J Comp Physiol B (2005) DOI 10.1007/s00360-005-0054-7 http://www.paper.edu.cn

ORIGINAL PAPER

Chongbin Liu Æ Rende Li Æ Zhonghu Liu Æ Shuming Yin Ziren Wang The role of prostaglandins and the hypothalamus in thermoregulation in the lizard, Phrynocephalus przewalskii ()

Received: 16 August 2005 / Revised: 24 October 2005 / Accepted: 1 November 2005 Springer-Verlag 2005

Abstract Typically, small lizards rely heavily on behav- Introduction ioral thermoregulation rather than physiological mech- anisms to control their rates of warming and cooling. Most are ectothermic vertebrates, which regulate We tested the hypothesis that prostaglandins participate body temperature (T ) by behavioral and physiological in mediating the cardiovascular response to heating and b means. The effectiveness of behavioral thermoregulation cooling and temperature regulating neurons in the depends on the hypothalamus as a thermostat and car- hypothalamus of the small lizard Phrynocephalus prze- diovascular responses during heating and cooling (Grigg walskii. In vivo and in vitro treatments, heart rates et al. 1979; Tosini et al. 2001; Franklin and Seebacher (HRs) were all found to be higher during heating than 2003; Seebacher and Franklin 2003). Numerous studies during cooling, hysteresis was distinct below 30 and on different groups of reptiles have shown different heart 26C, respectively. In vivo, as administration of COX rates (HRs) in warming and cooling (‘hysteresis’ pat- inhibitor, there were no differences in HR between tern), which allow reptiles to control rates of transient heating and cooling at any body temperature and heat transfer and peripheral flow between the environ- administration of agonist prostaglandins only produced ment and their core (Bartholomew and Tucker 1963, a significant effect on HR below 25C. Single-unit 1964; Morgareidge and White 1972; Smith 1976; Grigg activity was recorded extracellularly in vitro with mi- et al. 1979; Bartholomew 1982; Grigg and Seebacher croelectrodes, found the firing rate of the continuous 1999; O’Connor 1999; Seebacher and Franklin 2003). unit increased 23% when the temperature of the artificial However, the physiological mechanisms of ‘hysteresis’ cerebrospinal fluid dropped from 30–20C. We conclude pattern are not well known. that prostaglandins appear to play only a limited role in Prostaglandins are local hormones having diverse modulating heart activity in Phrynocephalus przewalskii and potent biological activities. Extensive investigation and suggest that cold-sensitive neurons in the preoptic concerning the physiological role of prostaglandins in and anterior hypothalamus (PO/AH) are involved in cardiovascular function have been carried out in mam- thermoregulatory control during heating or cooling. mals, yet only a few attempts have been made to eluci- date the role of these molecules in non-mammalian Keywords Body temperature Æ Hysteresis Æ vertebrates. Prostaglandin E (PGE ) is known to par- Hypothalamus Æ Lizard Æ Prostaglandins Æ 2 2 ticipate to the maintenance of organ blood flow and Thermoregulation regulation of blood pressure. Injection of PGE2 causes bradycardia in the eel Anguilla anguilla (Janvier 1997), but increases HRs in rainbow trout (Brown and Communicated by I.D. Hume Bucknall 1985). Prostaglandin F2a (PGF2a) is regarded as a vosoactive substance in amphibians and reptiles C. Liu Æ R. Li Æ Z. Liu Æ S. Yin Æ Z. Wang (&) (Robleto and Herman 1988; Altimiras et al. 1998). School of Life Sciences, Lanzhou University, Hysteresis in reptiles is triggered by prostaglandins, and Lanzhou, 730000 Gansu, People’s Republic of China E-mail: [email protected] to a lesser extent by the autonomic nervous system, but Tel.: +86-931-3658646 there exists considerable variation in the control mech- Fax: +86-931-8913562 anisms among (Morgareidge and White 1972; Altimiras et al. 1998; Seebacher and Franklin 2003, C. Liu 2004a, b). The importance of these differences in regu- Department of Life Science, Jinggangshan College, Ji‘an, 343009 Jiangxi, People’s Republic of China lating HRs of warming and cooling in reptiles have yet

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to be thoroughly examined and we test for this in a small movements. We used a 100 W incandescent light bulb, lizard, Phrynocephalus przewalskii, increasing the phy- suspended 40 cm above the plastic container, to heat the logenetic diversity of reptiles considered for this box to a maximum temperature of 38C (Li and Liu tendency. Moreover, HR and blood circulation in ver- 1992; Belliure and Carrascal 2002). During cooling, the tebrates are controlled by complex hormonal and chamber was allowed to cool convectively in a temper- nervous mechanisms (Wilson 1983; Robleto and ature-controlled room set at 20C. All monitoring Herman 1988; Altimiras et al. 1998) and stress under equipment was controlled from a separate room adjoin- artificial conditions may confound laboratory data. ing the experimental chamber. In in vitro experiments, Therefore, this study attempts to determine the HR we prepared an isolated perfused lizard heart-lung model effects of heating and cooling in vivo and in vitro, in (IPLHLM). Following sodium pentobartital injection, order to elucidate the mechanisms underlying these re- the heart was exposed and the posterior cardinal vein was sponses. cut at 2 mm in the front of the liver and a cannula of this After discovery of thermosensitive neurons in the vein was used by binding the proximal end with a thread. hypothalamus (Nakayama et al. 1961), some neurons of Next, the pericardium was opened and the anterior car- efferent side in the thermoregulatory network have been dinal veins, carotid and systemic arteries, and the trachea identified (Nagashima et al. 2000). Reptiles, as well as were severed, but the lung was left intact. The IPLHLM other ectothermic vertebrates, depend fundamentally on was isolated from the inner thoracic cavity and placed external heat sources and behavioral adjustments to upside down in a tub containing Ringer solution of the alter their body temperature. However, the fact that the following composition (mM): 80.0 NaCl, 2.5 KCl, 2.0 circadian rhythm of behavioral temperature selection of CaCl2, 1.0 MgCl2, 40.0 NaHCO3, and 10.0 glucose and Podarcis sicula (Lacertidae) is not definitely abolished equilibrated with 3% CO2 + 97% O2, pH was 7.75 after both parietalectomy and pinealectomy, suggests (Wasser et al. 1997). We set the preload (filling pressure) that the suprachiasmatic nuclei (SCN) or neighboring and afterload conditions by adjusting the height of the hypothalamic areas may also be involved in driving this perfusion reservoirs and the outflow catheter relative to rhythm (Innocenti et al. 1993). Interestingly, in Dipso- the heart (30±0.5 cm water pressure). The flow rate was saurus dorsalis, the daily bout of voluntary hypothermia directly dependent on water pressure. disappears after lesion to the periventricular preoptic area of the hypothalamus (Berk and Heath 1975). Fur- thermore, in ectothermic vertebrates, the temperature Drugs and treatments regulating neurons in the hypothalamus are still un- known. For this purpose, we record single-unit activity In in vivo experiments, used in the laboratory extracellulary in vitro with microelectrodes, using con- heating and cooling trials were starved for 24 h prior to stantly perfused preoptic and anterior hypothalamus experimentation. The non-steroidal anti-inflammatory (PO/AH) tissue slices with artificial cerebrospinal fluid drug Diclofenac (Sigma, 8 mg kgÀ1 body mass), an (aCSF) at different temperatures. inhibitor of COX activity (Rainsford 2001), was injected intraperitoneally 2.5 h before experimentation (Seebacher and Franklin 2003). Agonists prostaglandin À1 Materials and methods E2 (Sigma, 5 lgkg ) and prostaglandin F2a (Sigma, 10 lgkgÀ1) were administered intravenously at different Animals body temperatures and the total amount of fluid injected did not exceed 0.5–0.7% of total blood volume. PGE2 was Healthy adult lizards, Phrynocephalus przewalskii dissolved in 95% ethanol at 10 mg lÀ1 and further dilu- (n=48, mass=8.67±1.40 [SE] g, SVL=50.6±4.2 tions were made in physiological saline just prior to [SE] mm) were used after being captured in the desert administration (Janvier 1997). The concentration and and semi-desert area in Gansu province (3760¢S, amount of ethanol injected was too diluted to have a 10305¢E). They were housed in the laboratory (25–28C) physiological effect (Crashaw et al. 1988). PGF2a was and acclimated for at least 2 weeks and given free dissolved directly in physiological saline before the access to feed and water. Artificial illumination was experiment (Stenslokken et al. 2002). For the controls provided on a 12L:12D cycle. Only male adult lizards (injected saline), the same quantity of saline was injected were considered for this study to avoid influencing the as drugs in experimental treatments. reproductive status of females at this time of the year.

Heart rate and temperature measurements Experimental setup and surgery In in vivo experiments, HRs were taken from electro- In in vivo experiments were conducted in a temperature- cardiograms (ECG). The ECG was recorded from 5 mm controlled black plastic container with a custom-made long stainless steel electrodes (Medtronic, France) box measuring 15·5·10 cm3, which was large enough for placed subcutaneously in the limbs. The electrodes were the animals to fit comfortably but restricting sideways connected to a computerized data-acquisition system 中国科技论文在线 http://www.paper.edu.cn

(Powerlab, AD Instruments, Australia) fronted by a procedures were processed in a shielding chamber high-gain AC amplifier (BioAmp, AD Instruments, (PBG-1, Chengdu Instruments, Chengdu, China). Australia), and implanted at least 1 h prior to sampling to give the animals sufficient recovery time. Insertion of these needles took less than 5 min and could be per- Statistical analysis formed with minimal stress to the animals (Cabanac and Bernieri 2000; Cabanac and Cabanac 2000). Further- Heart rates means and standard errors were calculated and more, the wire electrodes did not appear to interfere with compared for resting HR (thermal equilibrium) before the normal behavior of the lizards. In in vitro experi- temperature treatments and HRs during heating and cool- ments, an electrophysiology system RM6240 (Chengdu ing. Before analysis, all data were corrected for body tem- Biological Instruments, Chengdu, China) connected a perature by regressing data from each treatment against tonotransducer was used to record HRs. In in vivo body temperature and then subtracting residuals where the experiments, body temperature (Tb) was measured by regressions were significant (heating in vivo: inserting a soft flexible temperature probe 2 cm into the Y =0.2077x2 À 3.2449x + 21.707, R2=0.997, cooling in cloaca and connected to a thermocouple pod (AD vivo: Y = 0.1769x2 À 1.774x + 10.097, R2=0.996; heat- Instruments, Australia). Baseline data were recorded for ing in vitro: Y = 0.147x2 À 0.2234x + 6.0506, R2=0.998, 15 min, the heating lamp was then turned on and HRs cooling in vitro: Y = 0.1162x2 + 0.6658x À 0.0494, 2 and Tb were recorded until Tb reached 36C. At this R =0.995). All data were used in the analysis of variance to temperature, the heating lamp was turned off, and Tb avoid inflating the degrees of freedom in the analysis by and HRs were monitored until Tb dropped to 20C. HRs treating measurements taken at different body temperatures were recorded continuously for at least 1 h after each as replicates (Seebacher and Franklin 2004a, b). Data were injection and all experiments were conducted during the analyzed with a one-way ANOVA followed by Student’s t- day. In in vitro experiments, temperature of the perfused test. The ratio of heating to cooling was calculated using the heart was regulated with an electric bathtub and a SY-2 formulae: f H = f1(x)/f2(x)(x body temperature). Statistical digital thermometer (Beijing Normal University Instru- significance was determined by comparing agonist treat- ments, Beijing, China) was used to measure the bath ments with control using two-sample t-tests (P<0.05) and temperature. graphs were made with Microsoft Excel 2000. All results were presented as mean ± SE.

Microelectrode recording Results

Lizards were killed by decapitation after sodium Heart rates during heating and cooling pentobartital injection. The stereotaxic coordinates for in vivo and in vitro experiments probe implantation (determined from parietal eye), for the optic chiasm, were 1.12±0.35 [SE] mm posterior, Heart rates during heating and subsequent cooling in in 2.28±0.36 [SE] mm lateral, and 3.5±0.29 [SE] mm vivo and in vitro experiments were shown in Figs. 1 and 4. below the cortical surface. The living brains were sub- In in vivo experiment, Tb increased gradually to 36C jected to vibratome (Vibrosilice NVSL1, WPI, Inc., within the first 0.5 h after turning the heat lamp on. The USA) and longitudinally coronal dissected segments of subsequent cooling phase, where Tb decreased from 36 to 400 lm were transferred to an experimental chamber 20C, lasted about 1 h. HRs increased with the applica- and incubated (as described below) for more than 1 h tion of radiant heat and decreased when the heat source before making recordings. The preparation was per- was removed despite the fact that Tb continued to increase fused with aCSF of the following composition (mM): within 3 – 4 min. HRs during cooling were lower than 134.0 NaCl, 5.0 KCl, 2.40 CaCl2, 1.30 MgSO4, 1.24 during heating, and significant below 30C, showing a KH2PO4, 26.0 NaHCO3, and 10.0 glucose. The solu- hysteresis pattern (F1,43=15.48, P<0.05). As adminis- tion was continuously aerated with a gas mixture (95% tration of COX inhibitor, there were no differences in HR O2 +5%CO2), and pH was 7.4–7.6. Extracellular between heating and cooling at any body temperature 2 recording from PO/AH was performed using glass (Y = À58.43 + 4.64x (R = 0.96), F1,43=2.43 P> microelectrodes filled with 3.0 M NaCl, their resis- 0.05) (Fig. 2). The ratio of heating to cooling HR de- tances were 10–30 MX. Then the sections were per- creased with increasing Tb, but the ratio between heating fused at a flow rate of 5 ml minÀ1 with aCSF of and cooling was close to unity when COX enzymes were different temperatures (the baseline firing rate examined inhibited (F1,43=2.61, P>0.05) (Fig. 3). In in vitro at 25C). Microelectrode potentials were amplified experiment, HRs increased in response to application of (MIS 9403, Institute of Neuroscience, Shanghai, Chi- heat from flowing hot Ringer solution, and decreased na), recorded, and monitored continuously with instantaneously on removal of the heat source (Fig. 4). Powerlab system (AD Instruments, Australia). All HR hysteresis was distinct below 26C(F1,43=12.09, 中国科技论文在线 http://www.paper.edu.cn

Body temperature

Fig. 1 HRs and time course of 40 210 changes in T in vivo during b 36 heating and subsequent cooling, Heart rate 180 in the lizard Phrynocephalus 32 przewalskii showing heart rates 28 150 were higher during heating than during cooling and significant 24 120 hysteresis below 30C 20 90 (F1,43=15.48, P<0.05) 16 12 60 Heart rate (beats/min)

Body temperature ( ° C) 8 30 4 0 0 10 20 30 40 50 60 70 80 90 Time (min)

Fig. 2 HRs during heating and 240 subsequent cooling in vivo after injecting with the COX 1 and 2 210 inhibitor showing that there 180 were no differences in heart rate between heating and cooling at 150 any body temperature 120 (F1,43=2.43 P>0.05). filled square Heart rates during 90 heating; filled diamond Heart 60 rates during cooling Heart rate (beates/min) 30 0 18 20 22 24 26 28 30 32 34 36 38 Body temperature (°C)

P<0.05). However, HR hysteresis of lizard was more injection of prostaglandin E2 and prostaglandin F2a at significant in vivo than in vitro. 20, 15 and 10C(F2,8=10.27, P<0.05; F2,8=14.01, P<0.01; F2,8=74.28, P<0.001, respectively) (Fig. 5).

Heart rates after agonist treatments in in vivo experiment Firing patterns of neurons from PO/AH slices and rate changes of continuous firing unit in response to the drop There were no differences in HRs between control and of aCSF temperatures from 30 to 20C agonist treatments at 25, 30 and 35C(F2,8=0.92, P>0.05; F2,8=0.84, P>0.05; F2,8=0.52, P>0.05, Firing patterns of neurons were recorded from the respectively). However, HRs increased significantly after PO/AH slices in vitro. Among the 18 firing patterns of

Fig. 3 The ratio of heart rates 1.5 during heating versus cooling at different Tb showing heart rates decreased with increasing Tb and the ratio between heating and cooling was close to unity when COX enzymes were 1 inhibited (F1,43=2.61, P>0.05). The control (filled diamond); The inhibitor treatment (filled square) 0.5 Heart-rate ratio (heating:cooling)

0 18 20 22 24 26 28 30 32 34 36 38 Body temperature (°C) 中国科技论文在线 http://www.paper.edu.cn

Fig. 4 In vitro heart rates 210 during heating and subsequent cooling showing hysteresis was 180 distinct below 26C (F1,43=12.09, P<0.05) 150

120

90

60

30 Heart rate (beats/min) 0 18 20 22 24 26 28 30 32 34 36 38 Body temperature (°C)

Fig. 5 Heart rates after 210 injection of saline, prostaglandin E2 and 180 prostaglandin F2a at different Saline Tb showing no differences in 150 heart rate between control and PGE2 agonists treatments above 25 C, 120 α but increased significantly PGF2 below 25C. ***P<0.001; 90 **P<0.01; *P<0.05 * 60 ** Heart rate (beats/min) 30 ** *

0 10 15 20 25 30 35 Body temperature (°C) neurons recorded, there were three types: irregular (n=2, Altimiras et al. 1998; Crossley et al. 2003; Ehmke and 11.3%), continuous (n=13, 72%), and paroxysmal Just 2003). Small lizards are predicted to control (n=3, 16.7%) (Fig. 6). When the sections of Phryno- warming and cooling primarily via changes in blood cephalus przewalskii were perfused with aCSF at different flow to the limbs (Turner and Tracy 1983; Fraser and temperatures, there were no obviouse changes to either Grigg 1984; Turner 1987; Dzialowski and O’Connor irregular or paroxysmal firing patterns. However, the 1999). HRs are controlled by peripheral and central firing rate of the continuous unit increased 23% from mechanisms (Seebacher 2000; Tosini et al. 2001; Viana 4.34±0.28 [SE] to 5.27±0.56 [SE] impulses sÀ1(n=25) et al. 2002; Viswanath et al. 2003) and may be modu- when the temperatures of the aCSF dropped from 30 to lated directly by the autonomic nervous system via 20C. These changes increased markedly from 25 to 20C cholinergic and ß-adrenergic receptors located on the (Fig. 7). heart, local hormones such as prostaglandins via the barostatic reflex, and by pacemaker cell activity (Morris and Nilsson 1994; Altimiras et al. 1998; Seebacher and Discussion Franklin 2001, 2004a, b; Kurata et al. 2002; Overgaard et al. 2002). However, the mechanisms of hysteresis ex- Physiological control of heating and cooling along with hibit considerable variation between species behavioral thermoregulation are important in the ecol- (Seebacher and Franklin 2004a, b). More detailed in ogy and survival of reptiles and other ectothermic vivo and in vitro investigations will provide valuable organisms (Huey 1982; Seebacher and Grigg 2001; An- insight into the cardiovascular control mechanisms and giletta et al. 2002). Reptiles govern circulation and their identify the factors affecting heart activities which can be dependent physiological functions primarily by changes controlled alone. in HR rather than by changes in stroke volume (Farrell The lizard Phrynocephalus przewalskii is active for 1991; Seebacher and Grigg 2001; Galli et al. 2004). most of the day, seeking shade rarely, and displaying Hysteresis and the interactions between changes in vessel typical basking behavior by sun exposure in the diameter and cardiac output are translated into changes morning. Hence, the thermal significance of modifica- in peripheral blood flow (Morgareidge and White 1972; tions in HR will be of importance during the heating Grigg and Alchin 1976; Smith 1976; Smith et al. 1978; phase in the morning and during cooling in the 中国科技论文在线 http://www.paper.edu.cn

Fig. 6 In vitro firing patterns of neurons from a slice of PO/AH exhibiting three firing patterns: irregular (n=2, 11.3%), continuous (n=13, 72%) and paroxysmal (n=3, 16.7%)

evenings (Liu and Li 1999). The hysteresis of HR ob- However, the pronounced differences are found below served in our in vivo experiment (Fig. 1) is not as 30C (Fig. 1) may indicate that there is a temperature dramatic as described in previous studies, which report threshold for upregulation of HR during heating which that the difference in HR, at any given body tempera- should be investigated further. Alternatively, this ture, may be as large as 20–30 beats minÀ1 (Barthol- finding may indicate that small lizards may not control omew and Tucker 1963; Bartholomew and Lasiewski rates of warming and cooling via changes in HR to an 1965; Zaar et al. 2004). It appears that the small lizard appreciable level at high Tb,butrather,relyprimarily cardiovascular response is primarily controlled by on behavioral thermoregulation. Further study is central autonomic mechanisms, an autonomic influ- warranted to elucidate the mechanisms of HR hyster- ence on HR when the is not in thermal equi- esis on both cellular and molecular level. As adminis- librium. This pattern is similar to observation in lizard tration of COX inhibitor, there were no differences in Gallotia galloti (De Vera and Gonzales 1997, 1999). HR between heating and cooling at any body temper-

Fig. 7 Rate changes of continuous firing unit in response to the drop of aCSF temperature from 25 to 20C showing the firing rate of the continuous unit increased when the temperatures of aCSF dropped from 25 to 20C (n=25) 中国科技论文在线 http://www.paper.edu.cn

ature (Fig. 2) and the ratio of HR during heating vs. Acknowledgements This work was supported by the National cooling is close to unity (Fig. 3). This shows that Natural Science Foundation of China (No. 30270194). We thank Prof. R.E. ESPINOZA and two anonymous reviewers for revising prostaglandins also play a role in regulating HR hys- our paper. This study and care of animals followed guidelines teresis in this small lizard. Prostaglandins act mainly in established by the Universities. constricting or dilating blood vessels so that their effect on HR occurs most probably via a barostatic reflex in response to peripheral constriction or dilation of blood vessels. In our in vivo experiment, the addition of References prostaglandins do not result in significant changes in HR at 25, 30 and 35C, but it do so at 20, 15 and 10C Altimiras J, Franklin CE, Axelsson M (1998) Relationships be- (Fig. 5). 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