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

Activation of cardiac A1 adenosine receptors slows atrioventricular conduction and attenuates the effects of catecholamines, whereas activation of A2 adenosine receptors causes coronary dilation. This study investigates the antagonism of the action of adenosine on A1 and A2 adenosine receptor subtypes by (+-)-N6-endonorbornan-2-yl-9-methyladenine (N-0861) in guinea pig isolated perfused hearts. Stimulus to His bundle interval, coronary perfusion pressure and left ventricular pressure were measured. In normoxic hearts, N-0861 competitively and reversibly antagonized stimulus to His bundle interval prolongation induced by adenosine (1-30 microM) but not that caused by carbachol (0.09 microM), verapamil (1 microM), MgCl2 (6.5 mM) or hypothermia. N-0861 (up to 100 microM) did not attenuate the decrease in coronary perfusion pressure caused by adenosine. N-0861 significantly attenuated the antagonism by adenosine of an isoproterenol-mediated elevation of left ventricular pressure. N-0861 significantly reduced stimulus to His bundle prolongation induced by either hypoxia or reduced perfusion ("ischemia") but did not attenuate the hypoxia-induced decrease in coronary perfusion pressure. Receptor binding studies indicated that N-0861 competitively displaced the binding of 8-cyclopentyl-1,3-[3H]dipropylxanthine to crude guinea pig and human atrial membranes (Ki values of 0.62 and 0.7 microM, respectively) but did not displace the binding of S-(p-nitro[3H]benzyl)-6-thioinosine. The results indicate that in the heart N-0861 is a reversible, specific and selective antagonist of adenosine at the A1 receptor subtype.
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PMID:Evaluation of N-0861, (+-)-N6-endonorbornan-2-yl-9-methyladenine, as an A1 subtype-selective adenosine receptor antagonist in the guinea pig isolated heart. 154 93

The present report reviews the biochemical and physiological responses to adenosine receptor activation and how these responses underlie the ability of adenosine to couple energy demand with energy supply. In addition, activation of adenosine receptors pharmacologically is shown to initiate various reactions which could be responsible for the observed adenosine-mediated attenuation of the neuropathological consequences of brain ischemia. Also reported is the extent to which side effects such as hypothermia can contribute to the observed efficacy of adenosine agonist administration in the small animal model of ischemia. Data from various in vitro and in vivo ischemia studies is presented showing that neuroprotection can be achieved following pharmacological activation of adenosine receptors either through agonists with high affinity for A1 adenosine receptors or drugs which potentiate endogenous adenosine levels. In general the data support utilization of adenosine receptor activation as a means of attenuating ischemic brain damage.
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PMID:Therapeutic potential for adenosine receptor activation in ischemic brain injury. 161 14

Caffeine induces a dose-dependent decrease in core body temperature in mice and the hypothermia induced by a 100 mg/kg dose of caffeine was seen to persist for greater than 160 min. Other alkylxanthines including theophylline, enprophylline, isbutylmethylxanthine and 1,3-dipropyl-7-methylxanthine also showed dose-dependent reductions in body temperature. The dose of these drugs required to reduce body temperature by 2 degrees C was calculated and correlated with the affinities for the compounds at adenosine A1 and A2 receptors and their activities in inhibiting calcium dependent and independent phosphodiesterases. Significant relationships were found between the 2 degrees C hypothermic dose (HD2) and soluble and membrane calcium-independent phosphodiesterase inhibiting activity (r2s = 0.950 and 0.940, respectively). No significant relationship was seen between HD2 and soluble calcium-dependent phosphodiesterase inhibiting activity or with A2 adenosine receptor affinity. The relationship between HD2 and A1 adenosine receptor affinity (r2 = 0.739) did however almost reach statistical significance. These results would suggest that phosphodiesterase inhibition, instead of or in addition to adenosine receptor blockade, may play an important role in the effects of alkylxanthines on body temperature.
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PMID:Hypothermic effects of alkylxanthines: evidence for a calcium-independent phosphodiesterase action. 180 62

Four isolated tissues were examined in which the responses to adenosine are mediated via either A1- or A2-receptors. The responses examined were the inhibition of cholinergic transmission of field-stimulated guinea-pig ileum (A1), inhibition of noradrenergic transmission of field-stimulated rat vas deferens (A1), inhibition of developed tension of rat paced left atria (A1) and relaxation of carbachol-contracted guinea-pig trachea (A2). Cumulative concentration-response curves for adenosine and 2-chloroadenosine were constructed at 37, 30 or 27 degrees C. When plotted as a percentage of the maximum response, the concentration-response curves were displaced to the left by cooling in the ileum, vas deferens and atria, indicative of supersensitivity. This increase in sensitivity does not arise from inhibition of uptake or deamination by cooling, since it occurs equally for adenosine and 2-chloroadenosine, the latter being immune to these processes. In contrast, the sensitivity of the trachea was not affected (2-chloroadenosine) or reduced (adenosine) by cooling. Thus responses mediated via adenosine receptors of the A1 subtype exhibit hypothermia-induced supersensitivity, whereas those mediated via A2-receptors do not. This suggests a fundamental temperature-dependent difference between the two adenosine receptor subtypes.
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PMID:Hypothermia-induced supersensitivity to adenosine for responses mediated via A1-receptors but not A2-receptors. 298 12

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

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

The behavioral and physiological effects of L-phenylisopropyladenosine, cyclohexyladenosine and 2-chloroadenosine were examined in mice and rats. These analogs of adenosine are agonists which bind with high affinity to putative central A1 receptors in vitro. Relatively low doses of these drugs administered i.p. produced marked sedation and hypothermia; higher doses resulted in an almost complete cessation of spontaneous motor activity as well as some ataxia. These analogs also antagonized seizures elicited by a variety of convulsants with different mechanisms of action. The differences observed in the anticonvulsant potencies of the analogs suggest that these effects are not produced by the interaction of these drugs with a single class of adenosine receptor. In particular, 2-chloroadenosine and cyclohexyladenosine appear to be more related to each other pharmacologically than to L-phenylisopropyladenosine. Because some of the anticonvulsant actions of L-phenylisopropyladenosine are not reversed by the adenosine antagonist theophylline, and are not shared by the other analogs, these may reflect actions mediated by other, perhaps nonpurinergic receptors. Although benzodiazepines also have sedative, hypothermic and anticonvulsant properties, responses to benzodiazepines can be clearly dissociated from responses to the adenosine agonists.
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PMID:Sedative and anticonvulsant effects of adenosine analogs in mouse and rat. 705 24

1. The effects of a range of adenosine receptor-selective ligands on body temperature were investigated following intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) injection in conscious mice. The compounds tested were the non-selective adenosine receptor agonist 5'-N-ethyl-carboxamidoadenosine (NECA), the adenosine A1 receptor-selective agonists cyclopentyl-adenosine (CPA), N6-(9R-phenyl-isopropyl)-adenosine (R-PIA) and N-(1S,trans)-[2-hydroxyclopentyl]-adenosine (GR79236), the A2a receptor selective agonist 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxyamidoaden osine (CGS-21680), the A2b receptor agonist N-[(2-methylphenyl)methyl[adenosine (metrifudil) and the A3 receptor agonist N6-(4-aminophenylethyl)adenosine (APNEA). 2. NECA (0.01-1 microgram, i.c.v.), all of the A1-selective agonists (0.01-1 microgram, i.c.v.) and APNEA (0.1-3 micrograms i.c.v.) produced profound and dose-related hypothermia and sedation. However, CGS-21680 (0.1-10 micrograms i.c.v.) and metrifudil (0.01-1 microgram i.c.v.), produced only mild hypothermia at the highest doses tested. 3. The hypothermic response to the A1 receptor-selective agonists, GR79236 and R-PIA was dose-dependently antagonized by peripheral administration of either the non-selective adenosine receptor antagonist, 8-phenyltheophylline (8-PT, approximately 40 and 30 fold rightward shifts of the dose-response curves respectively at 10 mg kg-1, i.p.), or the adenosine A1 receptor-selective antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, approximately 20 fold shift of the GR79236 dose-response curve at 1 mg kg-1, i.p.). The hypothermic response to APNEA was similarly dose-dependently antagonized by the A1 receptor-selective antagonist, DPCPX (5 fold shift at 0.1 mg kg-1, i.p.). 4.8(p-Sulphophenyl)theophylline (8-SPT, 10 and 30 mg kg-1, i.p.), a non-selective adenosine receptorantagonist that penetrates the blood brain barrier poorly, produced only modest antagonism (approximately 2 fold shift at 30 mg kg-1, i.p.) of the hypothermic response to GR79236.5. These data suggest that hypothermia induced by adenosine analogues in the conscious mouse is mediated via adenosine A1 receptors, which are probably located in the CNS.
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PMID:Characterization of the adenosine receptors mediating hypothermia in the conscious mouse. 788 96

1. Thermal responses to i.v. administration of N6-cyclohexyladenosine (CHA; 0.15 mg/kg), A1 adenosine receptor agonist, or 5'-N-ethylcarboxamidoadenosine (NECA; 0.15 mg/kg), A2 adenosine receptor agonist, were investigated in normothermic rabbits at an ambient temperature (Ta) of 20.0 +/- 1.0 degrees C. 2. Although both compounds inhibited metabolic heat production, only NECA produced hypothermia. 3. NECA showed strong hypotensive activity. 4. Both compounds produced vasoconstriction of the ear skin vessels and CHA, in addition, slowed down the respiratory rate. 5. The role of A1 or A2 adenosine receptors in the thermoregulatory activity of these compounds is discussed.
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PMID:The effect of N6-cyclohexyladenosine and 5'-N-ethylcarboxamidoadenosine on body temperature in normothermic rabbits. 872 28

Although adenosine receptor-based treatment of cerebral ischemia and other neurodegenerative disorders has been frequently advocated, cardiovascular side effects and an uncertain therapeutic time window of such treatment have constituted major obstacles to clinical implementation. Therefore, we have investigated the neuroprotective effects of the adenosine A1 receptor agonist adenosine amine congener (ADAC) injected after either 5 or 10 min ischemia at 100 micrograms/kg. When the drug was administered at either 6 or 12 h following 5 min forebrain ischemia, all animals were still alive on the 14th day after the occlusion. In both ADAC treated groups neuronal survival was approximately 85% vs. 50% in controls. Administration of a single dose of ADAC at times 15 min to 12 h after 10 min ischemia resulted in a significant improvement of survival in animals injected either at 15 or 30 min, or at 1, 2, or 3 h after the insult. In all 10 min ischemia groups, administration of ADAC resulted in a significant protection of neuronal morphology and preservation of microtubule associated protein 2 (MAP-2). However, postischemic Morris' water maze tests revealed full preservation of spatial memory and learning ability in animals injected at 6 h. On the other hand, the performance of gerbils treated at 12 h postischemia was indistinguishable from that of the controls. Administration of ADAC at 100 micrograms/kg in non-ischemic animals did not result in bradycardia, hypotension, or hypothermia. The data indicate that when ADAC is used postischemically, the most optimal level of protection is obtained when drugs are given at 30 min to 6 h after the insult. Although the mechanisms involved in neuroprotective effects of adenosine A1 receptor agonists require further studies, the present results demonstrate the feasibility of their clinical applications.
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PMID:Postischemic administration of adenosine amine congener (ADAC): analysis of recovery in gerbils. 898 84


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