Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of brain cytochrome P450 (P450) in regulating the levels of the potent anesthetic steroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha-OH-DHP) has been investigated. By analogy with the elimination of androgen from its target tissues, we present evidence that it is 3 beta-hydroxy-5 alpha-pregnan-20-one (3 beta-OH-DHP) and not 3 alpha-OH-DHP that represents the major pathway for the formation of more polar metabolites and thus the elimination of the 5 alpha-reduced metabolites of progesterone from target tissues. No polar metabolites were formed when 3 alpha-OH-DHP was incubated with microsomal fractions prepared from rat brain, but 3 beta-OH-DHP was hydroxylated at the 6 alpha- and 7 alpha-positions. These 3 beta-diols were not formed to any detectable extent in the liver or kidney but were formed in prostate, pituitary, brain, and breast. The highest catalytic activity, 512 nmol of products formed/g of tissue/hr, was found in the prostate. The corresponding rates in the pituitary, brain, and breast were 71.9, 28.1, and 6.7 nmol/g/hr, respectively. These hydroxylations were confirmed to be P450-catalyzed reactions by solubilization of the P450 from prostate, brain, and breast microsomes and reconstitution of the catalytic activity with NADPH-P450 reductase (EC 1.6.2.4) and lipid. Because 5 alpha-androstane-3 beta,17 beta-diol (3 beta-Adiol) has been shown to be a good substrate for prostate and brain P450, competition experiments were performed to determine whether the same form of P450 is involved in the elimination of 3 beta-Adiol and 3 beta-OH-DHP in the brain. These two substrates competed with each other for metabolism in microsomal fractions and in reconstitution experiments with P450 extracted from the brain or prostate. To test the hypothesis that the hydroxylation of 3 beta-OH-DHP represents a pathway for regulation of the level of 3 alpha-OH-DHP in the brain, the effect of inhibition of the hydroxylation of 3 beta-OH-DHP on the duration of 3 alpha-OH-DHP-induced anesthesia was examined. The nonanesthetic steroid 3 beta-Adiol was used as a competitive inhibitor of the metabolism of 3 beta-OH-DHP. The duration of anesthesia upon intravenous administration of 3 alpha-OH-DHP was increased by 33% when 3 beta-Adiol was coadministered.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Pharmacol 1993 Nov
PMID:Role of brain cytochrome P450 in regulation of the level of anesthetic steroids in the brain. 824 11

Neuropeptide Y (NPY) has a stimulatory effect on adrenocorticotropin (ACTH) and corticotropin-releasing factor (CRF) release. In the present study, to investigate the effect of NPY on CRF synthesis, the effect of centrally administered NPY on CRF messenger RNA (mRNA) levels in rat hypothalamus was examined under pentobarbital anesthesia. The administration of 0.01, 0.1 and 1 nmol of NPY into the lateral ventricle dose-dependently Increased the plasma ACTH levels, as well as the levels of proopiomelanocortin mRNA in the anterior pituitary. The CRF mRNA level in the hypothalamus also increased after administration of 0.1 and 1 nmol of NPY in a dose-dependent manner. The administration of 3 nmol of phentolamine or propranolol failed to block 0.1 nmol NPY-induced ACTH release or 1 nmol NPY-stimulated CRF mRNA levels in the hypothalamus. These results Indicate that the central administration of NPY increases the CRF mRNA levels in the hypothalamus and the probable CRF release, which increases the proopiomelanocortin mRNA levels and ACTH secretion in the anterior pituitary. Therefore, NPY seems to play a physiological role in the regulation of the release and synthesis of CRF in the hypothalamus.
Brain Res Mol Brain Res 1993 Jun
PMID:Neuropeptide Y increases the corticotropin-releasing factor messenger ribonucleic acid level in the rat hypothalamus. 839 33

Previous studies showed that anaesthesia with the barbiturate Thiopental induces an increase in membrane fluidity and a decrease in acetylcholinesterase activity in syncytiotrophoblast plasma membranes (SPM) obtained from placentas after Cesarean section. The aim of the present work was to compare the effect of a local anaesthetic (bupivacaine hydrochloride, trade name Marcaine) on SPM in vivo and to establish whether the anaesthetic is still present in the membrane after tissue preparation. The acetylcholinesterase activity was lower in Marcaine-anaesthetized SPM (27 +/- 3 against 39 +/- 6 in the control). The Marcaine action on the SPM can be ascribed to a competitive inhibition, similar to that reported for Thiopental. Fluorescence studies of the order parameter P showed it to be higher in SPM obtained from control (0.253 +/- 0.012) than in SPM obtained from Marcaine-exposed membranes (0.240 +/- 0.015). The local anaesthetic is still present in the SPM after their preparation (20.1 ng per mg membrane protein). It appears that the local anaesthetic exhibits an effect similar to that of the general anaesthetic, apparently due to binding to the membrane.
Biochem Mol Biol Int 1993 Mar
PMID:Local anaesthetic effects on trophoblast membrane fluidity. 848 67

The effects of intracerebroventricular and intrahypothalamic injections of picrotoxin, a GABA antagonist, on gastric acid secretion were studied in perfused stomachs of rats under anesthesia. Injection of picrotoxin into the lateral cerebroventricle inhibited the 2-deoxy-D-glucose-stimulated acid secretion. In experiments of intrahypothalamic injections, picrotoxin produced a significant depression of 2-deoxy-D-glucose-stimulated acid secretion when administered to the ventromedial hypothalamus but not to the lateral hypothalamus. In contrast, picrotoxin produced a definite stimulatory effect on basal acid secretion when injected to the lateral hypothalamus or ventromedial hypothalamus; the stimulatory effect of the injection to the lateral hypothalamus was greater than that of the injection to the ventromedial hypothalamus. These findings indicate that picrotoxin acts centrally, probably hypothalamus, to depress the 2-deoxy-D-glucose-stimulated acid secretion. On the other hand, blockade of GABA activity in the lateral hypothalamus or ventromedial hypothalamus may elicit gastric acid secretion. These results, indicate that central GABAergic mechanism is important in regulating gastric acid secretion in the rat.
Res Commun Mol Pathol Pharmacol 1995 Aug
PMID:Effect of intracerebroventricular and intrahypothalamic administrations of picrotoxin on basal and stimulated gastric acid secretion. 855 69

An oxygen electrode equipped with a thermocouple enabled us to determine the absolute oxygen tension (PO2) in brain regions by taking account of local changes in temperature. Under urethane anesthesia, the PO2 of rat cerebral cortex was significantly increased up to 90 min after N-methyl-DL-aspartate administration (200 mg/kg, i.p.). This suggests that stimulation of NMDA receptors enhances oxygen supply to the cerebrum in vivo.
Res Commun Mol Pathol Pharmacol 1995 Oct
PMID:Increase in oxygen tension after intraperitoneal N-methyl-DL-aspartate in rat cerebral cortex. 858 41

Progesterone and its metabolites have a variety of diverse effects in the brain, uterus, smooth muscle, sperm and the oocyte. The effects include changes in electrophysiological excitability, induction of anesthesia, regulation of gonadotropin secretion, regulation of estrogen receptors, modulation of uterine contractility and induction of acrosome reaction and oocyte maturation. The latency of the effects vary from several seconds to several hours. Thus, it is not surprising that multiple mechanisms of action are involved. The classical mechanism of steroid hormone action of intracellular receptor binding has been supplemented by the possibility of the steroid acting as a transcription factor after the binding of the receptor protein to DNA. Other mechanisms include influence of the steroids on membrane fluidity and acting through other cell signalling systems, membrane receptors and GABA(A) receptors. Of particular interest are multiple mechanisms for the same types of action. For example the effect of progesterone on gonadotropin release is largely exerted via the classical intracellular receptor as well as membrane receptors, whereas 3(alpha),5(alpha)-tetrahydroprogesterone-induced LH release occurs via the GABA(A) receptor system. The inhibition of uterine contractility by progesterone is regulated by progesterone receptors while the action of 3(alpha),5(alpha)-tetrahydroprogesterone on uterine contractility is regulated by GABA(A) receptors. The regulation of the differences in the pattern of progesterone effects on estrogen receptor dynamics in the anterior pituitary and the uterus in the same animal are also of considerable interest.
J Steroid Biochem Mol Biol 1996 Jan
PMID:Diverse modes of action of progesterone and its metabolites. 860 42

Estrogen treatment increases preproenkephalin (PPE) mRNA levels in the ventromedial nucleus of the hypothalamus (VMH). Roy et al. (Brain Res., 337 (1985) 163-166) discovered that anesthesia during estrogen priming could reduce female rat sexual receptivity. In the present study we tested whether the action of estrogen to induce PPE gene expression in the VMH could be similarly affected by anesthesia. By quantitative in situ hybridization and slot-blot analysis techniques we found a 1.8-fold increase in PPE mRNA levels in the VMH after 1 hour of estrogen treatment in ovariectomized (OVX) Sprague-Dawley female rats. Anesthetizing the rats with pentobarbital for 1 h during the exposure to estrogen blocked the estrogen induction of PPE mRNA in the VMH. By way of contrast no changes in the PPE mRNA levels were observed in the caudate putamen. A similar trend was seen using chloral hydrate. It appears that neuronal activity is required for the early phase of estrogen induction of PPE mRNA levels in the VMH. This in turn could be correlated with changes in female sociosexual behaviors.
Brain Res Mol Brain Res 1996 Jan
PMID:Anesthesia during hormone administration abolishes the estrogen induction of preproenkephalin mRNA in ventromedial hypothalamus of female rats. 871 66

The aim of the present study was to investigate whether the pre-ischemic and post-ischemic hemodynamic function of the heat-shocked rat heart is affected by changes in afterload and extracellular calcium concentrations ([Ca2+]e). Experiments were performed on isolated, ejecting Lewis rat hearts 24h after in vivo heat shock (LewHS) or anesthesia alone (Lewc). In vitro hearts were subjected to 60 min normoxic perfusion, 45 min global ischemia, and 60 min of reperfusion. Pre-ischemic and post-ischemic left ventricular performance was evaluated at [Ca2+]e ranging between 0.65 and 3.0 mM at afterloads of 8.0 kPa and 16.0 kPa. At 8.0 kPa, pre-ischemic function was comparable in LewHS and Lewc at [Ca2+]e equal to or above 2.25 mM. At lower [Ca2+]e, i.e., 0.65 and 1.25 mM, cardiac output (CO) was significantly lower in LewHS than in Lewc hearts. At 16.0 kPa, significantly lower CO values were found in LewHS than Lewc hearts at all [Ca2+]e levels. During post-ischemic reperfusion under basal conditions (8.0 kPa; [Ca2+]e = 2.25 mM) a significantly better recovery was observed in LewHS than Lewc hearts, persisting at [Ca2+]e equal to 1.25 mM. However, either by lowering [Ca2+]e to 0.65 mM or increasing afterload to 16.0 kPa (at all [Ca2+]e), heat shock-associated improvement of post-ischemic performance disappeared. In conclusion, pre-ischemic left ventricular performance of the isolated heat-shocked heart is depressed when it performs at low [Ca2+]e or against a relatively high afterload. The heat shock-mediated improvement of post-ischemic function is only present at relatively low afterload levels in combination with normal extracellular calcium concentrations.
J Mol Cell Cardiol 1996 Feb
PMID:Inability of the heat-shocked heart to adjust its pre-ischemic and post-ischemic performance to variable loading conditions. 872 61

Studies of cardiovascular physiology are frequently performed under barbiturate anesthesia even though the effect of barbiturates on the pressor response to catecholamines is controversial, and their effect on the response to other agonists is unknown. The effect of pentobarbital (PB) anesthesia on the pressor and heart rate (HR) dose responses to norepinephrine (NE), angiotensin II (AII), vasopressin (VP) and neuropeptide Y (NPY) was studied in vivo in normal and endotoxemic rats. Four groups of rats (5-6 rats/group) were studied for each agonist: 1) anesthetized/endotoxemic, 2) anesthetized/control, 3) conscious/endotoxemic, and 4) conscious/control. Anesthesia was maintained with 10 mg/kg of PB i.v. q 45 minutes. Endotoxemia was established by infusion of a non-hypotensive dose of E. coli lipopolysaccharide 0127:B8, (LPS, 10 micrograms/10 microliters/min) throughout the experiment. One hour after the LPS (or saline control) infusion was started, dose response curves of the pressor and HR responses to agonists were established. LPS infusion resulted in marked suppression of the pressor response to NE, AII, and VP in both conscious and anesthetized rats. LPS infusion suppressed the response to NPY in conscious, but not in anesthetized rats. LPS did not affect the baroreceptor reflex. In both normal and endotoxemic rats, PB anesthesia suppressed the pressor response and attenuated the baroreceptor reflex to AII and NPY, enhanced the pressor response without affecting the heart rate response to NE, and attenuated the baroreceptor reflex to VP. The pressor response to VP was suppressed by anesthesia in normal, but not in endotoxemic rats. PB anesthesia interferes with the cardiovascular effects of different agonists in a variable manner, depending on the agonist tested and the presence or absence of endotoxemia, indicating their different modes of action. These effects should be considered when planning in vivo experiments with these and other agonists.
Res Commun Mol Pathol Pharmacol 1995 Nov
PMID:Effect of pentobarbital anesthesia on the pressor response to agonists in vivo in normal and endotoxemic rats. 874 96

The proteinase inhibitor set in skeletal muscle is poorly characterized at present. This study was aimed to investigate in mouse skeletal muscle 1) the tissue-associated counterpart, if any, of serum protease inhibitors (which may also play antiproteolytic functions in tissues) and 2) calpastatin, a tissue inhibitor of calcium-activated neutral proteases (calpains). Triton-extracts were prepared from muscle homogenates of mice, which had been perfused extensively with phosphate buffered saline (PBS) (under deep anesthesia) to remove blood inhibitors. Among various inhibitors tested, the following muscle-associated inhibitors were identified by western-blotting: alpha-2-macroglobulin (185, 165, 35 kDa), alpha-1-antitrypsin (52 kDa), inter-alpha-trypsin inhibitor (220, 180 kDa) and calpastatin (70 kDa). Combined light microscope and confocal immunohistochemical experiments revealed that, in all muscles examined (soleus, plantaris, extensor digitorum longus) the above specific immunoreactivities were localized outside the muscle fibers (in periendomysium, blood vessel wall) as well as within them. Inter-alpha-trypsin inhibitor, however, completely lacked the intracellular localization. This wide distribution of proteinase inhibitors suggests that numerous muscular structures may be normally protected from unwanted proteolysis, thus providing an essential background for further studies on pathological models with altered proteolysis (m. dystrophy, denervation atrophy, etc.).
Cell Mol Biol (Noisy-le-grand) 1996 Jun
PMID:Protease inhibitors in mouse skeletal muscle: tissue-associated components of serum inhibitors and calpastatin. 882 9


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