Cold defense mechanisms in vagotomized rats - Regulatory ...

Cold defense mechanisms

in vagotomized

ANDREJ A. ROMANOVSKY, VLADIMIR A. KULCHITSKY, NAOTOSHI SUGIMOTO, AND MIKL& SZtiKELY Thermoregulation Laboratory, Legacy Research, Legacy Portland Hospitals, Portland, Oregon 97227 Romanovsky, Andrej A., Vladimir A. Kulchitsky, Christopher T. Simons, Naotoshi Sugimoto, and Mikl6s Sz6kely. Cold defense mechanisms in vagotomized rats. Am. J. PhysioL. 273 (Regulatory Integrative Comp. Physiol. 42): R784-R789, 1997. -Subdiaphragmatically vagotomized rats cannot mount a febrile response to pyrogens and are believed to have severe thermoregulatory deficiencies. We addressed the issue of thermoeffector competence of vagotomized rats by asking three questions. In Expt. 1 we asked, can vagotomized rats readily recruit tail skin vasoconstriction in the course of a moderate cold exposure? In Expt. 2 the question was, can brown adipose tissue (BAT) thermogenesis readily be activated in vagotomized rats (e.g., in response to a tail pinch)? In Expt. 3, we investigated the question: can vagotomized rats elevate their body temperature in response to ephedrine (a drug of high hyperthermizing potential) to the same extent as sham-operated controls? Rats were vagotomized or sham operated and implanted with a catheter into the jugular vein and a thermocouple into the interscapular BAT. To prevent the common complications of vagotomy, special perioperative care was given. During experiments, colonic, tail skin, and BAT temperatures (T,, Tsk, and TBAT, respectively) were measured. The vagotomized animals were well nourished and had a body mass (325 2 6 g) similar to that of the controls (338 t 6 g). In Expt. 1, in response to external cooling (15”C, 1 h), the vagotomized (n = 30) and sham-operated (n = 31) rats recruited tail skin vasoconstriction at close values of both T, (37.84 ? 0.08 and 37.97 ? 0.07”C) and Tsk (33.16 t 0.17 and 33.18 t O.l8”C, respectively). In Expt. 2, tail pinch-associated stress in vagotomized rats resulted in a sharp rise in the T, gradient by 0.3-l.O”C. In Expt. 3, ephedrine TBAT administered intravenously (whether in a 5 or 35 mg/kg dose) evoked similar hyperthermic responses in the vagotomized and sham-operated rats: a moderate (-2.5”C) T, rise in the low dose and a “supramaximal” (-5.O”C) rise in the high dose. In sum, the answer to all three questions asked is yes. Vagotomized rats, at least when well nourished, exhibit no signs of thermoeffector deficiency. It is, therefore, not effector incompetence but rather vagal deafferentation per se that can explain the febrile irresponsiveness of vagotomized rats. thermoregulation; sure; ephedrine

skin vasoconstriction;

brown

fat; cold expo-

TO the humoral mediatory cascade, peripheral neural afferents (most eminently, those of the vagus nerve) could also participate in the pathogenesis of fever (for review, see Refs. 2, 31). In the rat and guinea pig, complete subdiaphragmatic vagotomy has been shown to prevent the febrile response to peripheral injections of bacterial lipopolysaccharide (LPS) and a pyrogenic cytokine, interleukin-lp (16, 21, 27, 30). Damaging the abdominal afferent fibers of the rat by intraperitoneal capsaicin desensitization similarly resulted in a depression of LPS-induced fever (26,28). IN ADDITION

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rats CHRISTOPHER

T. SIMONS,

Both abdominal vagotomy and capsaicin treatment may per se cause severe pathological consequences such as malnutrition, altered behavior, loss of body weight, etc. (7, 14, 17, 19). Vagotomized rats have been reported to respond to cold exposure with inadequately small metabolic rate rises, insufficient to maintain homeothermy even when external cooling was mild (12). As for capsaicin desensitization, it is known to decrease the mass and functional reserve of the brown adipose tissue (BAT, see Refs. 5, 6), which normally is an important heat-production effector during both cold exposure (24) and pyrogen action (29), especially in the rat. Lesions to the nucleus of the solitary tract [a major site of termination of vagal afferents (1)] result in a decreased thermogenic response of the BAT to various humoral stimuli (9, 10). Vagotomy may also interfere directly with intermediary metabolism: this procedure alters the diurnal pattern of glucose and insulin (13) and prevents the development of “hypothalamic” obesity (even if the food intake is maintained at a control level; Ref. 4). In addition to vagotomy-associated metabolic abnormalities and a possible decrease of the thermogenic capacity, the involvement of the vagus nerve in vasomotor control (11) suggests that vagotomized animals may also have functional alterations in their heat conservation mechanisms, e.g., thermoregulatory skin vasoconstriction. It has been demonstrated that concurrent malnutrition is not responsible for inhibiting fever development (21). It has not been, however, specifically clarified whether the decreased febrile responsiveness of vagotomized animals could be due to a malnutrition-independent thermoeffector deficit (decreased thermogenic capacity or altered heat conservation ability or both). If the thermogenic potential is weakened or the heat conservation mechanisms are malfunctional, an inability to mount a febrile response becomes a direct and unavoidable consequence of the thermoeffector incompetence rather than a specific effect of the missing vagal afferentation. If it is indeed a deficiency of thermoeffector mechanisms that explains the febrile irresponsiveness, this deficiency should be gross and easily detectable because, as described in the preceding report (21), the thermal response of vagotomized rats to a low dose of LPS is altered grossly (completely abolished). In the present study, we tested the thermal responsiveness of well-nourished (21) vagotomized rats to several nonpyrogenic stimuli and assessed the animals’ ability to utilize cold defense (heat conservation and heat production) effector mechanisms. METHODS Animals Adult male Wistar rats (B & K Universal, Kent, WA) were used in the experiments. The animals were initially housed the American

Physiological

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three per box; for the last 4-5 days before the experiment, they were caged singly The room was on a 12:12-h light-dark cycle; room temperature was maintained at 22°C. Food and water were available ad libitum; the vagotomized animals were given reinforced food (21). The rats were handled and weighed regularly. They were also habituated (five training sessions, 3-4 h each) to a cylindrical restrainer that lightly restricted their back-and-forth movements and prevented them from turning around. The same restrainer was used later on in the experiments. Surgical

Preparation

Generally, the animals underwent two surgical procedures. First (1 wk after their acquisition), the rats had bilateral subdiaphragmatic truncal vagotomy or sham surgery. Before surgery, they were food deprived for 24 h and prophylactically given an antibiotic (enrofloxacin; 12 mg/kg SC). The surgery was performed under ketamine-xylazine-acepromazine (55.6, 5.5, and 1.1 mg/kg ip, respectively) anesthesia, as described previously (21). In brief, from the middle upper laparatomic approach, both vagal trunks (plus, for certainty, the hepatic branch separately) were exposed and cut; in sham surgery, the trunks were similarly exposed but not cut. Another dose of enrofloxacin (12 mg/kg) was administered, this time intraperitoneally, and the surgical wound was closed in layers. No other surgery was performed in animals assigned for Expt. 1. For the animals assigned to Expt. 2 or 3, a recovery period of 24-25 days was allowed. Thereafter, a second surgery was performed: for Expt. 2, a thermocouple was implanted into the interscapular BAT, for Expt. 3, a Silastic cannula was placed into the right jugular vein (for details on the latter surgery, see Ref. 21). The former surgery was performed under the same anesthesia as vagotomy (see above). From a small incision of skin in the interscapular area, the ending of a home-made copper-constantan thermocouple was introduced beneath a pad of BAT. The thermocouple was fabricated according to the same general plan (and using the same materials) as the intrabrain thermocouple described in an earlier paper (20). The lead was fixed to the underlying muscles, coiled, and tunneled under the skin to the animal’s head. Here, the thermocouple’s connecting plug was affixed to the skull (20). Experimental

Protocols

and Instrumentation

On days 27-32 postsurgery, the experiments were performed. On the day of the experiment, each animal was instrumented with thermocouples: colonic (9 cm from the anus) and tail skin (Expt. 1 and 3) or colonic, BAT, and tail skin (Expt. 2). The thermocouples were connected to a data acquisitor (model TCA-AI-24; Dianachart, Rockaway, NJ) and from there to a personal computer. The animal was then placed into its restrainer and transferred to a climatic chamber (Forma Scientific, Marietta, OH) set to an ambient temperature (T,) of 30°C (upper limit of the thermoneutral zone for rats) and a 50% relative humidity. For Expt. 3, the exteriorized portion of the intravenous catheter was also pulled through a wall port and connected to a syringe. After a l-h stabilization period, the measurements were begun, and colonic, skin, and BAT temperatures [T,, Tsk, TBAT (if applicable)], and T, were recorded every 2 min from 1 h before the stimulus to a variable time poststimulus. In Expt. 1, the stimulus was represented by external cooling (an exponential decrease in T, from 30.0 to --15.0°C over a 60-min period); the measurements were stopped at the end of cooling. In Expt. 2, the stimulus was a tail pinch; the temperatures were measured until 60 min poststimulus. In Expt. 3, the stimulus was the intravenous injec-

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tion of ephedrine hydrochloride (Research Biochemicals International, Natick, MA), which is known to excite both (x- and P-adrenergic receptors; activation of either receptor type increases the metabolic rate (3). The drug was administered either in a 5 mg/kg dose (to induce a moderate hyperthermia, comparable with a typical LPS fever) or in a 35 mg/kg dose (to achieve the maximal possible hyperthermizing effect). In the former case, the responses were monitored until 150 min poststimulus. In the latter case, recording was stopped at 60 min postinjection, and the animals were euthanized with an intravenous barbiturate. This was done to prevent unnecessary suffering of the rats: our pilot study has shown that the hyperthermic response to the 35 m&g dose peaks at -1 h after the drug administration; starting at 2 h postinjection, some animals receiving this dose (which is close to the median lethal dose) die. Data Processing

and Analysis

Besides the measured parameters (T,, TBAT, Tsk, and T,), several derived parameters were used in this study. They were the change in T, (AT,), the heat loss index (HLI), the BAT-colonic temperature gradient, and estimates of the threshold T, and Tsk for the initiation of tail skin vasoconstriction. The AT, was calculated as the deviation of T, from its average (over the last 30 min preceding the stimulus application) value. The HLI was calculated according to the formula HLI = (Tsk - T,)/(T, - T,); normally, the HLI changes between 0 (maximal heat conservation due to skin vasoconstriction) and 1 (maximal heat loss due to skin vasodilation); for details, see Ref. 20. As is obvious from its name, the BAT-colonic temperature gradient was calculated as the algebraic difference between TBAT and T,; this gradient is well known to reflect the thermogenic activity of the BAT, greater values referring to greater activity (29). Finally, to assess the threshold T, and Tsk, we determined (by a rapid fall in the HLI) the onset of vasoconstriction on the time plot of each individual experiment and found the corresponding values of Tsk and T, (Fig. 1); these two temperatures [representing the coordinates of a point of the Tsk (T,) plane] characterize the initiation of tail skin vasoconstriction. For the sake of simplicity, we referred to these two temperatures as the thresholds for skin vasoconstriction. All the data are presented as means t SE. To compare two single-point measurements (e.g., threshold temperatures), we used the unpaired Student’s t-test. To compare two T, curves, we integrated the AT, functions over the entire length of the experiment and treated the obtained integrals as single-point measurements. RESULTS

General Comments Two points should be clarified before we review the results of particular experiments. First, because of special perioperative care (21), the vagotomized animals were well fed, appeared healthy, and, at the time of the experiments, had a body mass of 325 t 6 g, which was similar (P > 0.130) to that of the sham-operated rats (338 t 6 g). Second, in each experiment, the initial values of both T, and HLI were similar between the vagotomized and sham-operated rats (see the corresponding figures below). Experiment

1 (Cooling

Test)

Thermal responses of the vagotomized and shamoperated rats to a mild cold exposure are shown in Fig. 2. During cooling, rats of both groups exhibited only a

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Figure 3 shows that, in vagotomized rats, a stress (induced by pinching the tail) resulted in a rapid T, rise preceded by skin vasoconstriction (a decrease of HLI) and, most important, by a steep increase in the TBAT T, gradient. Individual plots (Fig. 4) demonstrate that the T, rises were different in different experiments (probably depending on the severity of the stress) and that so were the accompanying changes of brown fat thermogenesis, the greater T, elevation being accompanied by the greater rise in the TBAT - T, gradient. Experiment

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Fig. 2. Responses of vagotomized and sham-operated rats to a mild cold exposure. Note that ambient temperature (T,) curves for the 2 groups appear to be indistinguishable and that their SEs are hidden by the symbols. AT,, change of T, from its precooling level. Initial (at time 0) T, values were 38.16 2 0.08OC (the sham group) and 38.10 t 0.07”C (the vagotomized group; P > 0.576).

moderate T, decline. Comparison between the integrals of the T, curves did not allow rejecting the null hypothesis of the two thermal responses being alike (P > 0.232). The HLI showed that heat conservation (tail skin vasoconstriction) commenced uniformly within -10 min after cooling had started, when the actual T, had changed only slightly. The threshold temperatures, characterizing the onset of vasoconstriction, were similar between the two groups: for T,, the values were 37.84 t 0.08 (n = 30) and 37.97 t 0.07”C (n = 31) for the vagotomized and sham group, respectively (P > 0.225); for Tsk, the values were 33.16 t 0.17 (n = 30) and 33.18 t 0.18”C (n = 31), respectively (P > 0.936). Experiment

1

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Time (min)

Time (min) Fig. 1. Time plots of data [colonic temperature (T,), skin temperature (T&, and heat loss index (HLI)] obtained in a single experiment in a vagotomized rat subjected to a cold exposure (cooling). Plots illustrate how “threshold” T, and T,k were determined. For further details, see Data Processing and Analysis.

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DISCUSSION

Tail Skin Vasoconstriction

in Vagotomized Animals

According to the present experiments, the heat conservation function (at least the component that depends on tail skin vasoconstriction) does not appear to be affected in vagotomized animals. The HLI values were similar between the vagotomized and shamoperated rats both at rest (thermoneutrality) and during thermoregulatory reactions, i.e., the response to external cooling (Expt. 1) and ephedrine-induced hyperthermia (Expt. 3). In stress-hyperthermia (Expt. 2), the HLI of vagotomized animals rapidly reacted to a tail pinch. In Expt. 1 (which involved more than 60 animals), no difference was found in the threshold for tail skin vasoconstriction between the vagotomized and control rats: in both groups, tail vessels constricted at the same values of T, and the same values of Tsk. Interestingly, even those reports in the literature that do suggest a defective cold defense in vagotomized rats (12) reveal no difference in Tsk changes between vagotomized and intact animals. We conclude, therefore, that vagotomized rats recruit tail skin vasoconstriction [an, if not the, important heat conservation mechanism (ls>] with the same readiness as control animals. Brown Fat Activation

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injection of the 5 mg/kg dose of ephedrine with a rapid T, rise peaking at 4.2-1.3OC above the initial value within -40 min; the T, rise was preceded by restlessness (suggesting a substantial rise in the metabolic rate) and tail skin vasoconstriction (Fig. 5). The analysis of the integrals of the thermal responses failed to reveal a statistically significant difference between the two groups (P > 0.349). High dose. To the 35 mg/kg dose, both the vagotomized and sham-operated rats responded with hyperthermia, skin vasoconstriction (both are illustrated by Fig. 6), urination, defecation, and a pronounced motor agitation (not illustrated). In both groups, the T, rise was extraordinary, reaching +OC (T, of -43°C) 1 h after the injection. No significant differences (P > 0.322) were observed between the groups.

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Although no difficulties in coping with cold exposure have been found in capsaicin-desensitized rats in our recent study (28), there have been reports by another group of investigators on morphological atrophy and functional impotence of the BAT of rats pretreated with capsaicin (6, 7). Could a similar atrophic process occur in the BAT of vagotomized animals? In view of the major contribution of BAT thermogenesis to the overall heat production of a small-sized rodent such as the rat

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(8), inactivation of the BAT could markedly limit the animal’s total thermogenic capacity. If, after vagotomy, BAT atrophy occurs and renders the tissue functionally inactive, this would explain the thermogenic weakness observed in vagotomized rats by Lin and Chern (12). The present study, however, does not support this explanation. Thus, although we did not compare the BAT-colonic temperature gradients of vagotomized rats with those of sham-operated counterparts (such a study would require an unacceptably high number of experiments because of the great technique-dependent variability of TB&, the data clearly demonstrated that the BAT was functional (BAT thermogenesis was readily activated) in our vagotomized rats. We have to conclude, therefore, that subdiaphragmatic vagotomy, at least when the operated animals are well nourished and healthy, does not lead to functional inactivation of the BAT. Vagotomixed

Rats: Any Thermoeffector

Incompetence?

Studying a single cold defense effector may not reveal the existing thermoeffector deficiency (even if it is extremely severe) simply because a wrong (undamaged) effector might have been chosen. By the same token, the deficiency of any effector component of cold defense, if severe enough, would modify the integral, resultant thermal response (e.g., as judged from T,) to a stimulus activating cold defense mechanisms. In the present experiments, we studied three thermoregulatory responses: the maintenance of homeothermy during a mild cold exposure, development of a moderate hyperthermia triggered by a low dose of ephedrine, and mounting a “supramaximal” hyperthermic reaction to an extremely high ephedrine dose. In none of these cases was there a significant difference in T, reactions between the vagotomized and sham-operated rats. It could be proposed, therefore, that there is no functionally meaningful deficiency of the cold defense thermoeffectors in vagotomized rats, at least when malnutrition and other deleterious side effects of vagotomy are prevented. This proposition is in line with the preliminary results of our two new studies (23, 25). The first study (23 ) dealt with thermal responses of vagotomized rats to LPS administered intravenously in a wide dose range; it has shown that, when the dose of LPS exceeds a minimally active (monophasic fever inducing) dose, the febrile response of vagotomized animals becomes indistinguishable from that of the sham-operated controls. The second study (25) was executed to test the thermal responsiveness to the intrabrain administration of prostaglandin (PG) E,; it has demonstrated that, independently of the dose, the PGE2-induced hyperthermic response of vagotomized rats practically duplicates that of sham-operated animals. In both studies, the vagotomized rats exhibited no thermoeffector incompetence. We conclude that the absence of thermal responsiveness to low doses of LPS (as observed earlier, Ref. 21) could not originate in any thermoeffector ins&i ciency, at least when the animals are well nourished.

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By the same token, the present data do not rule out the possibility that, without prevention of the nonspecific consequences of vagotomy, the vagotomized animals might exhibit malnutrition-associated thermoregulatory defects, including effector incompetence. From this point of view, it might be suggested that, whenever interpreting a particular paper on the interaction between the vagus nerve and thermoregulation (this literature contains several contradictions), it ought to be specifically clarified whether the studied animals could have suffered from deleterious (although potentially preventable; see Ref. 21) side effects of vagotomy, such as malnutrition. General Conclusion In well-nourished vagotomized rats, none of several different stimuli used to activate the cold defense mechanisms [intrabrain PGE2 (25), cold exposure, two doses of ephedrine, tail pinching (the present study), or intravenous LPS in a large dose (23)] revealed any thermoeffector deficiency severe enough that it could possibly account for the vagotomy-induced irresponsiveness to small doses of LPS (21). Because vagotomy appeared to have no dramatic consequences on the thermoeffector mechanisms subserving cold defense, the repeatedly observed attenuation of fever in vagotomized animals (16,21,22,25,30) is likely to reflect the absence of some vagus-carried signals normally affecting temperature regulation. In the preceding study (21), we rejected the possibility that the decreased responsiveness of vagotomized animals to LPS is due to malnutrition. The present data allow us to exclude one more potential mechanism, i.e., a malnutrition-independent, functionally meaningful defect of one or several cold defense thermoeffectors. By excluding these two possibilities, the data obtained provide further support for the concept of some peripherally originated, vagusmediated signals playing an important role in the genesis of the febrile response. Perspectives More and more data appear suggesting the intimate involvement of endogenous antipyretics in the central mechanisms of fever (15, 27). Is it possible that vagotomy activates the system of endogenous antipyresis? If this hypothesis is true, vagotomized animals will respond normally to any thermal stimuli, but will not respond to pyrogens, even if the pyrogenic signal successfully gets into the brain. This, however, was not the case in our recent study (25): when a pyrogenic stimulus (PGE2) was delivered directly into the brain, in either a low or a high dose, the vagotomized rats responded to it with the same hyperthermia as their sham-operated counterparts. These data confirm our current results by once again demonstrating that vagotomy per se induces no thermoeffector incompetence. Even more important, these data rule out an alternative explanation of the febrile irresponsiveness, i.e., as being due to vagotomy-induced antipyresis. Thus further support is provided to the general conclusion of the

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present paper: the decreased thermal responsiveness of vagotomized animals to intravenous LPS is likely to result from the inability of a peripheral pyrogenic signal to reach the vagotomized brain. Statistical consultations by Dr. L. D. Homer, critical comments on the manuscript by Dr. L. A. Kiesow, and editorial assistance by J. Emerson-Cobb and R. S. Hunter are gratefully acknowledged. Special thanks to S. L. Bennington, A. L. Jamieson, and N. V Romanovsky for their indispensable help with animal keeping, care, handling, and habituating. This study was made possible by intramural support and a research grant-in-aid by Legacy Portland Hospitals, Portland, OR. Preliminary results of this study have been reported elsewhere (lla, 21a). V. A. Kulchitsky was on leave from the Institute of Physiology, Minsk 220072, Belarus; M. Szekely was on leave from University Medical School P&s, P&s H-7643, Hungary; and N. Sugimoto is on leave from Kanazawa University Medical School, Kanazawa 920, Japan. Address for reprint requests: A. A. Romanovsky, Thermoregulation Laboratory, Legacy Research, Legacy Portland Hospitals, 2801 N. Gantenbein Ave., Portland, OR 97227. Received

26 December

1996;

accepted

in final

form

22 May

1997.

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