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PubMed1994

Clentiazem, diltiazem, and cold cardioplegia in isolated ischemic rabbit hearts: relation between additive cardioprotection, physicochemical properties, and preservation of myocardial lipid components.

Diltiazem is known to exert significant cardioprotection, but its efficacy under hypothermic conditions has not been documented. Because of its lipophilicity and its better tissue penetration, clentiazem, a chlorobenzothiazepine derivative of diltiazem, may offer cytoprotection additive to cold cardioplegia. We investigated the cardioprotective actions of clentiazem and diltiazem (10(-8) and 10(-6) M) when added to cold cardioplegia (myocardial temperature of 10 degrees-12 degrees C), in isolated rabbit heart subjected to 90-min global ischemia. Functional recovery was assessed by measuring left ventricular developed pressure (LVDP), coronary flow (CF) and heart rate (HR). To explore the potential beneficial mechanisms of these agents, we measured myocardial lipids and total calcium at the end of a 30-min period of reperfusion as well as their myocardial accumulation. Addition of 10(-8) M clentiazem to cold cardioplegia resulted in significant improvement in mechanical recovery (postischemic LVDP of 88.5 mm Hg with cardioplegia alone vs. 105.5 mm Hg with added clentiazem at 25 mm Hg diastolic pressure, DP). The additive cardioprotection afforded by clentiazem appeared to be concentration dependent since significant cardiodepression (postischemic LVDP of 79.8 mm Hg and 18% reduction in HR) was observed at a higher concentration (10(-6) M) and these effects were correlated with myocardial accumulation of the drug. The additive cardioprotective effect of clentiazem appeared to be structure related because diltiazem at both 10(-8) and 10(-6) M concentrations offered no benefits in addition to cold cardioplegia. These results indicate that the additive cardioprotection observed with 10(-8) M clentiazem could be related to its coronary vasodilator action since it reversed the cold cardioplegia-induced attenuation of hyperemic CF at reperfusion. Other factors must be involved, however, because addition of 10(-6) M diltiazem resulted in increased postischemic CF but without improving myocardial recovery. The functional protection offered by 10(-8) M clentiazem was associated with preservation of myocardial lipid components. Myocardial cholesterol content, which is essential for maintenance of membrane integrity, was preserved in that group, whereas a loss was observed in groups treated with cardioplegia alone and in the other treated groups. Total myocardial phospholipids were preserved in groups receiving 10(-8) M clentiazem plus cold cardioplegia or cold cardioplegia alone. A reduction in plasmalogen content, the predominant myocardial phospholipid species, and an increase in total myocardial calcium were noted only in ischemic hearts that received neither cardioplegia nor benzothiazepines, suggesting that cold cardioplegia is sufficient to prevent irreversible damage. Clentiazem affords cardioprotective benefits additive to cold cardioplegia.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2000

Swimming training prevents generation of suppressor macrophages during acute cold stress.

PURPOSE: Acute cold stress induces suppressor macrophages expressing large numbers of receptors to Fc portion of immunoglobulin G (MAC-1+ Fc gammaRII/IIIbright cells), resulting in suppression of splenocyte mitogenesis. The generation of MAC-1+ Fc gammaRII/IIIbright cells is partly mediated by increased glucocorticoid levels during acute cold stress. The aim of the current study was to investigate the effect of swimming training on the generation of the MAC-1+ Fc gammaRII/IIIbright suppressor macrophages by acute cold stress. METHODS: The trained mice underwent a 6-wk endurance swimming training (5 times/wk) in water at 35-36 degrees C for 90 min. The swimming training significantly increased brown adipose tissue mass, suggesting improved cold tolerance. Actually, when the swimming-trained mice were exposed to 5 degrees C for 3 h (acute cold stress), the rectal temperature was not decreased. The proportion of MAC-1+ Fc gammaRII/IIIbright cells in peritoneal exudate cells from swimming-trained mice was significantly lower than that from control mice. In addition, the proportion of MAC-1+ Fc gammaRII/IIIbright cells in peritoneal exudate cell population from swimming-trained mice was unaffected by the acute cold stress. The swimming training significantly attenuated the increases in serum corticosterone levels in response to acute cold stress. These results suggested that swimming training not only improves cold tolerance but also inhibits the generation of suppressor macrophages under acute cold stress as well as under normal conditions.

Acclimatization↗
PubMed1999

Morphologic alteration of hepatocytes and sinusoidal endothelial cells in rat fatty liver during cold preservation and the protective effect of hepatocyte growth factor.

BACKGROUND: Fatty liver grafts are considered to be one of the main factors of primary nonfunctioning graft in transplantation. We investigated here, the hepatic damage during cold preservation in a rat fatty liver model by ultrastructural observation, and examined the effect of human recombinant hepatocyte growth factor (hrHGF) on amelioration of the cold-preserved graft condition. METHODS: Wistar rats were fed a choline-deficient diet (CDD) for 7 days. Livers were stored in cold University of Wisconsin (UW) solution for 0, 4, and 24 hr. We evaluated the ultrastructural alteration of the hepatocytes, sinusoidal architecture, and endothelial cells (SECs) by scanning and transmission electron microscopy. Ex vivo, we measured alanine aminotransferase (ALT) in first effluent as an index of hepatocyte injury and the hyaluronic uptake rate (HUR) as that of SEC damage. We injected hrHGF into rats fed CDD for 7 days through the portal vein and also added it to the UW solution to determine whether or not the agent ameliorated the hepatic damage in cold-preserved fatty livers. RESULTS: In rats fed CDD for 7 days, the lesion occupied by fat deposits appeared to enlarge with the duration of cold preservation leading to the disarrangement of sinusoidal architecture. Furthermore, sinusoidal endothelial damage, in which gaps, blebs, microvilli, and sinusoid denudation were detected, appeared to be more severe in these livers than in the corresponding control livers. ALT significantly increased in the 4-hr cold-preserved livers of rats fed CDD for 7 days. HUR decreased with 4-hr cold preservation and/or with CDD feeding. Administration of hrHGF prevented the expansion of fatty droplets and reduced SEC injury as detected by morphological observations. Increase of ALT in first effluent was inhibited to about one fourth the level observed in the 4-hr cold-preserved livers of rats fed CDD. Moreover, HUR significantly increased with the pretreatment of hrHGF. CONCLUSION: The hepatic injury in both hepatocytes and SECs in cold-preserved fatty liver graft developed more rapidly and severely than in the corresponding controls and demonstrated a protective effect of hrHGF.

Animals↗
PubMed2005

The cold-induced early activation of phospholipase C and D pathways determines the response of two distinct clusters of genes in Arabidopsis cell suspensions.

In plants, a temperature downshift represents a major stress that will lead to the induction or repression of many genes. Therefore, the cold signal has to be perceived and transmitted to the nucleus. In response to a cold exposure, we have shown that the phospholipase D (PLD) and the phospholipase C (PLC)/diacylglycerol kinase pathways are simultaneously activated. The role of these pathways in the cold response has been investigated by analyzing the transcriptome of cold-treated Arabidopsis (Arabidopsis thaliana) suspension cells in the presence of U73122 or ethanol, inhibitors of the PLC/diacylglycerol kinase pathway and of the phosphatidic acid produced by PLD, respectively. This approach showed that the expression of many genes was modified by the cold response in the presence of such agents. The cold responses of most of the genes were repressed, thus correlating with the inhibitory effect of U73122 or ethanol. We were thus able to identify 58 genes that were regulated by temperature downshift via PLC activity and 87 genes regulated by temperature downshift via PLD-produced phosphatidic acid. Interestingly, each inhibitor appeared to affect different cold response genes. These results support the idea that both the PLC and PLD pathways are upstream of two different signaling pathways that lead to the activation of the cold response. The connection of these pathways with the CBF pathway, currently the most understood genetic system playing a role in cold acclimation, is discussed.

Arabidopsis↗
PubMedDate not supplied

Acute effects of cold on blood pressure, renin-angiotensin-aldosterone system, catecholamines and adrenal steroids in man.

In an attempt to study effects of cold on blood pressure and the renin-angiotensin-aldosterone system, 34 healthy young subjects with or without a family history of essential hypertension were exposed to moderate cold (4 degrees C for 1 h) or severe cold (immersion of the hands to 0 degrees C for 10 min). Moderate cold elevated blood pressure, aldosterone, cortisol and noradrenaline when the subjects wore summer clothing but not when the subjects wore winter clothing. Regardless of the clothing worn, skin blood flow and plasma renin activity decreased significantly in response to moderate cold but angiotensin II decreased insignificantly. Severe cold elevated blood pressure, cortisol, aldosterone and noradrenaline. Administration of dexamethasone significantly depressed an increase of aldosterone and cortisol in response to cold but failed to effect an elevation of blood pressure and noradrenaline. Plasma renin activity and angiotensin II concentration were not affected at all during and after cold exposure. It is suggested that, among the various hormones studied, noradrenaline is the only hormone responsible for an elevation of blood pressure in response to cold.

Adrenal Cortex Hormones↗
PubMed1972

The effect of cold storage on the adrenergic mechanisms of intestinal smooth muscle.

1. In the guinea-pig taenia caecum, fluorescent adrenergic fibres terminate in both muscle layers. The density of these fibres is greater in the taenia than in the underlying circular muscle layer. The myenteric plexus and individual ganglion cells are also densely innervated by intensely fluorescent adrenergic nerve fibres.2. After three days of cold storage, the specific fluorescence disappeared from all tissue layers of the taenia caecum and smooth muscle fibres. In contrast, cholinesterase active substances were still demonstrable in all tissue layers even after seven days of cold storage but the density of these substances was decreased.3. Cold storage (3-7 days) decreased the tissue noradrenaline content and did not modify the cholinesterase enzyme activity (4 days).4. In cold stored strips, the inhibitory response to nicotine, 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) or electrical transmural stimulation was abolished and enhancement of the contractile response occurred. Cold storage also inhibited the inhibitory action of tyramine. Similar results were observed after reserpine treatment.5. In fresh taenia, the relaxation produced by nicotine, DMPP and electrical transmural stimulation was inhibited by adrenoceptor blocking agents and bretylium. In cold storage preparations, contraction produced by these stimuli was blocked by parasympathetic blocking agents and potentiated by anti-cholinesterase. These results indicate that the inhibitory response to these stimulants is mediated by stimulation of the adrenergic nerve system more than by non-adrenergic nerves; the excitatory effect is probably due to stimulation of cholinergic nerves.6. These results suggest that the adrenergic mechanisms of the taenia caecum are more labile in cold storage than the cholinergic mechanisms. Thus, the inhibitory action of cold storage on the relaxation produced by nicotine, DMPP, and transmural stimulation is probably explained by selective physical degeneration of the adrenergic nerve terminal. Also, enhancement of the contractile response to these stimulants in cold stored preparations is explained by the lack of adrenergic inhibitory mechanisms.

Acetylcholinesterase↗
PubMed1972

The effect of cold storage on the inhibitory action of isoprenaline, phenylephrine and nicotine on the mechanical and membranal activities of guinea-pig taenia caecum.

1. The effects of prolonged cold storage on the mechanical and membranal responses to stimulation of alpha- and beta-adrenoceptors by phenylephrine and isoprenaline, respectively, were studied on the guinea-pig taenia caecum.2. Cold storage invariably caused a decrease in the resting membrane potential, and this effect was enhanced as the duration of treatment was prolonged.3. After cold storage (18 days) the tissue potassium ion content (89.7 +/- 1.7 mmol/kg wet wt.) was decreased to 30.5 +/- 1.9 mmol/kg wet wt. whereas that for sodium (69.2 +/- 1.4 mmol/kg wet wt.) increased to 134.0 +/- 2.3 mmol/kg wet wt.4. In the fresh preparations, phenylephrine (1 and 2 muM) caused a cessation of spontaneous action potentials, accompanied by hyperpolarization of the membrane and relaxation of the muscle. These effects were markedly diminished after 18 days of cold storage. Isoprenaline (1 and 2 muM) also blocked the action potentials and caused a concomitant muscle relaxation, but in most cases the hyperpolarization was not observed. After 14 days of cold storage these mechanical and membranal changes associated with isoprenaline treatment were not demonstrable in most preparations.5. Nicotine (5 muM and 50 muM) produced a biphasic effect, cessation of the action potential, hyperpolarization and subsequent relaxation followed by a long lasting depolarization, an accelerated discharge of action potentials and an increase in muscle tension. After a few days of cold storage the hyperpolarization effect disappeared but the intensity of the long-lasting depolarization as well as the contractile effects were increased. After cold storage for more than 7 days, nicotine did not affect mechanical or electrical activity.6. Dibutyryl 3'5' cyclic AMP (1 muM to 500 muM) failed to affect the mechanical and electrical activities of taenia caecum.7. Phenylephrine and isoprenaline had no effect on the high potassiumdepolarized taenia.8. These observations suggest that the electro-mechanical effect of an alpha-adrenoceptor stimulant on the guinea-pig taenia caecum is more resistant to cold treatment than that of a beta-adrenoceptor stimulant. This inhibitory system of stimulation of both a- and 8-receptors of guinea-pig taenia caecum may react by different mechanisms. The results also demonstrate that cold storage itself changes the membrane permeability to ions and the tissue ion content (Na+ and K+) of smooth muscle of guinea-pig taenia caecum.

Action Potentials↗
PubMed2006

Rescue of the cold preserved rat liver by hypothermic oxygenated machine perfusion.

The aim of the study was to investigate whether hypothermic oxygenated liver perfusion after cold liver preservation resuscitated metabolic parameters and whether this treatment had a benefit for liver viability upon reperfusion. We preserved rat livers either by cold storage (UW) for 10 h, or by perfusion for 3 h (oxygenated modified UW) after 10 h cold storage. We assessed viability of livers after preservation and after ischemic rewarming+normothermic reperfusion ex vivo. Ten hour cold storage reduced mitochondrial cytochrome oxidase and metabolically depleted the livers. Oxygenated perfusion after cold storage resulted in uploaded cellular energy charge and oxidized mitochondrial cytochrome oxidase. Reperfusion after 10 h cold storage increased formation of superoxid anions, release of cytosolic LDH, lipid peroxidation, caspase activities and led to disruption of sinusoidal endothelial cells. In contrast, reperfusion after 10 h cold storage+3 h hypothermic oxygenated perfusion resulted in no changes of lipid peroxidation, bile flow, energy charge, total glutathione, LDH release and of caspase activation, as compared to fresh resected livers. This study demonstrates, that a metabolically depleted liver due to cold storage can be energy recharged by short-termed cold machine perfusion. The machine perfused graft exhibited improved viability and functional integrity.

Animals↗
PubMed1982

Commentary on the reduced urinary noradrenaline excretion following cold stress and exercise in physically trained rats.

Urinary catecholamine excretions of rats trained by swimming or running were compared with those of cold-acclimated rats and controls i.e. sedentary warm-acclimated rats. During cold stress the trained rats excreted less noradrenaline (NA) than did controls. In fact rats trained by swimming excreted less NA than did cold-acclimated rats, while rats trained by running excreted about the same amount as did cold-acclimated rats. 2 h of swimming increased the urinary catecholamine (CA) excretion of all groups but trained rats excreted less NA than did controls and cold-acclimated rats, which had excretions of similar magnitude. The NA excretions of the two trained groups never deviated statistically from each other. It is concluded that concerning NA requirement in order to maintain homeostasis, training produces "cross tolerance" to cold stress but cold-acclimation does not produce "cross tolerance" to acute exercise. Furthermore the positive effect of training on NA excretion during the stress of cold or that of acute exercise seems essentially to be an effect of increased locomotor activity as such regardless of the type of training. It is also suggested that increased levels of locomotor activity of the rat may be of importance for seasonal acclimation of the species by increasing its tolerance to cold.

Animals↗
PubMed1986

Is swimming exercise or cold exposure for rats?

Rats were trained by daily swimming sessions (up to 3 h per day) for at least 6 weeks in water at 30, 36 and 38 degrees C. After this training, the adaptive changes obtained were compared with those typical of cold-acclimated (cold-specific changes) and running-trained (training-specific changes) rats. The most typical training-specific change, an increased activity of oxidative muscle enzymes was negligible for swimming-trained rats, while the lowered activity of muscle lactate dehydrogenase was evident for all trained groups. Cold-specific changes, such as increased food intake, increased calorigenic response to injected noradrenaline, an increase both in mass and metabolic capacity of brown adipose tissue, and maintenance of the stores of ascorbic acid and muscle glycogen during cold exposure, were observed for rats trained at 36 and 30 degrees C. The cold tolerance test in cold air did not make any distinct difference between the rats trained at different water temperatures, while in cool water the 30 degrees C -swimmers were clearly superior to other groups, that is, their cooling rate was slowest. Other adaptive changes were found, to a variable extent, for all trained groups. These included loss of body fat, cardiac hypertrophy, reduced urinary catecholamine excretion after test swimmings either in cold or warm water, increased tail-skin temperature response to isoprenaline, and a higher tail-skin temperature in response to cold. Generally, however, the adaptive changes observed for 30- and 36 degrees C-swimmers were similar, while the changes observed for 38 degrees C-swimmers were different. The latter group neither displayed any cardiac enlargement nor any cold-specific changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Physiological↗
PubMed1968

The biliary-faecal excretion of thyroxine during cold exposure in the rat.

1. The biliary-faecal route of thyroxine excretion has been examined by means of thyroxine labelled with (131)I in the thyroidectomized, thyroxine-maintained rat during cold exposure.2. The rate of excretion of thyroxine into the faeces is raised in rats exposed to cold for 2 weeks and fed ad libitum on a high roughage diet.3. When the faecal volumes of warm- and cold-exposed animals are made similar by controlling the roughage content of the diet the difference in their faecal thyroxine excretion rates is much reduced.4. Warm- and cold-exposed rats eating the same amount of food excrete thyroxine into their faeces at similar rates.5. Even when warm- and cold-exposed rats excrete thyroxine into their faeces at the same rate the cold-exposed animals still show a shorter half-life for blood thyroxine.6. An acceleration of the rate of loss of thyroxine from the blood is demonstrable in fasting animals within 10 hr of exposure to cold.7. Ligation of the bile-duct does not affect this acute response to cold.8. The amount of thyroxine lost into the bile within the first 8 hr after intravenous injection is similar in warm- and cold-exposed animals. The clearance of thyroxine into the bile is however greater in the cold-exposed animal since the liver is working against a lower level of blood thyroxine.9. An acceleration of the biliary-faecal route of thyroxine excretion is not the only process at work tending to reduce the biological half-life of thyroxine during cold exposure.

Animals↗
PubMed2000

Cold shock and its effect on ribosomes and thermal tolerance in Listeria monocytogenes.

Differential scanning calorimetry (DSC) and fatty acid analysis were used to determine how cold shocking reduces the thermal stability of Listeria monocytogenes. Additionally, antibiotics that can elicit production of cold or heat shock proteins were used to determine the effect of translation blockage on ribosome thermal stability. Fatty acid profiles showed no significant variations as a result of cold shock, indicating that changes in membrane fatty acids were not responsible for the cold shock-induced reduction in thermal tolerance. Following a 3-h cold shock from 37 to 0 degrees C, the maximum denaturation temperature of the 50S ribosomal subunit and 70S ribosomal particle peak was reduced from 73.4 +/- 0.1 degrees C (mean +/- standard deviation) to 72.1 +/- 0.5 degrees C (P < or = 0.05), indicating that cold shock induced instability in the associated ribosome structure. The maximum denaturation temperature of the 30S ribosomal subunit peak did not show a significant shift in temperature (from 67.5 +/- 0.4 degrees C to 66.8 +/- 0.5 degrees C) as a result of cold shock, suggesting that either 50S subunit or 70S particle sensitivity was responsible for the intact ribosome fragility. Antibiotics that elicited changes in maximum denaturation temperature in ribosomal components also elicited reductions in thermotolerance. Together, these data suggest that ribosomal changes resulting from cold shock may be responsible for the decrease in D value observed when L. monocytogenes is cold shocked.

Calorimetry, Differential Scanning↗
PubMed2006

Activation of zoosporogenesis-specific genes in Phytophthora infestans involves a 7-nucleotide promoter motif and cold-induced membrane rigidity.

Infections of plants by the oomycete Phytophthora infestans typically result from zoospores, which develop from sporangia at cold temperatures. To help understand the relevant cold-induced signaling pathway, factors regulating the transcription of the zoosporogenesis-specific NIF (nuclear LIM-interactor-interacting factor) gene family were examined. Sequences required for inducing PinifC3 were identified by analyzing truncated and mutated promoters using the beta-glucuronidase reporter in stable transformants. A 7-nucleotide (nt) sequence located 139 bases upstream of the major transcription start point (GGACGAG) proved essential for the induction of PinifC3 when sporangia were shifted from ambient to cold temperatures. The motif, named the cold box, also conferred cold inducibility to a promoter normally activated only during sexual development. An identical motif was detected in the two other zoosporogenesis-specific NIF genes from P. infestans and three Phytophthora sojae orthologues, and a closely related sequence was found in Phytophthora ramorum orthologues. The 7-nt motif was also found in the promoters of other zoosporogenesis-induced genes. The presence of a cold box-interacting protein in nuclear extracts of P. infestans sporangia was demonstrated using electrophoretic mobility shift assays. Furthermore, zoospore release and cold box-regulated transcription were stimulated by the membrane rigidizer dimethyl sulfoxide and inhibited by the membrane fluidizer benzyl alcohol. The data therefore delineate a pathway in which sporangia perceive cold temperatures through membrane rigidity, which activates signals that drive both zoosporogenesis and cold-box-mediated transcription.

Amino Acid Motifs↗
PubMed1985

Sympathetic and local vasoconstrictor response to cold in vibration induced white finger.

To study the relative roles of sympathetic and local vasoconstrictor response to cold in vibration induced white finger (VWF) seven lumberjacks with bilateral VWF and seven age matched controls were investigated. During body cooling finger systolic blood pressure was measured with a cuff technique simultaneously on one affected finger on each hand at 30 degrees, 15 degrees, and 6 degrees C. Both affected fingers had an increased vasoconstrictor response at 15 degrees and 6 degrees C compared with the control group (p less than or equal to 0.05). During unilateral sympathetic nerve block the cold provocation test was repeated on both fingers. The unblocked finger affected by VWF showed no significant difference in the cold response between the two cold provocation tests (p greater than 0.10). The local cold response of blocked finger did not differ from that of the control group (p greater than 0.10). The sympathetic vasoconstrictor response to cold was estimated as the difference between the cold response before nerve block and the cold response during nerve block. The median sympathetic vasoconstrictor response at 6 degrees C was about twice as large as the local response during nerve block (p less than 0.05). The results indicate that the sympathetic vasoconstrictor response to cold plays the dominant part in VWF.

Aged↗
PubMed1985

Pulmonary vascular responsiveness in cold-exposed calves.

The pulmonary vascular responses to acute hypoxia and to infusions of histamine and 5-hydroxytryptamine (5-HT) were recorded in unanesthetized standing bull calves under neutral (16-18 degrees C) and cold (3-5 degrees C) temperature conditions. Cold exposure alone resulted in a significant increase in pulmonary arterial wedge pressure from 10.2 +/- 3.5 to 15.9 +/- 4.9 Torr (1 Torr = 133.322 Pa). Resistance to blood flow between the pulmonary wedge and the left atrium significantly increased from 0.50 +/- 0.51 to 1.21 +/- 0.78 mmHg . L-1 . min-1 (1 mmHg = 133.322 Pa) with cold exposure. This apparent pulmonary venoconstrictor response to cold exposure was further evaluated to determine if hypoxia, histamine, or 5-HT responsiveness was altered by cold exposure. Twelve minutes of hypoxia increased pulmonary arterial and systemic arterial pressures, heart rate, and respiratory rate similarly in cold and neutral temperatures. Cold exposure did not alter the dose-related reductions of systemic arterial and pulmonary arterial pressures in response to histamine. Similarly, the decreases in systemic arterial pressure and heart rate and increases in pulmonary arterial and left atrial pressures in response to 5-HT were not significantly different in cold and neutral conditions. It was concluded that acute, mild cold exposure results in an increase in resistance to blood flow in the pulmonary venous circulation without a general increase in pulmonary vascular reactivity, as measured by responses to hypoxia, histamine, and 5-HT.

Animals↗
PubMed2005

Reactive oxygen species from smooth muscle mitochondria initiate cold-induced constriction of cutaneous arteries.

Cold constricts cutaneous blood vessels by selectively increasing the activity of smooth muscle alpha2-adrenoceptors (alpha2-ARs). In mouse tail arteries, alpha2-AR constriction is mediated by alpha2A-ARs at 37 degrees C, whereas the cold-induced augmentation in alpha2-AR activity is mediated entirely by alpha2C-ARs. Cold causes translocation of alpha2C-ARs from the trans-Golgi to the plasma membrane, mediated by cold-induced activation of RhoA and Rho kinase. The present experiments analyzed the mechanisms underlying these responses. Mouse tail arteries were studied in a pressure myograph. Cooling the arteries (28 degrees C) caused a rapid increase in reactive oxygen species (ROS) in smooth muscle cells, determined by confocal microscopy of arteries loaded with the ROS-sensitive probes, dichlorodihydrofluorescein or reduced Mitotracker Red. The inhibitor of mitochondrial complex I rotenone (10 micromol/l), the antioxidant N-acetylcysteine (NAC; 20 mmol/l), or the cell-permeable mimic of superoxide dismutase MnTMPyP (50 micromol/l) did not affect vasoconstriction to alpha2-AR stimulation (UK-14304) at 37 degrees C but dramatically inhibited the response at 28 degrees C. Indeed, these ROS inhibitors abolished the cold-induced increase in alpha2-AR constrictor activity. NAC (20 mmol/l) or MnTMPyP (50 micromol/l) also abolished the cold-induced activation of RhoA in human cultured vascular smooth muscle cells and the cold-induced mobilization of alpha2C-ARs to the cell surface in human embryonic kidney 293 cells transfected with the receptor. The combined results suggest that cold-induced constriction is mediated by redox signaling in smooth muscle cells, initiated by mitochondrial generation of ROS, which stimulate RhoA/Rho kinase signaling and the subsequent mobilization of alpha2C-ARs to the cell surface. Altered activity of ROS may contribute to cold-induced vasospasm occurring in Raynaud's phenomenon.

Acetylcysteine↗
PubMed1986

Effects of cold acclimation in dystrophic hamsters: reduction of heart necrosis.

The effects of cold acclimation on brown adipose tissue, heart, and skeletal muscles were evaluated to assess if the increase in metabolic activity associated with chronic exposure to 4 degrees C had any influence on the progression of the syndrome in dystrophic hamsters. Body weight gain was much slower in dystrophic animals kept at 22 degrees C and was unaffected by cold acclimation. Rates of O2 consumption and CO2 production were similar in normal and dystrophic hamsters kept at 22 degrees C, and both were increased in cold-acclimated normal and dystrophic animals. The amount of interscapular brown adipose tissue was about one-half of normal in dystrophic hamsters kept at 22 degrees C. In response to cold acclimation, as in normal hamsters, brown adipose tissue of dystrophic hamsters grew and increased its thermogenin content by more than fourfold. However, the concentration of thermogenin in isolated mitochondria remained unchanged. Heart ventricular hypertrophy was also observed in both normal and dystrophic hamsters after cold acclimation. The number and extent of cardiac necrotic lesions were significantly reduced in cold-acclimated dystrophic animals when compared with age-matched dystrophic hamsters kept at 22 degrees C. Heart calcium content and plasma creatine kinase levels were also reduced in dystrophic hamsters after cold acclimation. However, in soleus muscles the prevalence of centronucleated fibers, an indirect cumulative index of necrosis, as well as the extent of tissue necrosis were not significantly reduced in cold-acclimated dystrophic animals. Thus cold acclimation of dystrophic hamsters appeared to reduce necrosis predominantly in the heart.

Adaptation, Physiological↗
PubMed1995

Cold-induced alterations in uncoupling protein and its mRNA are seasonally dependent in ground squirrels.

We were interested in determining whether season affects the ability of cold exposure to increase brown adipose tissue (BAT) thermogenic function in 13-lined ground squirrels after acute and chronic cold (4 degrees C) exposure. Tissues were collected from animals in April and September after cold exposure for 12, 24, or 48 h. Animals chronically exposed to the cold (10 days) were killed in early May and mid-August. We found that mitochondrial uncoupling protein (UCP) concentrations varied seasonally, with concentrations in control animals (at 23 degrees C) higher in late summer (mid-August and September) than in the spring (April and early May). Cold exposure in late summer did not induce further increases in UCP concentrations. In contrast, when animals were cold exposed in the spring, UCP concentrations and total UCP increased. Surprisingly, 10 days at 4 degrees C did not cause a greater increase in UCP concentrations than did 24 h at 4 degrees C. Chronic cold exposure increased the UCP mRNA-to-beta-actin mRNA ratio 48% in May, whereas a fivefold increase occurred in August. GDP binding was increased after 12 h at 4 degrees C in April; in contrast, animals attempted to hibernate when placed in the cold in September, and no increase in GDP binding was observed. Chronic cold exposure caused GDP binding to increase at both times. These results indicate that mitochondrial UCP concentrations are seasonally regulated in the 13-lined ground squirrel.

Acclimatization↗