Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0020672 (hypothermia)
17,327 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A short review of the role of cyclic nucleotides and prostaglandins (PGs) in normal and pathological functions of the heart is given. Possible interrelationships of these two regulatory systems have been studied by using spontaneously beating rat atria preparations. Addition of noradrenaline (NA) to the incubate (1 . 10(-6) M) caused an increase in amplitude and frequency which was preceded and parallelled by an elevation of the tissue cAMP level. A transient increase in cGMP and PGE values was also seen. Propranolol (5 . 10(-6) M) abolished the increase in amplitude and frequency as well as in cAMP and PGE concentrations. Indomethacin (1 . 10(-5) M) inhibited the formation of PGE. The increase in cGMP was blocked by phenoxybenzamine. Interchange between beta- and alpha-receptors according as the temperature is lowered has been described earlier. Hypothermia (20 degrees C) had a positive inotropic effect on the atria and increased the tissue cAMP concentration. Loading of the atria caused an increase in cAMP without any effects on cGMP or PGs. Slight hypoxia did not change the cAMP or PG levels, but elevated the cGMP values. Arrhythmias induced by hypo- or hyperpotassemia did not modify the biochemical parameters measured. PGF2alpha (1. 10(-5) M) normalized the atrial rhythm and increased the amplitude without changing cyclic nucleotide or PG levels. PGE1 (1 . 10(-4) M) increased the amplitude of normorhythmic atria and the tissue concentration of cAMP. PGE2 was the only PG tested which stimulated the heart adenylate cyclase in vitro. There seems to be close but complicated relationships between cyclic nucleotides and PGs in the heart.
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PMID:The role of cyclic nucleotides and prostaglandins in heart function. 21 11

Hypothermia has previously been demonstrated to induce supersensitivity (defined as a decrease in the ED50) of guinea pig left atria to the negative inotropic effect of carbachol. In the present investigation, the dissociation constant (pKA or -log KA) for carbachol, determined using benzilylcholine mustard, was found to be significantly increased at 25 degrees C compared to 37 degrees C. However, the increase in pD2 (-log ED50) for carbachol at 25 degrees C was much less than would be predicted from the increase in pKA. Increasing the extracellular Ca2+ concentration or the frequency of stimulation, both of which, like hypothermia, are believed to increase Ca2+ influx into cardiac cells, resulted in a decrease in sensitivity to carbachol. Carbachol had no significant effect on cAMP or cGMP levels at either 37 degrees C or at 25 degrees C. These results suggest that the hypothermia-induced increase in sensitivity of left atria to carbachol can be explained by an increase in the affinity of the muscarinic receptor for this agonist. However, the expression of this increased affinity appears to be limited. This may be due to a concurrent decrease in the efficacy of the carbachol muscarinic receptor complex.
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PMID:The mechanism of hypothermia-induced supersensitivity of guinea pig left atria to carbachol. 285 62

With several notable exceptions, interest in the area of multiple molecular forms of phosphodiesterase remained relatively dormant during the decade following Thompson's discovery of more than one phosphodiesterase in brain in 1971. Within the last several years, however, over 20 novel agents have been identified that exert selective inhibitory effects on the various molecular forms of phosphodiesterase present within different cells. In addition, several studies have documented that such agents can produce discrete changes in cyclic AMP and cyclic GMP, an action that is not shared by "first generation" phosphodiesterase inhibitors such as theophylline. The purpose of this Perspective is to provide some clarity to this rapidly evolving area of selective phosphodiesterase inhibitors. Thus, we have attempted to characterize the different forms of phosphodiesterase present in various tissues and cells according to their kinetic properties, substrate specificity, etc. and also to characterize those major classes of agents that have been shown to inhibit phosphodiesterase activity, whether selectively or nonselectively. In addition, we have described several therapeutic areas wherein selective phosphodiesterase inhibitors might prove efficacious, paying particular attention to those areas in which selective phosphodiesterase inhibitors have already been shown to exert beneficial effects, namely, stimulation of myocardial contractility, inhibition of mediator release, and inhibition of platelet aggregation. Although focusing on these three areas, it is obvious that the potential therapeutic utility of selective phosphodiesterase inhibitors could conceivably extend to several other areas in which modulation of cyclic nucleotides can have desirable effects, including cancer chemotherapy, analgesia, the treatment of depression, Parkinson's disease, and learning and memory disorders. For example, the selective type III phosphodiesterase inhibitor rolipram has been shown to antagonize reserpine-induced hypothermia and also to potentiate yohimbine lethality, two tests that are indicative of antidepressant activity. In addition, microinjection of the selective PDE III inhibitor Ro 20-1724 into the rat brain stem has been shown to produce analgesia.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A new generation of phosphodiesterase inhibitors: multiple molecular forms of phosphodiesterase and the potential for drug selectivity. 298 81

Forskolin, a direct activator of the catalytic subunit of adenylate cyclase (AC), and the cyclic nucleotide analogs dibutyryl cAMP (dBcAMP), 8-bromo cAMP (8-BrcAMP) and dibutyryl cGMP (dBcGMP) were tested for their ability to reverse the hypothermia or hypokinesia of mice depleted of presynaptic endogenous monoamines by pretreatment with reserpine, alpha-methyl-p-tyrosine and p-chlorophenylalanine. Forskolin and the cAMP analogs decreased the rectal temperature and inhibited locomotor activity in normal mice. In mice depleted of brain monoamines forskolin reversed the hypothermia and hypokinesia; dBcAMP and 8-BrcAMP antagonized the hypothermia but were only marginally effective in reversing the hypokinesia. DBcGMP was inactive. The antihypothermic action of forskolin or salbutamol was enhanced by the novel antidepressant and cAMP selective phosphodiesterase inhibitor rolipram (4RS-[3-cyclopentyloxy-4-methoxy-phenyl]-2-pyrrolidone). As an indirect effect via release of endogenous monoamines stimulating postsynaptic receptors was precluded by the monoamine-depleting pretreatment, forskolin and the cAMP analogs are thought to exert their antidepressant action by directly increasing brain cAMP availability. This is achieved by forskolin via activation of the catalytic subunit of AC and by the cAMP analogs via substitution for cAMP. These findings suggest that antidepressant activity is crucially linked to enhanced cAMP availability within brain effector cells. The successful treatment of endogenously depressed patients with rolipram supports this assumption.
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PMID:Effects of forskolin and cyclic nucleotides in animal models predictive of antidepressant activity: interactions with rolipram. 302 33

1 Guanosine 3',5'-monophosphate (cyclic GMP) and N2-2'-O-dibutyryl guanosine 3',5'-monophosphate (db cyclic GMP) have been injected into the third cerebral ventricle (i.c.v.) of the unanaesthetized cat and the effects of rectal temperature and on behavioural and autonomic activities observed and compared with those of acetylcholine and physostigmine. 2 Acetylcholine (100 nmol) and physostigmine (100 nmol) injected together i.c.v. produced a rise in body temperature in cats at an environmental temperature of 20-24 degrees C, which was abolished by pretreatment i.c.v. with atropine (200 nmol). 3 Cyclic GMP and db cyclic GMP (10--1250 nmol) had no effect on body temperature in cats at an environmental temperature of 20--24 degrees C but produced hypothermia (1250 nmol) in cats at an environmental temperature of 9--11 degrees C. 4 The O-somatic antigen of Shigella dysenteriae (20 microgram/kg i.v.) produced fever in cats which was not potentiated by caffeine (25 mg/kg i.p.). Levels of endogenous cyclic GMP in c.s.f. taken from the cisterna magna during fever induced by bacterial endotoxin in the presence or absence of paracetamol (50 mg/kg i.p.) and/or caffeine were similar to values for afebrile cats. 5 It is concluded that exogenous cyclic GMP and db cyclic GMP can inhibit central events mediating autonomic and behavioural thermoregulation stimulated in cats by exposure to cold environments.
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PMID:Dissimilar effects on body temperature in the cat produced by guanosine 3',5'-monophosphate, acetylcholine and bacterial endotoxin. 627 63

The following 4 Wistar rat groups were sacrificed by microwave irradiation: 1) hypothermia-rebreathing anesthesia (kept 3 hr at 4 degrees C in a 4 1 box), 2) pentobarbital anesthesia (50 mg/kg, s.c., 1 hr after), 3) reserpinized rats (5 mg/kg/day, s.c. for 3 days), and 4) nontreated control rats. Cyclic nucleotides and noradrenaline were analyzed in seven brain regions: cerebellum, pons and medulla oblongata, hypothalamus, mid brain, striatum, hippocampus, and cerebral cortex. In most part of the brain regions, the levels of cyclic AMP, cycli GMP and noradrenaline had a tendency to decrease after the treatment by hypothermia-rebreathing or pentobarbital as compared with control animals. The levels of cyclic AMP in the cerebellum and cyclic GMP in the hypothalamus were not affected by these anesthesia. After reserpinization, the level of cyclic GMP markedly elevated in all regions of the brain except in the cerebellum. In all brain regions of the control and the hypothermia-rebreathing groups, the coefficients of correlation between cyclic AMP and noradrenaline, cyclic GMP and nonadrenaline, cyclic AMP and cyclic GMP were positive, negative and negative, respectively. The cyclic AMP/cyclic GMP ratio in most of the brain regions decreased in the reserpinized group, and increased in the hypothermia-rebreathing group as compared to the control and the pentobarbital groups. From these results, it is postulated that some other neurons, not only monoaminergic neuron, regulate the level of cyclic nucleotides, and that the different sensitivity of these neurons to the anesthesia brings about various effects on the metabolism of cyclic nucleotides in each brain region.
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PMID:[Effects of anesthesia on the levels of cyclic nucleotides in rat brain regions (author's transl)]. 627 52

Intracerebroventricular administration of dibutyryl cyclic AMP (Db-cAMP), induced hyperthermia in guinea-pigs which was not mediated through prostaglandins (PG) or norepinephrine since a prostaglandin synthesis inhibitor, indomethacin, and an alpha-adrenergic receptor blocking agent, phenoxybenzamine did not antagonize the hyperthermia. In contrast, the hyperthermic response to dibutyryl cyclic AMP was attenuated by central administration of a beta-adrenergic receptor antagonist, sotalol, indicating that cyclic AMP may be involved, through beta-adrenergic receptors, in the central regulation of heat production/conservation. Central administration of dibutyryl cyclic GMP (Db-cGMP) produced hypothermia which was not mediated via histamine H1- or H2-receptors and serotonin since the H1-receptor antagonist, mepyramine, the H2-receptor antagonist, cimetidine, and the serotonin antagonist, methysergide, had no antagonistic effects. The antagonism of hypothermia induced by dibutyryl cyclic GMP and acetylcholine + physostigmine, by central administration of a cholinergic muscarinic receptor antagonist, atropine, and not by a cholinergic nicotinic receptor antagonist, d-tubocurarine, suggests that cholinoceptive neurons and endogenous cyclic GMP may regulate heat loss through cholinergic muscarinic receptors. These results support a regulatory role in thermoregulation provided by a balance between opposing actions of cyclic AMP and cyclic GMP in guinea-pigs.
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PMID:Opposing actions of dibutyryl cyclic AMP and GMP on temperature in conscious guinea-pigs. 630 46

The N6-2'-O-dibutyryl derivative of adenosine 3',5'-monophosphate (db cyclic AMP) and related compounds have been micro-injected into the preoptic/anterior hypothalamic nuclei (PO/AH) of the unanaesthetized, restrained rabbit and the effects on deep body temperature observed. Db cyclic AMP (100-400 micrograms) produced hypothermia of rapid onset in rabbits at an ambient temperature of 20-23 degrees C. Hypothermia was also produced by N2-2'-O-dibutyryl guanosine 3',5'-monophosphate (db cyclic GMP), but not by saline, sodium n-butyrate, adenosine 3',5'-monophosphate (cyclic AMP), guanosine 3',5'-monophosphate, adenosine 5'-mono-, di- or triphosphate. The initial hypothermic response to db cyclic AMP and db cyclic GMP was followed by a sustained rise in temperature. However, all compounds injected into the PO/AH produced a similar hyperthermia which was attenuated by paracetamol. Development of this tissue-damage fever abolished the hypothermic response to db cyclic AMP in some rabbits. The effects of db cyclic AMP on body temperature and behaviour were not reproduced by the adenylate cyclase activators, cholera toxin (0.125-5 micrograms) and guanyl imidodiphosphate (5-400 micrograms). It is concluded that hypothermia is the principal effect of db cyclic AMP on body temperature when injected into the PO/AH in rabbits. These data do not support the proposal that endogenous cyclic AMP in the rabbit brain mediates pyrexia.
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PMID:Evidence that cyclic nucleotides are not mediators of fever in rabbits. 632 20

This study was undertaken to examine the possible role of nitric oxide (NO) on brown adipose tissue (BAT) thermogenesis in rats. The chronic administration of N omega-nitro-L-arginine methyl ester (L-NAME; NO synthase inhibitor) in drinking water given to rats decreased interscapular BAT (IBAT) weight as well as DNA content in a warm environment (25 +/- 1 degrees C; 2 and 4 weeks), and inhibited the cold-stimulated (5 +/- 1 degrees C; 2 weeks) increase in IBAT weight and DNA content. L-Arginine administration (4 weeks in a warm environment) increased the DNA content of IBAT. Chronic L-NAME administration (2 weeks in a warm environment) eliminated the NE-stimulated increase in in vivo oxygen consumption (VO2), caused hypothermia in acute cold exposure (0 degree C), and suppressed the NE-stimulated increase in in vitro IBAT VO2. In vitro incubation of native IBAT with L-NAME suppressed the basal and NE-stimulated increase in in vitro VO2. In vitro incubation of IBAT with methylene blue (soluble guanylate cyclase inhibitor and a scavenger of free NO) eliminated the NE-stimulated increase in in vitro IBAT VO2. These results suggest that the nitric oxide and NO-cGMP signaling systems are involved in the regulation of BAT cellularity and thermogenesis in rats.
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PMID:Effects of acute and chronic inhibition of nitric oxide synthase on brown adipose tissue thermogenesis. 904 15

The neuroprotective effects of pramipexole, a dopamine agonist, were investigated in 3-acetylpyridine (3-AP)-treated Wistar rats. Bromocriptine was used as a reference compound to compare the results obtained with pramipexole. A significant reduction (P < 0.01) in cerebellar cGMP and ATP was observed 96 h after treatment with 3-AP (500 micromol/kg, i.p.). Both pramipexole and bromocriptine significantly attenuated 3-AP-induced reduction in cerebellar cGMP and ATP. Consistent with the neurochemical effect, both pramipexole and bromocriptine prevented 3-AP-induced loss of motor coordination. 3-Acetylpyridine produced a significant (P < 0.01) loss of neurons in the inferior olivary nucleus. Treatment with pramipexole and bromocriptine partially, but significantly (P < 0.01), prevented the loss of inferior olivary neurons. There was no reduction in the temperature of the animals, indicating that hypothermia was not responsible for neuroprotection.
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PMID:Neuroprotective effects of the dopamine agonists pramipexole and bromocriptine in 3-acetylpyridine-treated rats. 913 74


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