Cardiovascular effects produced by choline injected into the lateral cerebral ventricle of the unanesthetized rat

Intracerebroventricular (icv) injection of choline (50–150 μg) causes a transient increase in blood pressure and a more prolonged decrease in heart rate (HR) in conscious rats. The bradycardia results from a centrally mediated increase in vagal tone. The cardiovascular effects do not appear to involve endogenous brain acetylcholine since there is no significant difference in the responses induced by choline before and after icv injection of hemicholinium-3. Intracerebroventricular ventricular injection of atropine or mecamylamine, alone, failed to influence the choline effect. However, atropine and mecamylamine, given together, abolished the reduction of HR, but still failed to modify the pressor response. The changes in blood pressure and HR appear to be due to effects of choline on post-synaptic receptors in different brain regions.     

Direct evidence that release-stimulating alpha7* nicotinic cholinergic receptors are localized on human and rat brain glutamatergic axon terminals

The existence on glutamatergic nerve endings of nicotinic acetylcholine receptors (nAChRs) mediating enhancement of glutamate release has often been suggested but not demonstrated directly. Here, we study the effects of nAChR agonists on [3 H]-d-aspartate ([3 H]-d-ASP) release from synaptosomes superfused in conditions known to prevent indirect effects. Nicotinic receptor agonists, while unable to modify the basal [3 H]-d-ASP release from human neocortex or rat striatal synaptosomes, enhanced the Ca2+ -dependent exocytotic release evoked by K+ (12 mm) depolarization. Their rank order of potency were anatoxin-a > epibatidine > nicotine > ACh (+ atropine). The anatoxin-a effect, both in human and rat synaptosomes, was antagonized by mecamylamine, alpha-bungarotoxin or methyllycaconitine. The basal release of [3 H]ACh from human cortical synaptosomes was increased by (-)-nicotine (EC50 = 1.16 +/- 0.33 microm) or by ACh plus atropine (EC50 = 2.0 +/- 0.04 microm). The effect of ACh plus atropine was insensitive to alpha-bungarotoxin, methyllycaconitine or alpha-conotoxin MII, whereas it was totally antagonized by mecamylamine or dihydro-beta-erythroidine. To conclude, glutamatergic axon terminals in human neocortex and in rat striatum possess alpha7* nicotinic heteroreceptors mediating enhancement of glutamate release. Release-enhancing cholinergic autoreceptors in human neocortex are nAChRs with a pharmacological profile compatible with the alpha4beta2 subunit combination.     

Pharmacological characterization of the response of the leech pharynx to acetylcholine

In this study we document the sensitivity of the leech pharynx to acetylcholine and begin to characterize the acetylcholine receptor mediating this response by examining the effects of selective cholinergic agonists and antagonists on the contractile behavior of the pharynx. The order of potency derived from the EC50 of each agonist was (+/-)epibatidine > acetylcholine (in the presence of physostigmine) > McN A-343 > carbachol > nicotine. However, when response amplitude was considered, the order of potency to the tested agonists was (+/-)epibatidine > nicotine > McN A-343 > carbachol > acetylcholine. Acetylcholine-induced contractions of the pharynx were antagonized by d-tubocurarine, but not by alpha-bungarotoxin, alpha-conotoxin M1, or mecamylamine. Application of high concentrations of hexamethonium (1 mM) augmented the acetylcholine-induced contractions. However, this augmentation was apparently due to inhibition of acetylcholinesterase by hexamethonium. The muscarinic antagonist atropine produced complex actions and apparently acted as a mixed agonist/antagonist. Atropine by itself produced an increase in basal tonus and increased the frequency and amplitude of phasic contractions. Atropine increased the peak tension of the acetylcholine-induced response; however, it reduced the amplitude of both the acetylcholine-induced increase in basal tonus and integrated area. Based on the pharmacological profile of the pharyngeal acetylcholine response, we conclude that the acetylcholine receptor mediating the response is a nicotinic receptor. However, the responsiveness of the pharynx to muscarinic agents diverges from that of a classical nicotinic receptor.     

Intracerebroventricular injection of hemicholinium-3 lowers blood pressure in conscious spontaneously hypertensive rats but not in normotensive rats

Intracerebroventricular (icv) injection of hemicholinium-3 (HC-3) in doses of 10–20 μg causes a dose-related decrease in the blood pressure of conscious spontaneous hypertensive (SH) rats but not of normotensive rats. HC-3 also reduces heart rate (HR) in both SH and normotensive rats. The bradycardia was blocked by intravenous injection of methylatropine, implicating increased vagal activity as a cause of the response. The decrease in HR also was blocked by icv injection of atropine but not by icv injection of mecamylamine, suggesting that the bradycardia is mediated via central muscarinic receptors. In contrast, the fall in blood pressure in SH rats was not influenced by intravenous administration of methylatropine or by the icv injection of either atropine or mecamylamine.     

Acetylcholine receptors of thoracic dorsal midline neurones in the cockroach, Periplaneta Americana

The actions of acetylcholine and cholinergic ligands have been studied using dorsal midline neurones from the rnetathoracic ganglion of the cockroach Periplaneta americana.Both nicotine and oxotremorine depolarized dorsal midline neuronal cell bodies.Dose-response curves for nicotine and oxotremorine saturated at different levels. Nicotine-induced depolarizations were completely or partially blocked by mecamylamine, d-tubocurarine, strychnine, and bicuculline, but were insensitive to alpha-bungarotoxin(100 nM), atropine (100 micronM),Scopolamine (10 micronM), and pirenzepine (50 micronM). Following pretreatment with collagenase, the dorsal midline neurones were sensitive to high doses of alpha-bungarotoxin (3 micronM). Oxotremorine-induced depolarizations were blocked by scopolamine (10 micronM) atropine (100 micronM), and pirenzepine (50 micronM) and were insensitive to mecamylamine (10 micronM) and d-tubocurarine (100 micronM). The results indicate the coexistence of at least two distinct acetylcholine receptors on dorsal midline neuronal cell bodies in the cockroach metathoracic ganglion.     

A central link between angiotensinergic and cholinergic systems; role of vasopressin

Participation of central cholinergic system in the effects of intracerebroventricular (i.c.v.) injection of angiotensin II (Ang II) on blood pressure and heart rate was studied in conscious, freely moving rats. Ang II dose-dependently increased blood pressure and decreased heart rate. Both atropine and mecamylamine (i.c.v.) pretreatments prevented the cardiovascular effects of Ang II. Pretreatment with a vasopressin V1 antagonist also prevented the cardiovascular responses to Ang II. Our data suggest that the central pressor effect of Ang II is mediated in part by central acetylcholine via both muscarinic and nicotinic receptors, and vasopressin participates in this effect through V1 receptors.     

Mechanism of tachycardia caused by intracarotid PGE2 in conscious ewes

Conscious adult ewes prepared with nonocclusive indwelling vascular catheters were used to determine the mechanism by which heart rate increases during central administration of prostaglandin E2 (PGE2). Heart rate increased 14 bpm during steady-state intracarotid infusion of PGE2, 10 ng/kg/min (P less than 0.05). Intravenous atropine methyl bromide, 1 mg/kg, increased heart rate 26 bpm (P less than 0.05) 5 min after injection. Heart rate remained elevated 30 min after injection. The heart rate response to PGE2 plus atropine was greater than the heart rate response to either atropine or PGE2 alone (P less than 0.05). Propranolol, 1 mg/kg bolus plus intravenous infusion, 0.025 mg/kg/min, did not change resting heart rate. Propranolol attenuated but did not abolish the increase in heart rate caused by intracarotid PGE2. Although heart rate increased in response to PGE2 after administration of either propranolol or atropine alone, the combination of propranolol and atropine prevented any further increase in heart rate during subsequent PGE2 infusion. The increase in heart rate when all three drugs were given together was not different from the increase observed during atropine alone. Thus, both beta-adrenergic activation and muscarinic deactivation contribute to the PGE2-induced tachycardia.     

Role of centrally administered melatonin and inhibitors of COX and NOS in LPS-induced hyperthermia and adipsia.

In the present study we have examined the effect of centrally administered non-steroidal anti-inflammatory drugs (NSAIDS), nitric oxide synthase (NOS) inhibitor and melatonin on lipopolysaccharide (LPS)-induced hyperthermia and its anti-dipsogenic effect. Intracerebroventricular (i.c.v.) administration of LPS (100-200 ng/rat) induces a dose dependent elevation in body temperature and decreases water consumption in 24 h water deprived rats. Coadministration of NSAIDS (indomethacin and nimesulide: 10 nM/rat each) with LPS (100 ng) reversed, whereas NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME: 10-20 microg/rat) enhanced LPS-induced hyperthermia. In contrast L-NAME reversed the LPS-induced anti-dipsogenic effect in a dose dependent manner, whereas NSAIDS showed no change in the effect of LPS. Further, centrally administered prostaglandin E2 (PGE2, 0.5-1 microg/rat) produced hyperthermia without affecting the drinking behavior, suggesting that two independent mechanisms operate in LPS-induced hyperthermia and in the anti-dipsogenic effect. The pineal hormone melatonin is known to inhibit cellular damage caused by LPS, produced dose dependent (5-10 nM i.c.v.) inhibition of LPS-induced hyperthermia and adipsia, but failed to reverse the PGE2-induced hyperthermia, shows reversal of LPS-induced hyperthermia by melatonin is due to inhibition of prostaglandin synthesis rather than antagonism of prostaglandin action. The overall study reveals that inhibition of both NO and prostaglandin production by melatonin might be responsible for its reversal of LPS-induced hyperthermia and adipsia.     

Contractile effects of prostaglandin E2 in rat rectum: sensitivity to the prostaglandin antagonists diphloretin phosphate and SC 19220.

Prostaglandin E2 (PGE2) applied cumulatively (1 nM-1 microM) induced concentration-dependent tonic contractions in the longitudinal muscle of isolated rat rectum. The PGE2 effects were not altered by guanethidine (50 microM), whereas atropine (3 microM), guanethidine plus atropine or tetrodotoxin (0.1 microM) reduced them to an almost equal extent and increased the EC50 values for PGE2. The after-contractions following electrical stimulation were enhanced by PGE2 (10 nM) and inhibited by atropine. Diphloretin phosphate (DPP, 100 microM) shifted the regression lines for PGE2 to the right in both untreated and tetrodotoxin-treated preparations, and thereby increased the EC50 values. Slopes of the concentration-effect lines for PGE2 before and after DPP differed in the presence of tetrodotoxin. The regression line for PGE2 with SC 19220 (100 microM) in tetrodotoxin-treated preparations was shifted to the right in a parallel fashion. It is concluded that PGE2 exerted both a neural (cholinergic) and a smooth muscle effect. There may be a competitive antagonism between SC 19220 and PGE2 but the block by DPP may be nonselective.     

Antinociceptive effect of spinal cholinergic stimulation: interaction with substance P

Activation of central muscarinic receptors results in an antinociceptive response in experimental animals. Employing intrathecal (i.t.) injection and radiant heat applied to a rat's tail as the experimental paradigm, a spinally-mediated antinociceptive response was obtained following injection of cholinergic agonists. Since "cholinergic' analgesia is mediated independently of the opiate system, the possibility was considered that this response was mediated through inhibition of the local release of substance P. Rats were prepared with indwelling i.t. catheters which terminated in the L2-L3 region of the spinal cord. I.t. injection of carbachol (0.05-5 micrograms) or neostigmine (1-10 micrograms), but not nicotine (0.5-10 micrograms) produced dose-related increases in tail flick latencies. Pretreatment with i.t. injection of atropine or hemicholinium-3 significantly inhibited the antinociceptive response to neostigmine. Spinal substance P levels were measured 30 min following 0.5 micrograms carbachol. Levels in the dorsal horn were reduced by 30% compared with saline controls. Levels in the ventral horn were unchanged by carbachol. These results support the role of endogenous spinal acetylcholine in pain modification and suggest an interaction with substance P neurons of the dorsal spinal cord.     

Modulating effects of prostaglandins on parasympathetic-mediated secretory activities of rat salivary glands

Exogenously administered PGE1 or PGE2, like atropine, markedly decreased both the flow and calcium concentration of parasympathetically evoked rat parotid saliva; PGF2 alpha was less effective. Despite the fact that prostaglandins greatly reduced the Ca concentration of nerve-evoked saliva, they did not change the glandular Ca concentration of either control or parasympathetically stimulated parotid glands. Prostaglandins (20 micrograms/kg, i.a.) decreased the Na or K concentration of nerve-evoked parotid saliva, but at lower doses had no significant effect. PGE1, PGE2, PGF2 alpha or atropine markedly decreased flow rates of similarly evoked rat submandibular saliva. Prostaglandins and atropine, however, decreased the Na concentration and increased the K concentration of parasympathetically evoked submandibular saliva. PGF2 alpha, like atropine, increased the Ca concentration of such saliva. Drug vehicle, ethanol, slightly decreased the flow of both parotid and submandibular saliva but not the ion secretion, Endogenous prostaglandins themselves may not play a role in secretory activities during parasympathetic nerve stimulation of rat salivary glands, since administration of indomethacin, and inhibitor of prostaglandin biosynthesis, prior to or during nerve stimulation did not significantly alter nerve-evoked salivary secretion, The mechanisms by which prostaglandins modulate secretory responses of salivary glands during parasympathetic stimulation are not understood.     

Release-enhancing pre-synaptic muscarinic and nicotinic receptors co-exist and interact on dopaminergic nerve endings of rat nucleus accumbens

Dopaminergic nerve endings in the corpus striatum possess nicotinic (nAChRs) and muscarinic cholinergic receptors (mAChRs) mediating release of dopamine (DA). Whether nAChRs and mAChRs co-exist and interact on the same nerve endings is unknown. We here investigate on these possibilities using rat nucleus accumbens synaptosomes pre-labeled with [³H]DA and exposed in superfusion to cholinergic receptor ligands. The mixed nAChR–mAChR agonists acetylcholine (ACh) and carbachol provoked [³H]DA release partially sensitive to the mAChR antagonist atropine but totally blocked by the nAChR antagonist mecamylamine. Addition of the mAChR agonist oxotremorine at the minimally effective concentration of 30 μmol/L, together with 3, 10, or 100 μmol/L (−)nicotine provoked synergistic effect on [³H]DA overflow. The [³H]DA overflow elicited by 100 μmol/L (−)nicotine plus 30 μmol/L oxotremorine was reduced by atropine down to the release produced by (−)nicotine alone and it was abolished by mecamylamine. The ryanodine receptor blockers dantrolene or 8-bromo-cADP-ribose, but not the inositol 1,4,5-trisphosphate receptor blocker xestospongin C inhibited the (−)nicotine/oxotremorine evoked [³H]DA overflow similarly to atropine. This overflow was partly sensitive to 100 nmol/L methyllycaconitine which did not prevent the synergistic effect of (−)nicotine/oxotremorine. Similarly to (−)nicotine, the selective α4β2 nAChR agonist RJR2403 exhibited synergism when added together with oxotremorine. To conclude, in rat nucleus accumbens, α4β2 nAChRs exert a permissive role on the releasing function of reportedly M₅ mAChRs co-existing on the same dopaminergic nerve endings.     

Impaired febrile responses to immune challenge in mice deficient in microsomal prostaglandin E synthase-1

Fever is a common, centrally elicited sign of inflammatory and infectious processes and is known to be induced by the action of PGE2 on its specific receptors in the thermogenic region of the hypothalamus. In the present work, using genetically modified mice, we examined the role of the inducible terminal PGE2-synthesizing enzyme microsomal prostaglandin E synthase-1 (mPGES-1) for the generation of immune-elicited fever. Animals with a deletion of the Ptges gene, which encodes mPGES-1, or their wild-type littermates were given either a subcutaneous injection of turpentine--a model for aseptic cytokine-induced pyresis--or an intraperitoneal injection of interleukin-1beta. While both procedures resulted in typical febrile responses in wild-type animals, these responses were strongly impaired in the mPGES-1 mutant mice. In contrast, both genotypes showed psychogenic stress-induced hyperthermia and displayed normal diurnal temperature variations. Both wild-type and mPGES-1 mutant mice also showed strongly reduced motor activity following turpentine injection. Taken together with previous observations on mPGES-1 induction in the brain vasculature during various inflammatory conditions and its role in endotoxin-induced pyresis, the present findings indicate that central PGE2 synthesis by mPGES-1 is a general and critical mechanism for fever during infectious and inflammatory conditions that is distinct from the mechanism(s) underlying the circadian temperature regulation and stress-induced hyperthermia, as well as the inflammation-induced activity depression.     

Comparative study of the pulmonary effects of intravenous leukotrienes and other bronchoconstrictors in anaesthetized guinea pigs

Pulmonary responses to intravenous leukotrienes C4, D4 and E4 administered as a bolus injection and by continuous infusion were studied in anesthetized guinea pigs. LTD4, LTC4 and LTE4 (respective ED50 of 0.21 +/- .1, 0.64 +/- .2 and 2.0 +/- .1 microgram kg-1) produced dose-dependent increases in insufflation pressure when given as a bolus injection to anesthetized guinea pigs (Konzett-R?ssler). Bronchoconstriction was antagonized by FPL-55712 (50-200 micrograms kg-1), and indomethacin (50-200 micrograms kg-1) but was not significantly altered by mepyramine (1.0 mg kg-1), methysergide (0.1 mg kg-1), intal (10 mg kg-1) mepacrine (5 mg kg-1) or dexamethasone (10 mg kg-1). The beta adrenoceptor blocker, timolol (5 micrograms kg-1) produced a significantly greater potentiation of the responses to the leukotrienes than to arachidonic acid, histamine and acetylcholine. Responses to bolus injection of LTE4 but not LTD4 or LTC4 were partially antagonized by atropine (100 micrograms kg-1) and bilateral vagotomy. In experiments of a different design, continuous infusion of LTD4 and LTE4 (2.8-3.2 micrograms kg-1 min-1) into indomethacin-treated animals produced slowly developing increases in pulmonary resistance and decreases in compliance. The increase in resistance produced by LTE4 and LTD4 was partly reversed by intravenous FPL-55712 (1.0 mg kg-1) and atropine (100 micrograms kg-1) but was almost completely reversed by FPL-55712 (3 - 10 mg kg-1). These findings indicate that leukotrienes can produce bronchoconstriction in guinea pigs through cyclooxygenase-dependent and cyclooxygenase independent mechanisms both of which are blocked by FPL-55712. Cholinergic mechanisms are involved in the mediation of part of the response to bolus injection of LTE4 as well as a small part of the initial response to continuous infusion of LTD4 and LTE4. Intrinsic beta adrenoceptor activation serves to down modulate responses to the leukotrienes to a greater extent than responses to arachidonic acid, histamine and acetylcholine.     

2-Deoxy-D-glucose inhibition of prostaglandin E1 hyperthermia and yeast fever in mice.

2-Deoxy-D-glucose (2-DG) and sodium salicylate were evaluated relative to their effects on body temperature in mice with prostaglandin E1 (PGE1)hyperthermia or yeast fever. Injection of 2-DG into the cerebral ventricles of conscious mice abolished the hyperthermia of PGE1 and reduced the fever produced by yeast, while sodium salicylate was effective only in yeast fever. The data are suggestive of glucose dependency of thermoregulatory centers in the brain.     

Cholinergic neurotransmission from mechanosensory afferents to giant interneurons in the terminal abdominal ganglion of the cricket Gryllus bimaculatus

Crickets respond to air currents with quick avoidance behavior. The terminal abdominal ganglion (TAG) has a neuronal circuit for a wind-detection system to elicit this behavior. We investigated neuronal transmission from cercal sensory afferent neurons to ascending giant interneurons (GIs). Pharmacological treatment with 500 muM acetylcholine (ACh) increased neuronal activities of ascending interneurons with cell bodies located in the TAG. The effects of ACh antagonists on the activities of identified GIs were examined. The muscarinic ACh antagonist atropine at 3-mM concentration had no obvious effect on the activities of GIs 10-3, 10-2, or 9-3. On the other hand, a 3-mM concentration of the nicotinic ACh antagonist mecamylamine decreased spike firing of these interneurons. Immunohistochemistry using a polyclonal anti-conjugated acetylcholine antibody revealed the distribution of cholinergic neurons in the TAG. The cercal sensory afferent neurons running through the cercal nerve root showed cholinergic immunoreactivity, and the cholinergic immunoreactive region in the neuropil overlapped with the terminal arborizations of the cercal sensory afferent neurons. Cell bodies in the median region of the TAG also showed cholinergic immunoreactivity. This indicates that not only sensory afferent neurons but also other neurons that have cell bodies in the TAG could use ACh as a neurotransmitter.     

Hyperthermic action of somatostatin-28

An intracisternal injection of somatostatin-28 produced hyperthermia in rats at cold, thermoneutral, warm ambient temperatures. The hyperthermic response to somatostatin-28 was not prevented by pretreatment of rats with the following agents: α-methylparatyrosine, phenoxybenzamine, propranolol, sulpiride, atropine, methysergide or naloxone. Somatostatin-28 prevented hypothermia induced by bombesin and γ-MSH when it was administered simultaneously, but it left the hyperthermic response to TRH intact. The results indicate that somatostatin-28 produces hyperthermia by elevating a “set point” or regulated level of termperature. Under the conditions tested, the hyperthermic response to somatostatin-28 does not appear to be dependent on muscarinic cholinergic, serotonergic, α- or β-adrenergic, dopaminergic or endogenous opiate system.     

k-银环蛇毒素敏感的烟碱受体激活引起的去甲肾上腺素释放参与烟碱诱导的长时程增强样反应

烟碱可以增强学习记忆功能,但其相关机制仍不清楚。海马长时程增强被认为是学习记忆的细胞机制。本研究室以往研究表明,当单脉冲的强度为诱发80％最大群体锋电位时,烟碱（10μmol/L）可以在海马CA1区诱导长时程增强样反应。本文通过细胞外记录离体海马脑片CA1区锥体细胞层群体锋电位,探讨烟碱诱导长时程增强样反应所涉及的烟碱受体亚型与相应的神经递质释放。结果显示,烟碱诱导的长时程增强样反应可以被美加明（mecamylamine,1μmol／L）或K-银环蛇毒素（K．bungarotoxin,0．1μmol／L）阻断,但不被dihydro-β-erythtroidine（DHβE,10μmol／L）阻断。烟碱诱导的长时程增强样反应可以被普萘洛尔（propranolol,10μmol/L）阻断,但不被酚妥拉明（phentolamine,10μmol／L）或阿托品（atropine,10μmol／L）阻断。以上结果提示,K-银环蛇毒素敏感的烟碱受体激活引起的去甲肾上腺素释放参与烟碱诱导的海马CA1区长时程增强样反应。     

κ-银环蛇毒素敏感的烟碱受体激活引起的去甲肾上腺素释放参与烟碱诱导的长时程增强样反应

烟碱可以增强学习记忆功能,但其相关机制仍不清楚.海马长时程增强被认为是学习记忆的细胞机制.本研究室以往研究表明,当单脉冲的强度为诱发80%最大群体锋电位时,烟碱(10μmol/L)可以在海马CAI区诱导长时程增强样反应.本文通过细胞外记录离体海马脑片CA1区锥体细胞层群体锋电位,探讨烟碱诱导长时程增强样反应所涉及的烟碱受体亚型与相应的神经递质释放.结果显示,烟碱诱导的长时程增强样反应可以被美加明(mecamylamine,1 μmol/L)或κ-银环蛇毒素(κ-bungarotoxin,0.1μmol/L)阻断,但不被dihydro-β-erythtroidine(DHβE,10μmol/L)阻断.烟碱诱导的长时程增强样反应可以被普萘洛尔(propranolol,10μmol/L)阻断,但不被酚妥拉明(phentolamine,10μmol/L)或阿托品(atropine,10 μmol/L)阻断.以上结果提示,κ-银环蛇毒素敏感的烟碱受体激活引起的去甲肾上腺素释放参与烟碱诱导的海马CA1区长时程增强样反应.     

Involvement of prostaglandins and histamine in radiation-induced temperature responses in rats

Exposure of rats to 1-15 Gy of gamma radiation induced hyperthermia, whereas exposure to 20-150 Gy produced hypothermia. Since radiation exposure induced the release of prostaglandins (PGs) and histamine, the role of PGs and histamine in radiation-induced temperature changes was examined. Radiation-induced hyper- and hypothermia were antagonized by pretreatment with indomethacin, a cyclooxygenase inhibitor. Intracerebroventricular administration of PGE2 and PGD2 induced hyper- and hypothermia, respectively. Administration of SC-19220, a specific PGE2 antagonist, attenuated PGE2- and radiation-induced hyperthermia, but it did not antagonize PGD2- or radiation-induced hypothermia. Consistent with an apparent role of histamine in hypothermia, administration of disodium cromoglycate (a mast cell stabilizer), mepyramine (H1-receptor antagonist), or cimetidine (H2-receptor antagonist) attenuated PGD2- and radiation-induced hypothermia. These results suggest that radiation-induced hyperthermia is mediated via PGE2 and that radiation-induced hypothermia is mediated by another PG, possibly PGD2, via histamine.