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