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Hyperthermic effect of centrally administered natriuretic peptides in the rat
Peptides 20 (1999) 193-197
Hyperthermic effect of centrally administered natriuretic peptides in the rat Imre Pataki, Miklo´s Ja´szbere´nyi, Gyula Telegdy* Department of Pathophysiology, Albert Szent–Gyo¨rgyi Medical University, Semmelweis u. 1, PO Box 531, H-6701 Szeged, Hungary Received 22 June 1998; accepted 16 September 1998
Abstract The effects of atrial natriuretic peptide (ANP-28), brain natriuretic peptide (BNP-32) and C-type natriuretic peptide (CNP-22) on body temperature were investigated in rats. Intracerebroventricular administration of each peptide in doses of 400 or 1000 ng caused a dose-related elevation in colon temperature 30 and 60 min after injection. A 40 ng dose of ANP-28 was also hyperthermic at 60 min. An intramuscular (IM) injection of noraminophenazone (a cyclooxygenase inhibitor) abolished the natriuretic peptide-induced hyperthermia. The results show that natriuretic peptides may participate in thermoregulatory processes in the central nervous system, and that their hyperthermic effect may be mediated via a cyclooxygenase-involved pathway. © 1999 Elsevier Science Inc. All rights reserved. Keywords: Natriuretic peptides; Thermoregulation; Rat
1. Introduction The natriuretic peptide family currently consists of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). ANP was first found in cardiocytes [14] and later discovered in the brain [20,25]. The biologic actions of the natriuretic peptides are mediated through association with specific, high-affinity receptors located on the surface of the target cells. There are three subtypes of receptors: A, B and C [45]. The A- and B-type receptors probably act via cyclic-GMP as a second messenger, whereas the C-type receptor is less clearly linked to a second messenger system, and is presumed to be a clearance receptor [30]. The sequence of affinity for the A-type receptor is ANP . BNP . CNP, whereas that for the B-type receptor appears to be CNP . BNP . ANP [45]. Natriuretic peptides have been found in human cerebrospinal fluid, CNP in the highest concentration [23]. The presence of natriuretic peptides and their receptors in astrocytes has also been demonstrated [26,34,48]; however, their physiological importance is not clear. The locations of the natriuretic peptide receptors suggest
*Corresponding author. Tel.: 136-62-310-651; fax: 136-62-310-651. E-mail address: [email protected] (G. Telegdy)
that the natriuretic peptides may be involved in regulatory processes in the neuroendocrine system. Relatively little is known about the action of these peptides on the integrated functions of the central nervous system (CNS). Our Department has recently carried out systemic studies to explore the roles of ANP and related peptides in learning [4,6], behavior [5] and opiate effects [1–3]. Anxiolytic properties of these peptides have also been demonstrated in an elevated plusmaze model [7,8]. Although abundant information is available regarding the action of natriuretic peptides on sites in the pituitary and the hypothalamus [33,36,38,41–43], no study has yet correlated these neuropeptides with thermoregulatory processes. To establish the roles of the natriuretic peptides in neurohormonal regulation, we set out to investigate their possible effects on the central control of body temperature.
2. Materials and methods 2.1. Animals The animals were kept and handled during the experiments in accordance with the instructions of Albert Szent– Gyo¨rgyi Medical University Ethical Committee for the Protection of Animals.
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Adult male Wistar rats weighing approximately 200 g were used. Each animal was used only once for the experiments. The animals were housed in groups of 5–7 in cages in a room maintained at constant temperature (23 6 1°C) and on a 12 h dark/light cycle (lights on from 6:00 a.m. to 6:00 p.m.) with free access to tap water and standard laboratory food. At least a week of recovery from surgery was allowed before the beginning of experiments. 2.2. Surgery To allow intracerebroventricular (ICV) peptide administration, the rats were implanted with a cannula introduced into the right lateral brain ventricle before the experiment. Under pentobarbital (Nembutal 35 mg/kg), intraperitoneal (IP) anesthesia, the stainless steel cannula was stereotaxically inserted into the ventricle with coordinates 0.2 mm posterior; 1.7 mm lateral to the bregma; 3.7 mm deep from the dural surface according to the atlas of Pellegrino et al. [40]. The cannula was secured with dental acrylic cement. Rats were allowed a minimum of 5 days to recover from surgery before peptide treatment. Upon conclusion of the experiments, 10 ml methylene blue was injected into the ventricle of decapitated animals and the position of the cannula was inspected visually. Animals with improper cannula placement were excluded from the final statistical analysis. 2.3. Treatments Rat ANP-28, BNP-32 and CNP-22 were purchased from Bachem (CA, USA). For ICV treatment, different doses of ANP-28, BNP-32 or CNP-22 were dissolved in sterile pyrogen-free 0.9% saline and injected in a volume of 2 ml. The control groups were treated with saline for all experiments. A pyrazolone derivative noraminophenazone (Algopyrin; Chinoin, Hungary) was used to inhibit cyclooxygenase. Noraminophenazone was administered IM in a dose of 50 mg/kg.
Fig. 1. The effects of atrial natriuretic peptide (ANP) on colon temperature. ANP groups of rats (n $ 9) received an injection of ANP-28 (40, 400 or 1000 ng, ICV). The control group received an ICV injection of saline. The vertical lines denote the SEM. * p , 0.05, compared with the control; ** p , 0.05, compared with the control and with the 40 ng ANP group; *** p , 0.05, compared with the control and with the 40 and 400 ng ANP groups.
natriuretic peptides were injected ICV in different doses (40 –1000 ng). 2. In studies with noraminophenazone on the hyperthermic effect of the natriuretic peptides, noraminophenazone was administered IM once 30 min before ICV peptide treatment (ANP-28, BNP-32 or CNP-22 being injected in doses of either 400 ng or 1000 ng) and the colon temperature was measured 30, 60 and 90 min later. 2.5. Statistical analysis Statistical analysis of the data were made by ANOVA. For significant ANOVA values, groups were compared by Tukey’s test for multiple comparisons with unequal cell size. A probability level of 0.05 was accepted as indicating significant differences.
2.4. Procedures On the day of the experiment, the animals were transferred to the laboratory 2 h before the beginning of the test in order for them to habituate to the experimental environment. The room temperature was maintained at 23.0 6 0.5°C throughout the experiment. Each animal was then removed from the cage and gently restrained on the table with a cloth. The colon temperature was monitored by inserting a Vaseline-lubricated thermistor probe of a digital electric thermometer (Model: Thermini 130) 5 cm into the rectum of the animal. The probe was inserted the same distance into the rectum each time it was used. All experiments started at 8:00 a.m. with an initial colon temperature measurement, colon temperature being measured before and 30, 60 and 90 min after peptide treatment. The following experiments were performed 1. The effects of centrally administered ANP-28, BNP-32 and CNP-22 on body temperature were studied. The
3. Results 3.1. Effects of ANP-28, BNP-32 and CNP-22 on body temperature Doses of ANP-28 (400 and 1000 ng) had a hyperthermic effect 30 min [F(3, 33) 5 40.56; p , 0.05], 60 min [F(3, 33) 5 77.94; p , 0.05] and 90 min [F(3, 33) 5 15.56; p , 0.05] after ICV administration, the magnitude of the effect being smaller at 90 min than at 60 min. ANP-28 in a dose of 40 ng increased the colon temperature only at 60 min (Fig. 1). Both 400 and 1000 ng BNP-32 increased the colon temperature at 30 min [F(3, 53) 5 32.63; p , 0.05], 60 min [F(3, 53) 5 41.83; p , 0.05] and 90 min [F(3, 53) 5 6.5; p , 0.05] (Fig. 2). CNP-22 in doses of 400 and 1000 ng was hyperthermic both 30 min [F(3, 34) 5 15.72; p , 0.05] and 60 min [F(3, 34) 5 28.48; p , 0.05] after ICV administration. The 1000 ng dose of CNP-22 was also hyperthermic at
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90 min [F(3, 34) 5 4.54; p , 0.05]. A 40 ng dose of CNP-22 had a mild, but statistically not significant hyperthermic effect (Fig. 3).
Fig. 4. Inhibitory effect of noraminophenazone on ANP-induced hyperthermia. Groups of rats (n $ 8) received an IM injection of saline (ANP groups) or 50 mg noraminophenazone (ANP 1 noraminophenazone groups) 30 min before an ICV injection of 400 or 1000 ng ANP-28. The noraminophenazone group received an ICV saline injection 30 min after noraminophenazone pretreatment (50 mg, IM). The control group received an IM saline injection 30 min before saline treatment (ICV). The vertical lines at the top of the bars denote the SEM. * p , 0.05, compared with the control and with the noraminophenazone, the 400 ng ANP 1 noraminophenazone and the 1000 ng ANP 1 noraminophenazone groups; ** p , 0.05, compared with the control and with the noraminophenazone, the 400 ng ANP, the 400 ng ANP 1 noraminophenazone and the 1000 ng ANP 1 noraminophenazone groups.
3.2. Effects of noraminophenazone on natriuretic peptideinduced hyperthermia
4. Discussion
Fig. 2. The effects of brain natriuretic peptide (BNP) on colon temperature. BNP groups of rats (n $ 10) received an injection of BNP-32 (40, 400 or 1000 ng, ICV). The control group received an ICV injection of saline. The vertical lines denote the SEM. * p , 0.05, compared with the control and with the 40 ng BNP group.
A 50 mg/kg IM injection of the cyclooxygenase inhibitor noraminophenazone 30 min before peptide administration abolished the hyperthermic effects of 400 and 1000 ng ANP-28 [F30;60;90 min(5,44) 5 27.94; 43.30; 7.52; p , 0.05] (Fig. 4), BNP-32 [F30;60;90 min(5,44) 5 21.05; 32.25; 3.11; p , 0.05] (Fig. 5) and CNP-22 [F30;60;90 min(5,45) 5 49.25; 113.18; 0.91; p , 0.05] (Fig. 6). Noraminophenazone alone in a dose of 50 mg/kg IM did not affect the body temperature.
Fig. 3. The effects of C-type natriuretic peptide (CNP) on colon temperature. CNP groups of rats (n $ 9) received an injection of CNP-22 (40, 400 or 1000 ng, ICV). The control group received an ICV injection of saline. The vertical lines denote the SEM. * p , 0.05, compared with the control and with the 40 ng CNP group; ** p , 0.05, compared with the control and with the 40 and 400 ng CNP groups.
Thermogenesis is under the direct control of the CNS, and particularly of specific regions of the hypothalamus. Cytokines, such as interleukin-1 (IL-1) [12,19] and IL-6 [18,29], act as endogenous pyrogens in the brain and stimulate thermogenesis at least partially via the synthesis of prostaglandins [15,35,44]. Antipyretic drugs reduce fever
Fig. 5. Inhibitory effect of noraminophenazone on BNP-induced hyperthermia. Groups of rats (n $ 8) received an IM injection of saline (BNP groups) or 50 mg noraminophenazone (BNP 1 noraminophenazone groups) 30 min before an ICV injection of 400 or 1000 ng BNP-32. The noraminophenazone groups received an ICV saline injection 30 min after noraminophenazone pretreatment (50 mg, IM). The control group received an IM saline injection 30 min before saline treatment (ICV). The vertical lines at the top of the bars denote the SEM. * p , 0.05, compared with the control and with the noraminophenazone, the 400 ng BNP 1 noraminophenazone and the 1000 ng BNP 1 noraminophenazone groups.
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Fig. 6. Inhibitory effect of noraminophenazone on CNP-induced hyperthermia. Groups of rats (n $ 8) received an IM injection of saline (CNP groups) or 50 mg noraminophenazone (CNP 1 noraminophenazone groups) 30 min before an ICV injection of 400 or 1000 ng CNP-22. The noraminophenazone group received an ICV saline injection 30 min after noraminophenazone pretreatment (50 mg, IM). The control group received an IM saline injection 30 min before saline treatment (ICV). The vertical lines at the top of the bars denote the SEM. * p , 0.05, compared with the control and with the noraminophenazone, the 400 ng CNP 1 noraminophenazone and the 1000 ng CNP 1 noraminophenazone groups; ** p , 0.05, compared with the control and with the noraminophenazone, the 400 ng CNP, the 400 ng CNP 1 noraminophenazone and the 1000 ng CNP 1 noraminophenazone groups.
by blocking the production of specific prostaglandins, and in particular PGE2. Many endogenously produced substances, often peptides, are capable of affecting body temperature when injected into experimental animals [11]. Some peptides such as arginine vasopressin [24,27], a-melanocyte-stimulating hormone [16,37], neuropeptide Y [22,47], galanin [32,39], cholecystokinin [9] and pituitary adenylate cyclase-activating polypeptide [31] that can be found in the CNS may be of overriding importance, because theoretically they might be involved in thermoregulatory processes under physiological conditions. Numerous studies have reported on neuropeptides that can affect body temperature under experimental circumstances, but their physiological importance remains unclear. The distributions of ANP and related peptides and their receptors in the CNS have been investigated by several authors. The central presence and localization of these peptides and their receptors has been identified, and it is now widely accepted that natriuretic peptides participate in neuroendocrine regulation and also that some of them may act in neuromodulation between glial cells and neurons [28,49]. ANP and CNP-encoding messenger RNA-positive neurones have been successfully detected in the medial preoptic area of the hypothalamus (a brain region that is known to take part in temperature control) in rats [41]. Nevertheless, no data are yet available to demonstrate that natriuretic peptides affect thermoregulatory events in the CNS. Connection between natriuretic peptides and prostaglandins was recently reported. Peptide effects mediated by the generation of PGE2 were found in the kidney [17,21,50],
and ANP, that increases cellular cGMP by activating membrane-bound guanylate cyclase, was suggested to amplify the IL-1b-induced cyclooxygenase-2 mRNA expression [46]. Bone endothelial cells have been demonstrated to bear receptors for natriuretic hormones associated with changes in prostaglandin production [13]. The effects of centrally administered natriuretic peptides on body temperature have been revealed in this study. Injections of either ANP-28, BNP-32 or CNP-22 into the lateral ventricle of the brain elevated the body temperature of the experimental animals. A positive correlation between the hyperthermic effect and the dose of peptide administration could be observed for ANP-28 and CNP-22. The inhibition of prostaglandin production by noraminophenazone—a known inhibitor of prostaglandin synthesis [10], completely abolished the hyperthermia induced by ANP and related peptides. These results reinforce the significance of the roles of natriuretic peptides in neuroendocrine regulation. Our data suggest that these peptide neurohormones may play a part in thermoregulatory processes at a central level, and also that their probable participation in these events is mediated at least partially by cyclooxygenase products. Acknowledgments This work was supported by grants from OTKA (T022230), ETT (T-02– 670/96) and FKFP (0091–1997). References [1] Azarov A, Szabo´ G, Telegdy G. Effects of natriuretic peptide on acute and chronic effects of morphine. Pharmacol. Biochem. Behav. 1992; 43:193–197. [2] Babarczy E, Vizi Z, Szabo´ G, Telegdy G. Effects of brain natriuretic peptide on effects of morphine in mice. Neuropeptides 1996;30:438 – 442. [3] Babarczy E, Vizi Z, To´th G, Telegdy G. C-type natriuretic peptide can modify the acute and chronic effects of morphine. Neuropeptides 1995;29:145–149. [4] Bidzseranova A, Gueron J, Bala´spiri L, Telegdy G. Intracerebroventricularly administered ANP antiserum attenuates fear-motivated learning behavior in rats. Peptides 1992;13:957–960. [5] Bidzseranova A, Gueron J, To´th G, Penke B, Varga J, Telegdy G. Behavioral effects of atrial and brain natriuretic peptides in rats. NeuroReport 1992;3:283–285. [6] Bidzseranova A, Gueron J, To´th G, Varga J, Telegdy G. Structureactivity studies on the effects of atrial natriuretic peptide, brain natriuretic peptide and their analogs on fear-motivated learning behavior in rats. Neuropeptides 1991;23:61– 65. [7] Bı´ro´ E, To´th G, Telegdy G. Effect of receptor blockers on brain natriuretic peptide and C-type natriuretic peptide caused anxiolytic state in rats. Neuropeptides 1996;30:59 – 65. [8] Bı´ro´ E, To´th G, Telegdy G. Involvement of neurotransmitters in the ‘anxiolytic-like’ action of atrial natriuretic peptide in rats. Neuropeptides 1995;29:215–220. [9] Boschi G, Launay N, Rips R. Facilitation of amphetamine-induced hypothermia in mice by GABA agonists and CCK-8. Br. J. Pharmacol. 1991;102(4):986 –990.
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Hyperthermic effect of centrally administered natriuretic peptides in the rat Imre Pataki, Miklo´s Ja´szbere´nyi, Gyula Telegdy* Department of Pathophysiology, Albert Szent–Gyo¨rgyi Medical University, Semmelweis u. 1, PO Box 531, H-6701 Szeged, Hungary Received 22 June 1998; accepted 16 September 1998
Abstract The effects of atrial natriuretic peptide (ANP-28), brain natriuretic peptide (BNP-32) and C-type natriuretic peptide (CNP-22) on body temperature were investigated in rats. Intracerebroventricular administration of each peptide in doses of 400 or 1000 ng caused a dose-related elevation in colon temperature 30 and 60 min after injection. A 40 ng dose of ANP-28 was also hyperthermic at 60 min. An intramuscular (IM) injection of noraminophenazone (a cyclooxygenase inhibitor) abolished the natriuretic peptide-induced hyperthermia. The results show that natriuretic peptides may participate in thermoregulatory processes in the central nervous system, and that their hyperthermic effect may be mediated via a cyclooxygenase-involved pathway. © 1999 Elsevier Science Inc. All rights reserved. Keywords: Natriuretic peptides; Thermoregulation; Rat
1. Introduction The natriuretic peptide family currently consists of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). ANP was first found in cardiocytes [14] and later discovered in the brain [20,25]. The biologic actions of the natriuretic peptides are mediated through association with specific, high-affinity receptors located on the surface of the target cells. There are three subtypes of receptors: A, B and C [45]. The A- and B-type receptors probably act via cyclic-GMP as a second messenger, whereas the C-type receptor is less clearly linked to a second messenger system, and is presumed to be a clearance receptor [30]. The sequence of affinity for the A-type receptor is ANP . BNP . CNP, whereas that for the B-type receptor appears to be CNP . BNP . ANP [45]. Natriuretic peptides have been found in human cerebrospinal fluid, CNP in the highest concentration [23]. The presence of natriuretic peptides and their receptors in astrocytes has also been demonstrated [26,34,48]; however, their physiological importance is not clear. The locations of the natriuretic peptide receptors suggest
*Corresponding author. Tel.: 136-62-310-651; fax: 136-62-310-651. E-mail address: [email protected] (G. Telegdy)
that the natriuretic peptides may be involved in regulatory processes in the neuroendocrine system. Relatively little is known about the action of these peptides on the integrated functions of the central nervous system (CNS). Our Department has recently carried out systemic studies to explore the roles of ANP and related peptides in learning [4,6], behavior [5] and opiate effects [1–3]. Anxiolytic properties of these peptides have also been demonstrated in an elevated plusmaze model [7,8]. Although abundant information is available regarding the action of natriuretic peptides on sites in the pituitary and the hypothalamus [33,36,38,41–43], no study has yet correlated these neuropeptides with thermoregulatory processes. To establish the roles of the natriuretic peptides in neurohormonal regulation, we set out to investigate their possible effects on the central control of body temperature.
2. Materials and methods 2.1. Animals The animals were kept and handled during the experiments in accordance with the instructions of Albert Szent– Gyo¨rgyi Medical University Ethical Committee for the Protection of Animals.
0196-9781/99/$ – see front matter © 1999 Elsevier Science Inc. All rights reserved. PII: S 0 1 9 6 - 9 7 8 1 ( 9 9 ) 0 0 1 7 3 - 9
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Adult male Wistar rats weighing approximately 200 g were used. Each animal was used only once for the experiments. The animals were housed in groups of 5–7 in cages in a room maintained at constant temperature (23 6 1°C) and on a 12 h dark/light cycle (lights on from 6:00 a.m. to 6:00 p.m.) with free access to tap water and standard laboratory food. At least a week of recovery from surgery was allowed before the beginning of experiments. 2.2. Surgery To allow intracerebroventricular (ICV) peptide administration, the rats were implanted with a cannula introduced into the right lateral brain ventricle before the experiment. Under pentobarbital (Nembutal 35 mg/kg), intraperitoneal (IP) anesthesia, the stainless steel cannula was stereotaxically inserted into the ventricle with coordinates 0.2 mm posterior; 1.7 mm lateral to the bregma; 3.7 mm deep from the dural surface according to the atlas of Pellegrino et al. [40]. The cannula was secured with dental acrylic cement. Rats were allowed a minimum of 5 days to recover from surgery before peptide treatment. Upon conclusion of the experiments, 10 ml methylene blue was injected into the ventricle of decapitated animals and the position of the cannula was inspected visually. Animals with improper cannula placement were excluded from the final statistical analysis. 2.3. Treatments Rat ANP-28, BNP-32 and CNP-22 were purchased from Bachem (CA, USA). For ICV treatment, different doses of ANP-28, BNP-32 or CNP-22 were dissolved in sterile pyrogen-free 0.9% saline and injected in a volume of 2 ml. The control groups were treated with saline for all experiments. A pyrazolone derivative noraminophenazone (Algopyrin; Chinoin, Hungary) was used to inhibit cyclooxygenase. Noraminophenazone was administered IM in a dose of 50 mg/kg.
Fig. 1. The effects of atrial natriuretic peptide (ANP) on colon temperature. ANP groups of rats (n $ 9) received an injection of ANP-28 (40, 400 or 1000 ng, ICV). The control group received an ICV injection of saline. The vertical lines denote the SEM. * p , 0.05, compared with the control; ** p , 0.05, compared with the control and with the 40 ng ANP group; *** p , 0.05, compared with the control and with the 40 and 400 ng ANP groups.
natriuretic peptides were injected ICV in different doses (40 –1000 ng). 2. In studies with noraminophenazone on the hyperthermic effect of the natriuretic peptides, noraminophenazone was administered IM once 30 min before ICV peptide treatment (ANP-28, BNP-32 or CNP-22 being injected in doses of either 400 ng or 1000 ng) and the colon temperature was measured 30, 60 and 90 min later. 2.5. Statistical analysis Statistical analysis of the data were made by ANOVA. For significant ANOVA values, groups were compared by Tukey’s test for multiple comparisons with unequal cell size. A probability level of 0.05 was accepted as indicating significant differences.
2.4. Procedures On the day of the experiment, the animals were transferred to the laboratory 2 h before the beginning of the test in order for them to habituate to the experimental environment. The room temperature was maintained at 23.0 6 0.5°C throughout the experiment. Each animal was then removed from the cage and gently restrained on the table with a cloth. The colon temperature was monitored by inserting a Vaseline-lubricated thermistor probe of a digital electric thermometer (Model: Thermini 130) 5 cm into the rectum of the animal. The probe was inserted the same distance into the rectum each time it was used. All experiments started at 8:00 a.m. with an initial colon temperature measurement, colon temperature being measured before and 30, 60 and 90 min after peptide treatment. The following experiments were performed 1. The effects of centrally administered ANP-28, BNP-32 and CNP-22 on body temperature were studied. The
3. Results 3.1. Effects of ANP-28, BNP-32 and CNP-22 on body temperature Doses of ANP-28 (400 and 1000 ng) had a hyperthermic effect 30 min [F(3, 33) 5 40.56; p , 0.05], 60 min [F(3, 33) 5 77.94; p , 0.05] and 90 min [F(3, 33) 5 15.56; p , 0.05] after ICV administration, the magnitude of the effect being smaller at 90 min than at 60 min. ANP-28 in a dose of 40 ng increased the colon temperature only at 60 min (Fig. 1). Both 400 and 1000 ng BNP-32 increased the colon temperature at 30 min [F(3, 53) 5 32.63; p , 0.05], 60 min [F(3, 53) 5 41.83; p , 0.05] and 90 min [F(3, 53) 5 6.5; p , 0.05] (Fig. 2). CNP-22 in doses of 400 and 1000 ng was hyperthermic both 30 min [F(3, 34) 5 15.72; p , 0.05] and 60 min [F(3, 34) 5 28.48; p , 0.05] after ICV administration. The 1000 ng dose of CNP-22 was also hyperthermic at
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90 min [F(3, 34) 5 4.54; p , 0.05]. A 40 ng dose of CNP-22 had a mild, but statistically not significant hyperthermic effect (Fig. 3).
Fig. 4. Inhibitory effect of noraminophenazone on ANP-induced hyperthermia. Groups of rats (n $ 8) received an IM injection of saline (ANP groups) or 50 mg noraminophenazone (ANP 1 noraminophenazone groups) 30 min before an ICV injection of 400 or 1000 ng ANP-28. The noraminophenazone group received an ICV saline injection 30 min after noraminophenazone pretreatment (50 mg, IM). The control group received an IM saline injection 30 min before saline treatment (ICV). The vertical lines at the top of the bars denote the SEM. * p , 0.05, compared with the control and with the noraminophenazone, the 400 ng ANP 1 noraminophenazone and the 1000 ng ANP 1 noraminophenazone groups; ** p , 0.05, compared with the control and with the noraminophenazone, the 400 ng ANP, the 400 ng ANP 1 noraminophenazone and the 1000 ng ANP 1 noraminophenazone groups.
3.2. Effects of noraminophenazone on natriuretic peptideinduced hyperthermia
4. Discussion
Fig. 2. The effects of brain natriuretic peptide (BNP) on colon temperature. BNP groups of rats (n $ 10) received an injection of BNP-32 (40, 400 or 1000 ng, ICV). The control group received an ICV injection of saline. The vertical lines denote the SEM. * p , 0.05, compared with the control and with the 40 ng BNP group.
A 50 mg/kg IM injection of the cyclooxygenase inhibitor noraminophenazone 30 min before peptide administration abolished the hyperthermic effects of 400 and 1000 ng ANP-28 [F30;60;90 min(5,44) 5 27.94; 43.30; 7.52; p , 0.05] (Fig. 4), BNP-32 [F30;60;90 min(5,44) 5 21.05; 32.25; 3.11; p , 0.05] (Fig. 5) and CNP-22 [F30;60;90 min(5,45) 5 49.25; 113.18; 0.91; p , 0.05] (Fig. 6). Noraminophenazone alone in a dose of 50 mg/kg IM did not affect the body temperature.
Fig. 3. The effects of C-type natriuretic peptide (CNP) on colon temperature. CNP groups of rats (n $ 9) received an injection of CNP-22 (40, 400 or 1000 ng, ICV). The control group received an ICV injection of saline. The vertical lines denote the SEM. * p , 0.05, compared with the control and with the 40 ng CNP group; ** p , 0.05, compared with the control and with the 40 and 400 ng CNP groups.
Thermogenesis is under the direct control of the CNS, and particularly of specific regions of the hypothalamus. Cytokines, such as interleukin-1 (IL-1) [12,19] and IL-6 [18,29], act as endogenous pyrogens in the brain and stimulate thermogenesis at least partially via the synthesis of prostaglandins [15,35,44]. Antipyretic drugs reduce fever
Fig. 5. Inhibitory effect of noraminophenazone on BNP-induced hyperthermia. Groups of rats (n $ 8) received an IM injection of saline (BNP groups) or 50 mg noraminophenazone (BNP 1 noraminophenazone groups) 30 min before an ICV injection of 400 or 1000 ng BNP-32. The noraminophenazone groups received an ICV saline injection 30 min after noraminophenazone pretreatment (50 mg, IM). The control group received an IM saline injection 30 min before saline treatment (ICV). The vertical lines at the top of the bars denote the SEM. * p , 0.05, compared with the control and with the noraminophenazone, the 400 ng BNP 1 noraminophenazone and the 1000 ng BNP 1 noraminophenazone groups.
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Fig. 6. Inhibitory effect of noraminophenazone on CNP-induced hyperthermia. Groups of rats (n $ 8) received an IM injection of saline (CNP groups) or 50 mg noraminophenazone (CNP 1 noraminophenazone groups) 30 min before an ICV injection of 400 or 1000 ng CNP-22. The noraminophenazone group received an ICV saline injection 30 min after noraminophenazone pretreatment (50 mg, IM). The control group received an IM saline injection 30 min before saline treatment (ICV). The vertical lines at the top of the bars denote the SEM. * p , 0.05, compared with the control and with the noraminophenazone, the 400 ng CNP 1 noraminophenazone and the 1000 ng CNP 1 noraminophenazone groups; ** p , 0.05, compared with the control and with the noraminophenazone, the 400 ng CNP, the 400 ng CNP 1 noraminophenazone and the 1000 ng CNP 1 noraminophenazone groups.
by blocking the production of specific prostaglandins, and in particular PGE2. Many endogenously produced substances, often peptides, are capable of affecting body temperature when injected into experimental animals [11]. Some peptides such as arginine vasopressin [24,27], a-melanocyte-stimulating hormone [16,37], neuropeptide Y [22,47], galanin [32,39], cholecystokinin [9] and pituitary adenylate cyclase-activating polypeptide [31] that can be found in the CNS may be of overriding importance, because theoretically they might be involved in thermoregulatory processes under physiological conditions. Numerous studies have reported on neuropeptides that can affect body temperature under experimental circumstances, but their physiological importance remains unclear. The distributions of ANP and related peptides and their receptors in the CNS have been investigated by several authors. The central presence and localization of these peptides and their receptors has been identified, and it is now widely accepted that natriuretic peptides participate in neuroendocrine regulation and also that some of them may act in neuromodulation between glial cells and neurons [28,49]. ANP and CNP-encoding messenger RNA-positive neurones have been successfully detected in the medial preoptic area of the hypothalamus (a brain region that is known to take part in temperature control) in rats [41]. Nevertheless, no data are yet available to demonstrate that natriuretic peptides affect thermoregulatory events in the CNS. Connection between natriuretic peptides and prostaglandins was recently reported. Peptide effects mediated by the generation of PGE2 were found in the kidney [17,21,50],
and ANP, that increases cellular cGMP by activating membrane-bound guanylate cyclase, was suggested to amplify the IL-1b-induced cyclooxygenase-2 mRNA expression [46]. Bone endothelial cells have been demonstrated to bear receptors for natriuretic hormones associated with changes in prostaglandin production [13]. The effects of centrally administered natriuretic peptides on body temperature have been revealed in this study. Injections of either ANP-28, BNP-32 or CNP-22 into the lateral ventricle of the brain elevated the body temperature of the experimental animals. A positive correlation between the hyperthermic effect and the dose of peptide administration could be observed for ANP-28 and CNP-22. The inhibition of prostaglandin production by noraminophenazone—a known inhibitor of prostaglandin synthesis [10], completely abolished the hyperthermia induced by ANP and related peptides. These results reinforce the significance of the roles of natriuretic peptides in neuroendocrine regulation. Our data suggest that these peptide neurohormones may play a part in thermoregulatory processes at a central level, and also that their probable participation in these events is mediated at least partially by cyclooxygenase products. Acknowledgments This work was supported by grants from OTKA (T022230), ETT (T-02– 670/96) and FKFP (0091–1997). References [1] Azarov A, Szabo´ G, Telegdy G. Effects of natriuretic peptide on acute and chronic effects of morphine. Pharmacol. Biochem. Behav. 1992; 43:193–197. [2] Babarczy E, Vizi Z, Szabo´ G, Telegdy G. Effects of brain natriuretic peptide on effects of morphine in mice. Neuropeptides 1996;30:438 – 442. [3] Babarczy E, Vizi Z, To´th G, Telegdy G. C-type natriuretic peptide can modify the acute and chronic effects of morphine. Neuropeptides 1995;29:145–149. [4] Bidzseranova A, Gueron J, Bala´spiri L, Telegdy G. Intracerebroventricularly administered ANP antiserum attenuates fear-motivated learning behavior in rats. Peptides 1992;13:957–960. [5] Bidzseranova A, Gueron J, To´th G, Penke B, Varga J, Telegdy G. Behavioral effects of atrial and brain natriuretic peptides in rats. NeuroReport 1992;3:283–285. [6] Bidzseranova A, Gueron J, To´th G, Varga J, Telegdy G. Structureactivity studies on the effects of atrial natriuretic peptide, brain natriuretic peptide and their analogs on fear-motivated learning behavior in rats. Neuropeptides 1991;23:61– 65. [7] Bı´ro´ E, To´th G, Telegdy G. Effect of receptor blockers on brain natriuretic peptide and C-type natriuretic peptide caused anxiolytic state in rats. Neuropeptides 1996;30:59 – 65. [8] Bı´ro´ E, To´th G, Telegdy G. Involvement of neurotransmitters in the ‘anxiolytic-like’ action of atrial natriuretic peptide in rats. Neuropeptides 1995;29:215–220. [9] Boschi G, Launay N, Rips R. Facilitation of amphetamine-induced hypothermia in mice by GABA agonists and CCK-8. Br. J. Pharmacol. 1991;102(4):986 –990.
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