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Biomedical subjects

M J Blake

Publications and source records attributed to M J Blake.

At least 37 records · Page 2Linked to original sources
PubMed1993

Vascular heat shock protein expression in response to stress. Endocrine and autonomic regulation of this age-dependent response.

Adaptation to stress requires coordinated interactions between the vascular and endocrine systems. Previously we demonstrated that restraint stress induces the expression of the major heat shock protein, HSP70, in the adrenal cortex of the rat. Here we demonstrate that restraint also induces expression of HSP70 in the vasculature. We further demonstrate that the adrenal and vascular responses are differentially regulated: the adrenal response is adrenocorticotropin dependent, whereas the vascular response is under adrenergic control. In addition, the adrenal response is restricted to members of the HSP70 gene family, whereas in vascular tissue the low molecular weight HSP, HSP27, is also induced by restraint. Further characterization of the vascular response revealed that HSP70 induction occurred in both the thoracic and abdominal aortas as well as in the vena cava. However, no HSP70 induction was apparent in the heart or in a wide variety of other tissues examined. In situ hybridization showed that the vascular expression was localized to the aortic smooth muscle cells with minimal expression in the endothelium. Induction of HSP70 mRNA in both the adrenal cortex and aorta was followed by an elevation in HSP70 protein. Maximum HSP70 protein levels were seen within 3-12 h after restraint, but declined thereafter. Stress induced HSP70 expression was dramatically reduced with age, which may explain, in part, the diminished tolerance to stress seen in elderly individuals.

Adrenal Cortex↗
PubMed1993

Dopaminergic regulation of heat shock protein-70 expression in adrenal gland and aorta.

The induction of heat shock proteins (HSPs) by cellular stress and activation of the hypothalamic-pituitary-adrenal axis and sympathetic nervous system by physiological stress are biological responses that aid in the maintenance of cellular and organismal homeostasis, respectively. Based on previous studies, we have hypothesized that HSPs play a functional role in neural and endocrine stress response mechanisms in mammalian organisms. To determine the endocrine and/or neural components regulating stress-induced HSP70 expression in vivo, we have employed the long-acting synthetic propylergoline dopamine agonist CQP 201-403 (CQP). We report the novel observation that CQP mimics the effect of restraint stress to induce HSP70 expression in both adrenal gland and aorta of the rat. The presence of CQP-induced HSP70 mRNA and protein was preceded by the activation of a protein factor capable of binding to the heat shock transcriptional control element. CQP-induced HSP70 expression in the adrenal gland was restricted to the cortex, as previously observed in restraint-stressed animals. However, the distribution of expression among the three cortical layers was distinct. Hypophysectomy virtually eliminated the effects of CQP on the adrenal gland and markedly reduced HSP70 induction in the aorta. Collectively, these results provide evidence that dopaminergic systems contribute to the physiological regulation of HSP70 expression in adrenal gland and aorta directly through actions on receptors in responsive tissues and/or indirectly through the release of pituitary hormones.

Adrenal Cortex↗
PubMed1992

Concurrent bacterial lung infection in patients with AIDS, PCP, and respiratory failure.

STUDY OBJECTIVES: To determine and compare the incidence of concurrent bacterial lung infection in intubated and nonintubated patients with the acquired immunodeficiency syndrome (AIDS) and Pneumocystis carinii pneumonia (PCP) requiring medical intensive care unit (MICU) admission for support of their respiratory function. DESIGN: Retrospective review of medical records. SETTING: A large university hospital and AIDS treatment center. PATIENTS: All AIDS/PCP patients admitted to the MICU for support of oxygenation and/or ventilation between 1985 and 1989. Survival was defined as discharge from the hospital; nonsurvival was defined as death any time during the hospitalization. Patients with acute spinal cord injury (SCI) were used as controls to determine the incidence of nosocomial pneumonia in ICU patients of similar age without AIDS. MEASUREMENTS AND RESULTS: Twenty-nine AIDS/PCP patients met study criteria; eight (28 percent) were survivors and 21 (72 percent) were nonsurvivors. There was no significant difference in duration of intubation or duration of ICU stay between survivors and nonsurvivors with or without intubation. The incidence of bacterial concurrent lung infection (CLI) in AIDS/PCP patients overall was 7 percent and in intubated AIDS/PCP patients it was 10 percent. There was no statistically significant difference in the incidence of bacterial CLI between the survivors and nonsurvivors or between intubated and nonintubated patients with AIDS/PCP. The incidence of nosocomial pneumonia in SCI overall was 17 percent and in intubated SCI patients it was 30 percent. CONCLUSIONS: The incidence of bacterial lung infections in our retrospective study of AIDS patients with PCP is remarkably less than in the general ICU population with respiratory failure and in our control patients with SCI, although the differences did not attain statistical significance. This finding may be related to antimicrobial therapy directed against P carinii. Endotracheal intubation in patients with AIDS and PCP, who were undergoing appropriate antimicrobial therapy, did not result in a significantly higher incidence of bacterial lung infections than in those who were not intubated. There was no significant difference in the incidence of bacterial lung infections between those AIDS/PCP patients who survived episodes of severe respiratory failure and those who did not. Endotracheal intubation should not be delayed or withheld from this patient population due to concerns of pulmonary bacterial superinfection.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Cellular localization of retinoic acid receptor-gamma expression in normal and neoplastic skin.

Retinoids profoundly affect the normal growth and differentiation of epithelial tissues. Retinoic acid receptor-gamma (RAR-gamma) is a member of a family of retinoid receptors, and has been shown to be expressed almost exclusively in skin. However, little is known about the cellular localization of this receptor in human skin. The authors studied the expression of RAR-gamma in normal skin and human skin tumors by Northern blot analysis and in situ hybridization. RAR-gamma mRNA was detected in normal skin as well as in cultures of neonatal keratinocytes. Using an oligonucleotide specific for the RAR-gamma cDNA isoform 1 (RAR-gamma 1), RAR-gamma 1 mRNA was localized to all layers of the epidermis, the outer root sheath of hair follicles, follicular hair bulbs, eccrine and sebaceous glands. Basal cell carcinoma constitutively expressed gamma-1 mRNA and one of seven squamous cell carcinomas showed loss of gamma-1 mRNA expression, relative to adjacent epithelium. By contrast, normal melanocytic nevi and tumor-associated lymphocytes expressed little or no RAR-gamma mRNA. These results suggest that RAR-gamma 1 may play an important role in the maintenance and differentiation of normal epidermis and skin appendages.

Blotting, Northern↗
PubMed1991

Stress-induced heat shock protein 70 expression in adrenal cortex: an adrenocorticotropic hormone-sensitive, age-dependent response.

The induction of heat shock proteins (HSP) by cellular stress and the activation of the hypothalamic-pituitary-adrenal axis by physiologic stress are biological responses that aid in the maintenance of cellular and organismal homeostasis, respectively. In this report, restraint stress, known to activate the hypothalamic-pituitary-adrenal axis, is shown to induce expression of HSP70 mRNA selectively in the adrenal cortex of the rat. Restraint-induced HSP70 expression in the adrenals is rapid and is preceded by the activation of a protein factor capable of binding to the heat shock transcriptional control element. The ability of restraint to induce HSP70 expression in the adrenal is virtually eliminated in hypophysectomized rats but can be restored by the exogenous administration of adrenocorticotropic hormone. The magnitude of this induction declines as a function of increasing age, which may contribute to a reduced stress tolerance by aged animals. These results support a role for HSP70 in the physiologic stress response mediated by the hypothalamic-pituitary-adrenal axis.

Adrenal Cortex↗
PubMed1991

Loss of D2 receptors during aging is partially due to decreased levels of mRNA.

Corpora striata of old rats (24-25 months) contain only about half as much mRNA for D2 dopamine receptors as those of young (6 months) counterparts. This reduction can be observed by in situ hybridization of brain slices as well as with Northern and dot blot analyses of striatal extracts. Decreased levels of D2 receptor mRNA as described in this study are consistent with reductions in receptor containing neurons (20%) and receptor biosynthesis (40%), as previously observed in this and other laboratories. Thus, age related changes in D2 receptor gene expression appear to be partially responsible for loss of these receptors.

Aging↗
PubMed1991

Concomitant decline in heat-induced hyperthermia and HSP70 mRNA expression in aged rats.

An age-related impairment in the induction of heat-shock proteins (HSPs), which are thought to comprise a protective or adaptive response to cellular stress, may contribute to a reduction in thermal tolerance with age. When 5- and 24-mo-old rats were exposed to ambient temperatures of 23, 35, 37.5, or 40 degrees C for 90 min, a graded increase in the level of HSP70 mRNA expression was observed in brain, lung, and skin of animals from both groups. However, at temperatures above 23 degrees C, HSP70 expression was less in tissues of older rats when compared with those of young animals. This relative decline of heat-induced HSP70 mRNA levels with age correlated with an attenuated increase in colonic temperature (Tc) of old rats resulting from heat exposure. In other experiments, it was determined that the duration of hyperthermia was also an important factor in determining the level of HSP70 mRNA expression in vivo. Thus age-related differences in heat-induced HSP70 mRNA expression appear to result from differences in Tc due to heat stress rather than an impairment in the regulation of HSP70 gene expression.

Aging↗
PubMed1991

Molecular response to surgical stress: specific and simultaneous heat shock protein induction in the adrenal cortex, aorta, and vena cava.

The endocrine response to surgical stress results in activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. The cellular response to a wide variety of stresses results in the synthesis of a family of stress response proteins termed heat shock proteins. Potential interactions between endocrine and cellular stress responses have not been investigated in vivo. A surgical model was developed to define the genetic response to surgical stress. Wistar rats underwent ether anesthesia, laparotomy, hemorrhage, and variable recovery periods. Tissues were subsequently harvested and the RNA was isolated and probed for HSP70 messenger RNA levels. These studies showed a strong induction of HSP70 but only in the adrenal gland, aorta, and vena cava. This specific induction was rapid, occurring 30 minutes after surgery, and dramatic (greater than twentyfold induction). The induction occurred in parallel with HPA axis activation and was adrenal cortical specific as determined by in situ hybridization. These observations suggest a functional interaction between the molecular stress response and HPA axis activation.

Adrenal Cortex↗
PubMed1990

Discordant expression of heat shock protein mRNAs in tissues of heat-stressed rats.

Although the induction of heat shock proteins (HSP) has been studied extensively in cultured cells, comparatively few studies have examined their expression in vivo. In this report, mRNA expression of two HSP families, HSP70 and HSP27, was investigated in brain, liver, lung, and skin of rats exposed to elevated ambient temperatures. The time course and relative magnitude of the heat-induced expression for these two HSP differed between tissues of the same animal. Even within the same tissue, HSP70 and HSP27 displayed differential kinetics of induction. In brain, lung, and skin, induction of HSP70 was dependent on the duration and temperature of the heat stress. This induction was transient with maximal HSP70 expression occurring at 1 h and returning to baseline 3 h after removal of the animals from heat stress. In liver, HSP70 expression did not show a direct relationship with temperature conditions and maximal induction did not occur until 6 h after heat stress. Heat-induced HSP27 expression was dependent on time and temperature of exposure in lung and skin but not in brain and liver. These findings demonstrate that the heat shock response in vivo lacks much of the coordinate control of expression characteristic of cultured cell populations and suggest that mechanisms controlling this cellular stress response are influenced by physiologic factors that cannot be studied in vitro.

Animals↗
PubMed1990

In vivo hyperthermia induces expression of HSP70 mRNA in brain regions controlling the neuroendocrine response to stress.

Regional localization of HSP70 expression in brain of rats exposed to increased ambient temperatures was examined using in situ hybridization. In addition to the cerebellar granule cell layer and choroid plexus, selective hybridization was observed in the hippocampal dentate gyrus, paraventricular and dorsomedial hypothalamic nuclei, median eminence, and medial habenula. Apparently, cells in brain regions coordinating the neuroendocrine response to stress show a preferential induction of cellular stress proteins in response to heat.

Animals↗
PubMed1989

Punishment modifies the effects of chlordiazepoxide and benzodiazepine receptors.

Littermate groups of male albino rats responded under a procedure which generated comparable rates of punished and nonpunished responding. Chlordiazepoxide (3.0-30.0 mg/kg, IP) increased punished responding but had no effect on nonpunished responding. Homogenate receptor binding studies with [3H]Ro 15-1788 indicated increased benzodiazepine receptor binding in the striatum of rats who received shock. Moreover, a third group of rats exposed to noncontingent shock showed greater increases than those whose responses had been punished, suggesting that predictability and control of shock may have attenuated the effects of the noxious stimulus. Increased binding seen in the cerebellum, however, was related to the punishing effects of the electric shock since it occurred only in those animals receiving response-contingent shock. There were no changes in binding affinity in any of the brain regions tested. Site-specific alterations benzodiazepine receptors following electric footshock are related to the contingencies under which the noxious stimuli are administered. Furthermore, changes in benzodiazepine receptor binding may underlie the differential effects of benzodiazepine agonists on punished and nonpunished responding.

Animals↗
PubMed1987

Brain stimulation of the ventral tegmental area attenuates footshock escape: an in vivo autoradiographic analysis of opiate receptors.

An in vivo autoradiographic technique was employed to visualize discrete neuroanatomical changes in opiate receptor binding as a result of aversive footshock (FS) and rewarding electrical brain stimulation (ICS). Footshock-induced escape responding was shown to be attenuated by the simultaneous presentation of non-contingent ICS. Rats were divided into 4 groups (n = 6) receiving ICS, FS, ICS + FS or neither stimulus in an escape paradigm. During the final behavioral test session, rats were injected with 0.002 mg/kg [3H]diprenorphine ( [3H]Dpr) and subsequently prepared for autoradiography. Results indicated two groups of brain areas distinguishable by their treatment-induced changes in [3H]Dpr binding. One group of areas included the nucleus accumbens, claustrum, claustrocortex, perirhinal cortex and ventral tegmental area. These structures showed increased binding due to both FS and ICS. The other group consisted of the diagonal band of Broca, bed nucleus of the stria terminalis, lateral hypothalamus-medial forebrain bundle and amygdala. In these regions, an increase in binding ipsilateral to the electrode was observed in animals receiving ICS with no apparent effect of FS. These results demonstrate that non-contingent ICS may not be strictly aversive and suggest an anatomic, opioid-sensitive basis for both a rewarding and aversive component of this stimulus. It appears, further, that ICS can inhibit the release of endogenous opioid peptides in areas along the mesotelencephalic dopamine pathways, possibly to regulate the activity of neurons conveying reward information. Finally, the observed changes in opiate receptor binding may indicate a mechanism for ICS to produce both drive and reward.

Animals↗
PubMed1987

Drinking-induced alterations in reward pathways: an in vivo autoradiographic analysis.

An in vivo autoradiographic technique permitted the visualization of discrete neuroanatomical changes in opiate receptor binding as a result of 23-h water deprivation and drinking. Two groups of rats (n = 5) were placed on a 23-h water deprivation schedule for 10 days. On the last day, one group was given access to water for 15 min. These groups, plus a matched ad libitum water control group (n = 5), received an injection of 0.002 mg/kg [3H]diprenorphine ([3H]Dpr) through chronically implanted jugular catheters followed by preparation for opiate receptor autoradiography. Relative cerebral blood flow was estimated non-quantitatively by the injection of 75 microCi/kg iodo-[14C]antipyrene into 3 additional groups identically treated. Results indicated that water-deprivation stress increased [3H]Dpr binding in the claustrum, lateral hypothalamus, amygdala and ventral tegmental area while decreasing binding in the medial frontal cortex, lateral septum, dorsolateral thalamus and central gray. All effects of water deprivation were reversed in animals receiving water. Observations of changes in relative blood flow were shown to have no correlation with changes in opiate receptor binding. It appears that water deprivation stress causes a reduction in opioid release in areas along the mesotelencephalic dopamine pathway which may contribute to a drive state. Water intake may then reduce or otherwise alter the drive state through the release of opioids along these pathways, contributing to the perception of reward.

Animals↗
PubMed1984

Drinking behavior is modulated by CNS administration of opioids in the rat.

While opiate antagonists have been shown to reliably attenuate drinking following both central and peripheral administration, relatively few data exist on the effects of agonist agents on this behavior. To address this issue, two opiate agonists, morphine sulfate, a mu agonist, and [D-ala2, D-leu5]-enkephalin (DADLE), a semi-synthetic delta analog of a delta agonist, were administered into several CNS sites in rats. There was a dose-related, naloxone-reversible reduction of water intake following morphine injections into the lateral hypothalamus (LH) and preoptic area (POA). In addition, injections of DADLE also attenuated drinking when injected into LH and POA, but not following the ventral tegmental area or zona incerta administration. These data are discussed in view of a role for the endogenous opioid peptides in the regulation of drinking behavior.

Animals↗
PubMed1983

Naloxone-induced hypodipsia: a CNS mapping study.

Opiate antagonists have been shown to reliably attenuate drinking behavior. Recent research points to a central site of action for this antidipsogenic effect. To pursue this issue of site specificity, naloxone, a specific opiate antagonist, was delivered into a number of discrete subcortical areas in 23 hour water-deprived rats. Water intake was measured at 5, 15, 30 and 60 minutes post drug injection. Compared to saline control injections, naloxone reliably depressed water intake, in a dose-related manner, in lateral hypothalamus, preoptic area and zona incerta. Previous research has repeatedly implicated these areas in drinking behavior. Placements which were not generally effective included lateral ventricle, nucleus accumbens, substantia nigra and cortex/corpus callosum. Latency to drink was never affected by any dose of naloxone injected into any site, suggesting an opioid influence on mechanisms involved in termination and/or maintenance rather than on initiation of drinking.

Animals↗