Vasopressin and the regulation of evaporative water loss and body temperature in the cat

Brain Research, 251 (1982) 127-136 Elsevier Biomedical Press

127

Vasopressin and the Regulation of Evaporative Water Loss and Body Temperature in the Cat P. A. DORIS*

Division of Biomedical Sciences and Department of Biology, University of California, Riverside, CA 92521 (U.S.A.) (Accepted April 15th, 1982)

Key words: plasma vasopressin - - cerebrospinal fluid vasopressin - - temperature regulation - - dehydration - body temperature - - heat stress

The role of vasopressin as a possible mediator of the inhibition of evaporative water loss (EWL) in dehydrated, heat-stressed cats has been examined by intravenous (i.v.) and intracerebroventricular (i.c.v.) injections of arginine vasopressin (AVP). In normally hydrated cats exposed to an ambient temperature (Ta) of 38 °C, neither EWL nor body temperature (Tb), measured in the hypothalamus, was significantly altered by i.v. AVP infusion. Measurements of plasma osmolality (pOsm), pAVP and cerebrospinal fluid AVP (csfAVP) were made in normally hydrated cats at Tas of 25 and 38 °C and after dehydration for 1-4 days at these temperatures. The relationship between pOsm and pAVP can be described equally well by either a linear model or a log-linear model (r = 0.81 for both models). The pOsm--csfAVP relationship is best described by a log-linear model (r = 0.80). A possible role for intracranially released AVP in body temperature regulation and control of EWL was examined by injecting various doses of AVP into the lateral ventricles of normally hydrated cats. No effect of AVP injection on Tb was observed at either a Ta of 23 °C or 38 °C. EWL was also unaffected by i.c.v. AVP administration at a Ta of 38 °C. To confirm further that intracranial AVP is not responsible for elevation of Tb and reduction of EWL during dehydration and heat-stress, specific antiserum to AVP was injected into the ventricles of dehydrated animals at a Ta of 38 °C. No significant effect on either Tb or EWL was measured subsequent to antiserum infusion. These negative findings indicate that AVP does not suppress EWL by either a peripheral or a central action and is therefore not responsible for lowered EWL and elevated Tb seen in dehydrated heat-stressed cats. INTRODUCTION V a s o p r e s s i n is released f r o m the n e u r o h y p o p h y s i s to the c i r c u l a t i o n d u r i n g d e h y d r a t i o n a n d plays a f u n d a m e n t a l role in r e g u l a t i n g renal water clearance. T h e release o f vasopressin can also be increased b y a variety o f o t h e r stimuli, including heat stress 17. D u r i n g heat stress, w a t e r loss b y t h e r m o r e g u l a t o r y e v a p o r a t i o n can g r e a t l y exceed renal w a t e r loss. In negative w a t e r balance renal excretion o f w a t e r falls r a p i d l y to low levels. It is a p p a r e n t t h a t e v a p o r a t i v e water loss ( E W L ) can also be r e d u c e d u n d e r these conditions. R e d u c t i o n s in e v a p o r a t i o n have been r e p o r t e d in a wide variety o f d e h y d r a t e d , heatstressed m a m m a l s , including mant0,a6, 4s. The present studies were designed to e x a m i n e the possibility t h a t vasopressin (AVP) m i g h t act to b r i n g a b o u t this

r e d u c t i o n in evaporative w a t e r loss. Studies e x a m i n i n g the possible role o f A V P in the r e g u l a t i o n o f E W L in m a n have p r o d u c e d equivocal results when A V P is injected into water-replete subjects. Some a u t h o r s r e p o r t a r e d u c t i o n in sweat r a t O 6, 19, while others are u n a b l e to show a n y change 2,1s,31, aT. One r e p o r t suggests t h a t an increase in sweating occurs u n d e r some conditions, a n d a decrease in others ~8. The studies r e p o r t e d here have extended this question to a p a n t i n g m a m m a l , the cat, which has been previously shown to reduce e v a p o r a t i o n when d e h y d r a t e d in the heat 18, a n d which maintains higher p l a s m a A V P levels when d e h y d r a t i o n is c o m b i n e d with h e a t stress than occur in d e h y d r a t i o n alone 4. A n o t h e r possible site o f i n t e r a c t i o n between osm o t i c a l l y i n d u c e d suppression o f e v a p o r a t i o n 15 a n d

* Address for correspondence: Department of Physiology and Biochemistry, University of Reading, Whiteknights, Reading RG6 2AJ, U.K. 0006-8993/82/0000-0000/$02.75 © 1982 Elsevier Biomidecal Press

132 TABLE II Infusion o f A VP into the lateral cerebral ventricle. Effect on body temperatures at an ambient temperature o f 23 °C nx, no. of experiments; n2, no. of animals used in ha; t, t-test value for difference between mean Tb pre-infusion and mean Tb postinfusion ; P, probability mean pre-infusion Tb is different from mean post-infusion Tb. Dose

Weightedmean Tb 4- S.E. (°C) Pre-inf.

0 (saline) 2 mU 5 mU 10mU 20 m U

38.3 38.4 38.4 38.3 38.4

± i 44±

nl

n2

t

P

5 8 6 6 6

3 4 5 5 4

0.46 1.60 0.60 1.66 0.27

>0.05 :>0.05 :0.05 >0.05 ~-0.05

Post-inf. 0.03 0.05 0.08 0.04 0.06

38.3 38.3 38.5 38.5 38.4

± 4± ± 4-

0.03 0.06 0.05 0.05 0.06

TABLE III Infusion into the lateral cerebral ventricle o f A VP in normally hydrated cats and A VP-antiserum in dehydrated cats. Effect on body temperature at an ambient temperature o f 38 °C nl, no. of experiments; n2, no. of animals used in nl; t, t-test value for difference between mean Tb pre-infusion and mean Tb postinfusion ; P, probability mean pre-infusion Tb is different from mean post-infusion Tb. Dose

0 (saline) 1 mU 2mU 5 mU 10 mU 20 mU AVP-antiserum

Weighted mean Tb 4- S.E. (°C) Pre-inf.

Post-inf

38.8 38.7 38.9 38.8 38.7 38.9 39.8

38.9 38.8 38.9 38.8 38.8 38.8 39.7

4- 0.05 4- 0.08 4- 0.05 4- 0.05 ± 0.06 4- 0.07 ± 0.10

4- 0.06 4- 0.10 4- 0.04 4- 0.04 4- 0.04 ± 0.07 4- 0.10

nl

n2

t

P

6 4 5 5 6 4 4

4 3 3 3 5 3 3

0.86 0.22 0.15 0.05 0.37 0.93 0.58

-~0.05 >-0.05 >0.05 >0.05 >0.05 ;~>0.05 >0.05

TABLE IV Infusion into the lateral cerebral ventricle o f A VP in normally hydrated cats and A VP-antiserum in dehydrated cats. Effect on evaporative water loss at an ambient temperature o f 38 °C m, no. of experiments; n~, no. of animals used in n~; t, t-test value for difference between mean EWL pre-infusion and mean EWL post-infusion ; P, probability mean pre-infusion EWL is different from mean post-infusion EWL. Dose

0 (saline) 1 mU 2 mU 5 mU 10 m U 20 m U AVP-antiserum

Weightedmean E W L 4- S.E. (W/kg) Pre-inf

Post-inf

1.45 1.41 1.35 1.82 1.39 1.51 0.95

1.42 1.43 1.47 1.79 1.36 1.65 1.07

± 0.07 -4- 0.08 4- 0.09 4- 0.05 4- 0.06 4- 0.10 4- 0.08

_-%0.06 i 0.07 4- 0.07 ± 0.08 4- 0.06 4- 0.10 4- 0.10

nl

n2

t

P

6 4 5 5 6 4 4

4 3 3 3 5 3 3

0.37 0.22 1.13 0.33 0.37 0.93 0.98

> 0.05 > 0.05 > 0.05 > 0.05 >0.05 >0.05 >0.05

133 (Table IV). In dehydrated animals at 38 °C pre-infusion Tb was elevated above the level occurring in hydrated animals at 38 °C., Preinfusion levels of' EWL were lower in dehydrated animals at 38 °C than in hydrated animals. These findings reflect the inhibition of evaporation and consequent elevation of body temperature that we have previously reported to occur in dehydrated animals. Intracerebroventricular injection of AVP-antiserum into dehydrated cats at 38 °C, however, was without significant effect on either Tb or EWL. DISCUSSION Previous studies in this laboratory have indicated that, when the heat-stressed cat becomes dehydrated, EWL can be reduced to conserve body water. As a consequence body temperature rises 13. When body temperatures reach extreme limits evaporation is again activated and can continue at levels greater than those occurring in the hydrated animal at the same Ta 13. This suggests a central inhibition of neural processes controlling evaporation rather than a failure of the peripheral evaporative process in the upper respiratory tract. Kozlowski and colleagues have shown that the degree of elevation of rectal temperature in exercising dogs is under osmotic contro126. Our own studies in the resting, heat-stressed cat indmate that both EWL and Tb are altered by a s~gnal which is mediated at least in part by the level of pOsm ~5. In view of the role of vasopressin in regulating renal water exchange and the regulation of release of this hormone by changes in pOsm 85, the possibility that vasopressin might be a link in the chain of events leading to evaporative water conservation in the heat-stressed, dehydrated cat has been explored. This investigation has examined two avenues by which AVP might inhibit thermoregulatory evaporation. The first of these avenues is via the general circulation. Vasopressin is normally released to the circulation and it is possible that this peptide hormone could act upon central neural sites regulating evaporation from the blood side of the blood-brain barrier. This route of action seems to operate for at least one other similar-sized peptide hormone, angiotensin5. The experiments in which AVP was infused i.v. into normally hydrated cats at 38 °C in-

dicate that if AVP is the mediator of suppressed evaporation it does not act from the circulation to perform this role in the cat. Similar studies in man., where sweating is the principal avenue of thermoregulatory evaporation, have not produced a uniform result when the effects of vasopressin injections on evaporation have been examined2,l~,ta,19,a1,aT. However, the more recent studies are in general agreement that vasopressin injections do not alter thermoregulatory evaporation in man2, is,aT. The second avenue by which dehydration might act via AVP to inhibit evaporation is within the central nervous system per se. As a preface to examining this possibility it seemed appropriate to analyze changes in central nervous system extracellular AVP levels during dehydration. The presence of AVP in the CSF has been suggested at least since the early studies of Mestrezat and Van Caulaert3°. More recently sensitive bioassays20,45 and specific radioimmunoassays12, 2z have been employed to confirm the presence of AVP in the CSF of a variety of mammals. Zaidi and Heller4s have clearly demonstrated that AVP does not normally cross the blood-CSF barrier and histological studies suggest that AVP might enter the ventricles from AVP-containing neurons lying under the ependyma7. Several studies have examined changes in csfAVP levels after stimulation which is known to increase AVP release to the circulation. Heller et al. z0. stimulated the vagus nerve electrically and measured large increases in csfAVP levels. Vorherr et al. 45 and Wang et al. 46 have shown that hemorrhage cart increase csfAVP concentration in rabbits and dogs. Without reporting data on changing plasma osmolality, Sulakhvelidze4° has reported the appearance of bioassayable vasopressin activity in CSF of dogs after 3 days of dehydration, though none was detectable in the CSF of hydrated dogs or dogs subjected to 2 days of dehydration. Dogterom et al. lz have used radioimmunoassay to measure csfAVP in normally hydrated dogs and in dogs dehydrated for 24 h, and report an insignificant increase of approximately 50~o in csfAVP levels in the dehydrated animals. This group also did not report changes in plasma osmolality. Numerous such studies, as well as our own, have relied on samples of CSF from anesthetized animals for the measurement ofcsfAVP. Anesthesia may influence the release of AVP to the circu-

134 lation17 and therefore possibly to CSF. It was one of the purposes of the present studies to systematically examine the relationship between pOsm and csfAVP in the cat at various levels of hydration. The results indicate a log-linear relationship between these variables, suggesting that during dehydration in the cat vasopressin release into both the CSF and the general circulation is increased. Plasma AVP levels could be related to pOsm equally well by either a linear model or a log-linear model in this study. Reaves et al. have reported a linear relationship between these variables in the cat 34. However, inspection of this group's data suggests that a log-linear relationship might be equally valid. Furthermore, unusually high levels of plasma osmolality were reported for normally hydrated animals in the study of Reaves et al. such that the threshold level of pOsm for AVP release was 311 mOsm/kg. In our own linear model this threshold would correspond to 302 mOsm/kg. Several studies have linked intracranially-released vasopressin to central neural functions which do not parallel its principal function in regulating body water balance s,9,23-25,29. However, Szczepanska-Sadowska and Koslowski have found evidence that intraventricular infusion of exogenous AVP can alter the osmotic reactivity of the thirst mechanism27,4z, thus providing a central neural link between the osmotic state of body fluids and processes functioning to regulate body fluid composition. That centrally acting AVP cart alter thermoregulation has been demonstrated in several species. Kasing et al. have induced antipyresis in febrile sheep by push-pull perfusion of AVP solution through the septal region8, 23. The same group have injected AVP (1/zg, ca. 385 mU) into the lateral ventricles of rats and report immediate hypothermic responses at ambient temperatures around 19 °C 24. Lipton and Glyn have systematically examined thermoregulatory effects of intraventricular infusion of several peptide hormones in the rabbit2L In their study, AVP was found to consistently produce a hyperthermia which occurred rapidly after infusion and lasted up to 3 h. The hypothesis examined in the intracerebroventricular infusion experiments reported here has sought to link the osmotic control of intracranial AVP release to the thermoregulatory changes occurring as the result of an osmotically induced alteration

in the control of evaporative water loss. The doses of AVP administered, when considered in terms of brain size33 range from approximately half the smallest dose reported to produce hyperthermia in the rabbit to three times the highest dose examined which produced hyperthermia in the rabbit 29. Vasopressin was found to be without effect on body temperature when injected at various doses into the ventricles of cats at 23 °C. The failure of AVP to produce hyperthermia in the cat compared with the moderate hyperthermias occurring in rabbits at the same ambient temperature29 may indicate a species difference between the central role of this hormone in the two animals. The negative findings at 23 °C, however, do not represent a failure to support the hypothesis that centrally acting AVP can lower EWL, since at an ambient temperature of 23 c'C the evaporative pathway is not actively participating in body temperature regulation in the caP. At 38 °C, evaporative heat loss plays a considerable role in thermal homeostasis in the cat 1. The failure of AVP to alter either body temperature or evaporation under these ambient conditions can be taken as strong evidence to indicate that centrally released AVP present in dehydrated animals does not normally produce the inhibition of evaporative water loss and consequent elevation of body temperature occurring in these animals 13. Additional evidence to support this view comes from experiments reported here in which specific AVP-antiserum was injected into the ventricles of dehydrated animals. Passive intracranial immunization has been previously used to antagonize the effects of centrally acting peptides. Van Wimersma Greidanus et al. have reported that intraventricular infusion of AVP-antiserum inhibits memory consolidation in rats a3. A similar approach has been successfully employed to examine the central role of thyrotropin-releasing hormone in body temperature regulation in rats 32 and cholecystokinin in the regulation of food intake in sheep~L Thus, it is reasonable to expect that arty effect on evaporation or body temperature of AVP released intracerebrally in dehydrated cats could be antagonized by antiserum administration. As a result, thermoregulatory parameters would tend toward those of the normally hydrated animal. In these experiments AVP-antiserum administration into dehydrated animals at 38

135 °C produced no significant alteration in either EWL or Tb. This can be interpreted as consolidating evidence that central AVP is not responsible for the altered pattern of thermoregulation occurring in dehydrated animals. In a final overview of the information generated thus far on the mechanisms involved in the alterations of temperature regulation occurring during dehydration in the cat, several salient points need to be emphasized. Firstly, elevation of body temperature during combined heat stress and dehydration is produced by an inhibition of evaporative heat loss 13. This inhibition does not represent a failure of the peripheral pathway for evaporation from the upper respiratory tract, but occurs as a result of diminution of the response of the central neural pathways governing evaporative heat loss to driving signals from hypothalamic thermoregulatory centers 14. This alteration can be induced and reversed by changes in plasma osmolalitylL The link between elements sen-

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