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)

Nifedipine exhibits a greater incidence of side effects than the other currently marketed calcium channel antagonists. In addition to those effects attributable to calcium channel blockade, nifedipine produces side effects similar to the effects of adenosine. It is probable that nifedipine exerts part of its physiological actions through potentiation of adenosine. Adenosine, an endogenous calcium channel blocker, modifies synaptic events throughout the nervous system and causes sedation, smooth and skeletal muscle relaxation, anticonvulsion, hypotension and hypothermia, all reversible by caffeine or theophylline administration. Nifedipine inhibits adenosine uptake from, and release into, the extracellular space and binds at an adenosine receptor. Both nifedipine and adenosine interact with benzodiazepine binding sites. Interaction between nifedipine and adenosine should be kept in mind when treating patients with nifedipine.
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PMID:Nifedipine: more than a calcium channel blocker. 301 14

3,7-Dimethyl-1-propargylxanthine (DMPX), a caffeine analog that exhibits in vitro selectivity for A2-adenosine receptors, compared to A1-adenosine receptors, has now been investigated with respect to in vivo potency and selectivity. DMPX potently and selectively blocked the actions of the potent A2 adenosine agonist, 5'-N-ethylcarboxamidoadenosine (NECA), in DBA/2 mice, compared to blockade of the same responses elicited by the selective A1-adenosine agonist, N6-cyclohexyladenosine (CHA). DMPX was 57-fold more potent versus NECA-induced hypothermia than versus CHA-induced hypothermia and 11-fold more potent versus NECA-induced behavioral depression than versus CHA-induced behavioral depression. The hypothermia is mediated by peripheral receptors, based on blockade by 8-(p-sulfophenyl)theophylline (PSPT), while the behavioral depression is centrally mediated, based on lack of blockade by PSPT. DMPX was 28- and 15-fold more potent than caffeine in blocking peripheral and central NECA-responses, respectively. DMPX was equipotent with caffeine versus CHA-induced hypothermia and 2.5-fold more potent than caffeine versus CHA-induced behavioral depression. The motor stimulating potency of DMPX (ED50 10 mumol/kg) was slightly greater than caffeine.
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PMID:3,7-Dimethyl-1-propargylxanthine: a potent and selective in vivo antagonist of adenosine analogs. 319 54

We identified changes in hippocampal afterdischarge activity that follow administration of subcon vulsant doses (one-half the convulsant dose) of analeptic agents with known pharmacological action. Long-Evans rats (N = 104) with chronic bipolar electrodes implanted in the dorsal hippocampus, were injected i.p. with saline, caffeine (75 mg/kg), picrotoxin (2 mg/kg), or pentylenetatrazol (20 mg/kg) in 1 ml/kg volume 15 min before testing. Body temperature was measured at the beginning of the session to determine if significant change was associated with any of the treatments. Beginning at 10 microA, current (2-s train of 50-Hz biphasic pulses) was applied to hippocampal electrodes and intensity was increased in 10-microA steps until the afterdischarge sequence was elicited. Afterdischarge threshold, wet dog shake frequency, and the duration of the primary afterdischarge, the postprimary depression, and the rebound afterdischarge were measured. Caffeine administration produced a dramatic prolongation of the rebound afterdischarge, without affecting the duration of the primary afterdischarge. All other afterdischarge variables were unchanged by the caffeine treatment. Because caffeine blocks adenosine receptors at physiologic concentrations, adenosine action is implicated in the termination of the second, but not the first, spike train. Picrotoxin and pentylenetetrazol had no influence on the EEG, despite evidence of slight (1 degrees C) hypothermia. A decrease in wet dog shake frequency, however, was associated with picrotoxin administration. As picrotoxin and pentylenetetrazol are known gamma-aminobutyric acid (GABA) antagonists, the results suggest that GABA is involved minimally, if at all, in the hippocampal afterdischarge sequence.
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PMID:Differential effects of caffeine, picrotoxin, and pentylenetetrazol on hippocampal afterdischarge activity and wet dog shakes. 356 62

The pathogenesis of the calcium paradox has not been established. In calcium-free perfused hearts, caffeine, which releases calcium from the sarcoplasmic reticulum, causes severe myocardial injury, with creatine kinase (CK) release and contraction band necrosis similar in many respects to the calcium paradox. It has been postulated that contracture, initiated by a small rise in intracellular calcium, may cause sarcolemmal injury in both the calcium paradox and caffeine-induced myocardial injury. The present study was initiated to determine whether interventions which modulate caffeine-induced contracture will also correspondingly alter cellular injury. The effects of caffeine dose, procaine, extended calcium-free perfusion, elevated potassium, temperature, and increasing intracellular sodium on caffeine-induced contracture were examined in Langendorff-perfused adult rat hearts. Caffeine-induced contracture at 22 C increased over a dose range of 5-40 mM caffeine. Procaine, which inhibits caffeine-induced calcium release at doses between 5 and 20 mM, progressively reduced contracture caused by addition of 20 mM caffeine at 22 C. Hearts perfused with calcium-free solution containing 16 mM K+ showed a reduction in caffeine-induced contracture. Extended calcium-free perfusion (20 minutes) at temperatures from 18 to 37 C resulted in a progressive reduction of caffeine-induced contracture. Each of these interventions was also found to inhibit caffeine-induced injury at 37 C. Low temperature was found to have complex effects. Hypothermia enhanced caffeine contractures but also protected hearts from cell separations and CK release. Increasing intracellular sodium was found to enhance caffeine-induced contracture at 37 C. There was a direct correlation between measured intracellular sodium levels and the magnitude and duration of caffeine-induced contracture. These results demonstrate a direct correlation between the magnitude of contracture and myocardial injury in calcium-free hearts. It is proposed that contracture is the primary mediator of sarcolemmal membrane injury in hearts with intercalated disks weakened by prior calcium-free perfusion.
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PMID:Modification of caffeine-induced injury in Ca2+-free perfused rat hearts. Relationship to the calcium paradox. 370 96

The methylxanthine, theobromine (3,7-dimethylxanthine), was tested in mice, to determine whether theobromine could function in vivo as an adenosine receptor antagonist, in keeping with its reported in vitro effects as a blocker of agonist binding to the adenosine A-1 receptor. Theobromine doses, which themselves had no direct effects on spontaneous locomotor activity, completely blocked N6-cyclohexyladenosine-induced suppression of locomotor activity but were without effect on 5'-N-ethylcarboxamide adenosine (NECA)-induced decreases in motor activity. In contrast to the specific antagonism, theobromine blocked the hypothermia induced by both of these adenosine analogs. These results demonstrate that theobromine is an active in vivo adenosine receptor antagonist and that the antagonism of N6-cyclohexyladenosine sensitive systems occurs even though theobromine does not stimulate spontaneous locomotor activity. Thus, the behavioral stimulant effects of methylxanthines may be more related to effects on NECA-sensitive systems, which are not blocked by theobromine. The use of in vivo differences in the effects xanthine may provide a useful tool in the development of compounds to probe the mechanisms of caffeine induced CNS effects.
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PMID:Differential antagonism of the behavioral depressant and hypothermic effects of 5'-(N-ethylcarboxamide) adenosine by theobromine. 378 37

Two inbred mouse strains, SWR and CBA, differed significantly in their susceptibility to acute dose dependent theophylline- and caffeine-induced stimulation of locomotor activity. The efficacy of both methylxanthines was reduced in the SWR strain compared to the CBA strain. When brain levels of theophylline were determined at a dose (32 mg/kg IP) which gave maximal behavioral separation of the two strains, no significant differences were found between them (SWR levels 12.5 +/- 1.9, CBA levels 14.3 +/- 1.7 micrograms/g wet weight brain). The dose dependent ability of several adenosine agonists (N6-cyclohexyladenosine, (-)-N6-phenylisopropyladenosine, 5'-N-ethylcarboxamidoadenosine) to depress locomotor activity was investigated. SWR mice were found to be significantly more sensitive to NECA-induced depression of locomotor activity and the NECA-induced hypothermia than were CBA mice (respective ED50 values for inhibition of activity, 11.6 and 30.5 nmoles/kg IP). No differences were found in brain [3H]-NECA levels at doses which produced marked differences in behavioral effects between the two strains. The differences in adenosine agonist sensitivity between the strains were both agonist- and behavior-specific. These data indicate that an inherited alteration in behavioral responsiveness to methylxanthine administration can be inversely associated with inherent alterations in susceptibility to the action of specific adenosine analogs. An adenosine A-2 receptor sub-class may be involved in these changes in in vivo pharmacological susceptibility to the action of both methylxanthines and adenosine agonists on locomotor activity.
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PMID:Inherent hyporesponsiveness to methylxanthine-induced behavioral changes associated with supersensitivity to 5'-N-ethylcarboxamidoadenosine (NECA). 380 30

1. Ouabain given by intracerebroventricular injection to mice in small doses (0.1-0.4 mug) produced a dose related depression of central nervous activity, characterized by a reduction in spontaneous locomotor activity, hypothermia, catalepsy and ptosis, lowered body posture and lack of response to external stimuli. Doses above 0.4 mug were excitatory, convulsant and lethal.2. The depressant effects could be antagonized by (+)-amphetamine, desmethylimipramine, dibutyryl cyclic 3'5'-adenosine monophosphate and caffeine.3. The MAO inhibitor nialamide produced only a small antagonism of ouabain, resulting in a greater rate of recovery from the depressant effects of ouabain.4. The depressant effects were associated with a marked elevation of whole-brain dopamine levels with little change in noradrenaline or 5-hydroxytryptamine.5. The dopamine-beta-hydroxylase inhibitor sodium diethyldithiocarbamate, administered by intracerebroventricular injection, produced effects qualitatively similar to those seen after ouabain.6. An interference with central transmitter function is postulated as a possible mode of action of intracerebroventricularly injected ouabain.
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PMID:Pharmacological properties of centrally administered ouabain and their modification by other drugs. 432 23

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

Effect of adenosine, 2-chloroadenosine (P1-purinoceptor agonists) and adenosine triphosphate (ATP), adenosine-5'-tetraphosphate (P2-purinoceptor agonists) on body temperature was studied in mice. Adenosine (7.5-200 mg/kg) as well as 2-chloroadenosine (0.25-7.5 mg/kg) induced hypothermia in a dose-dependent manner. However, ATP or adenosine-5'-tetraphosphate did not show any effect on body temperature. Caffeine and theophylline, P1-purinoceptor antagonists, blocked the hypothermic response of adenosine and 2-chloroadenosine. Treatment with quinidine or phenoxybenzamine (non-specific P2-purinoceptor antagonists) did not modify the hypothermic response. Similarly, treatment with drugs which modify adrenergic (reserpine, propranolol, labetalol or haloperidol), serotonergic (cyproheptadine) or histaminergic functions failed to block adenosine or 2-chloroadenosine-induced hypothermia. These results demonstrated that P1-purinoceptors mediated the hypothermic response of these purines.
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PMID:Effect of purinergic substances on rectal temperature in mice: involvement of P1-purinoceptors. 631 20

Calcium-free rat hearts develop separations of fascia adherens junctions of intercalated discs. Such hearts are susceptible to membrane injury and enzyme release during anoxic contracture. Anoxic enzyme release was exacerbated by distention of heart ventricles with a balloon. Dinitrophenol (DNP) and caffeine were used to induce contracture in calcium-free hearts. Both DNP and caffeine caused a massive enzyme release from calcium-free but not from control hearts. Caffeine-induced enzyme release occurred despite Amytal inhibition of mitochondrial respiration. These results demonstrate that in calcium-free hearts with contracture or ventricular distention, enzyme release occurred without calcium repletion, from hearts depleted of ATP and in the absence of mitochondrial function. A relationship between contracture-mediated enzyme release and the calcium paradox was suggested by studies of the effects of hypothermia on enzyme release. Hypothermia to 22 degrees C protects hearts against both the calcium paradox and anoxic, DNP and caffeine injury. The parallel temperature dependence of protection between contracture-mediated enzyme release and the calcium paradox is evidence that contracture may also be a mediator of sarcolemmal membrane injury and enzyme release in the calcium paradox.
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PMID:Mechanism of enzyme release in the calcium paradox. 666 35


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