Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “actionable alterations”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 469 records · Page 26Linked to original sources
PubMed1984

Alterations in hepatic heme and cytochrome P-450 metabolism in Murphy-Sturm lymphosarcoma-bearing rats. Implications for drug metabolism.

Previous studies have shown that tumor-bearing rats have significantly decreased hepatic microsomal cytochrome P-450 content and NADPH-cytochrome c reductase activity with, consequently, significantly decreased capacity for microsomal oxidative drug metabolism. Subsequent investigations have revealed that the rates of hepatic cytochrome P-450 apo-protein synthesis and degradation are decreased significantly and hepatic microsomal heme oxygenase activity is increased significantly in rats bearing an extra-hepatic tumor. Further studies have been done to attempt to clarify the pathogenesis and significance of these observations. Hepatic delta-aminolevulinic acid (ALA) synthetase activity in male Wistar rats declined to a nadir of 162 +/- 34 (S.E.) pmoles ALA per mg protein per 30 min 6 days following i.m. transplantation of Murphy-Sturm lymphosarcoma (vs control = 218 +/- 36 pmoles per mg per 30 min). Turnover of 3H-labeled heme in microsomal CO-binding particles (i.e. cytochrome P-450 heme) was increased significantly 8 days following i.m. transplantation of Murphy-Sturm lymphosarcoma with a T 1/2 of 5.5 hr for the fast phase of hepatic cytochrome P-450 heme disappearance in tumor-bearing rats as compared with a T 1/2 of 7 hr in control rats. Hepatic cytochrome P-450 apo-protein concentration was slightly, but not significantly, increased in Murphy-Sturm lymphosarcoma-bearing rats as compared with control rats up to 10 days following tumor transplantation. These results suggest that, in Murphy-Sturm lymphosarcoma-bearing rats, decreased microsomal cytochrome P-450 concentration is the result of both decreased cytochrome P-450 apo-protein synthesis and increased cytochrome P-450 heme turnover. Apo-cytochrome P-450 concentration was not appreciably altered because increased cytochrome P-450 heme turnover and decreased cytochrome P-450 apo-protein degradation were balanced by decreased cytochrome P-450 apo-protein synthesis. Because of their effects on cytochrome P-450 concentration and action, these alterations in heme and hemoprotein metabolism may be of importance in regulating oxidative drug metabolism in the tumor-bearing state.

5-Aminolevulinate Synthetase↗
PubMed2005

Cooperative binding of the leucine-responsive regulatory protein (Lrp) to DNA.

The leucine-responsive regulatory protein (Lrp) of Escherichia coli activates expression of a number of operons and represses expression of others. For some members of the Lrp regulon, exogenous leucine mitigates the effect of Lrp, for some it potentiates the effect of Lrp, and for others it has no effect on Lrp action. For the ilvIH operon that we study, Lrp activates expression in vivo and mediates the repression of the operon by exogenous leucine. We studied Lrp-1, a leucine-insensitive variant, to investigate mechanisms by which leucine alters Lrp action as an activator of ilvIH expression. The Asp114Glu change did not have much effect on the amount of total Lrp-1 in cells but decreased the amount of free Lrp-1 two- to threefold. Lrp monomers associate to form octamers and hexadecamers (hexadecamer form predominates at micromolar concentrations; Kd=5.27x10(-8) M), and leucine promotes the dissociation of Lrp hexadecamer to a leucine-bound octamer. By contrast, Lrp-1 exists primarily as an octamer in solution (equilibrium dissociation constant 6.5x10(-5) M) and leucine had little effect on the equilibrium. Thus, the hexadecameric form that Lrp assumes in the absence of DNA is not required for activation of the ilvIH operon. Both leucine and the lrp-1 mutation reduced the apparent affinity of Lrp binding to ilvIH DNA (contains two groups of binding sites separated by 136 bp) but they have different effects on intrinsic binding affinity and binding cooperativity. Whereas leucine reduced intrinsic binding affinities and interactions of Lrps bound at upstream and downstream regions of ilvIH DNA, it increased cooperative dimer-dimer interactions of Lrps bound to two adjacent sites. By contrast, the lrp-1 mutation did not have much effect on intrinsic binding affinities but it decreased cooperative adjacent dimer-dimer interactions and enhanced interactions of Lrps bound at upstream and downstream regions of ilvIH DNA. Our analysis is consistent with the idea that leucine enhances dimer-dimer interactions that contribute to octamer formation, concomitantly reducing dimer-dimer interactions that contribute to the longer range interactions of Lrps that are required for activation of the ilvIH promoter.

Acetolactate Synthase↗
PubMed1998

Sparfloxacin but not levofloxacin or ofloxacin prolongs cardiac repolarization in rabbit Purkinje fibers.

Sparfloxacin, a fluoroquinolone antibacterial, has been reported to prolong cardiac repolarization in some patients. In this study, we have investigated the in vitro cardiac electrophysiological effects of two other fluoroquinolones, levofloxacin and ofloxacin, and compared them with those exerted by sparfloxacin. Cardiac action potentials have been recorded from rabbit Purkinje fibers using conventional glass microelectrodes. The influence of a sudden decrease in stimulation rate on repolarization is examined. It is found that ofloxacin and levofloxacin (1-100 microM) do not alter the action potential parameters even at a concentration as high as 100 microM. The stimulation rate is without effect on repolarization. On the contrary, sparfloxacin (1-100 microM) lengthens concentration-dependently the duration of action potential, this effect being significant from the concentration of 10 microM. A non significant decrease in maximal rate of rise of phase 0 depolarization was observed at the concentration of 100 microM. Under low stimulation rate, the sparfloxacin-induced prolonging effect was magnified and early afterdepolarizations occurred in one of seven fibers from the concentration of 30 microM and in four other fibers at the concentration of 100 microM. These results suggest that levofloxacin and ofloxacin had no effect on cardiac cellular electrophysiology whereas sparfloxacin exerts pure class III electrophysiological effects, which can explain the prolongation of QT interval observed clinically in some patients and might become arrhythmogenic in the presence of other predisposing factors.

Action Potentials↗
PubMed2006

Glucose, insulin, and leptin signaling pathways modulate nitric oxide synthesis in glucose-inhibited neurons in the ventromedial hypothalamus.

Glucose-sensing neurons in the ventromedial hypothalamus (VMH) are involved in the regulation of glucose homeostasis. Glucose-sensing neurons alter their action potential frequency in response to physiological changes in extracellular glucose, insulin, and leptin. Glucose-excited neurons decrease, whereas glucose-inhibited (GI) neurons increase, their action potential frequency when extracellular glucose is reduced. Central nitric oxide (NO) synthesis is regulated by changes in local fuel availability, as well as insulin and leptin. NO is involved in the regulation of food intake and is altered in obesity and diabetes. Thus this study tests the hypothesis that NO synthesis is a site of convergence for glucose, leptin, and insulin signaling in VMH glucose-sensing neurons. With the use of the NO-sensitive dye 4-amino-5-methylamino-2',7'-difluorofluorescein in conjunction with the membrane potential-sensitive dye fluorometric imaging plate reader, we found that glucose and leptin suppress, whereas insulin stimulates neuronal nitric oxide synthase (nNOS)-dependent NO production in cultured VMH GI neurons. The effects of glucose and leptin were mediated by suppression of AMP-activated protein kinase (AMPK). The AMPK activator 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) increased both NO production and neuronal activity in GI neurons. In contrast, the effects of insulin on NO production were blocked by the phosphoinositide 3-kinase inhibitors wortmannin and LY-294002. Furthermore, decreased glucose, insulin, and AICAR increase the phosphorylation of VMH nNOS, whereas leptin decreases it. Finally, VMH neurons express soluble guanylyl cyclase, a downstream mediator of NO signaling. Thus NO may mediate, in part, glucose, leptin, and insulin signaling in VMH glucose-sensing neurons.

AMP-Activated Protein Kinase Kinases↗
PubMed2006

Kinase-specific phosphorylation of the estrogen receptor changes receptor interactions with ligand, deoxyribonucleic acid, and coregulators associated with alterations in estrogen and tamoxifen activity.

Posttranslational modifications of the estrogen receptor (ER) are emerging as important regulatory elements of cross talk between different signaling pathways. ER phosphorylation, in particular, has been implicated in the ligand-independent effects of ER and in tamoxifen resistance of breast tumors. In our studies, Western immunoblot analysis of endogenous ER in parental MCF-7 cells reveals specific, ligand-dependent phosphorylations at S118 and S167, with this ligand dependence being lost in tamoxifen-resistant, MCF-7 Her2/neu cells. Using highly purified components and sensitive fluorescence methods in an in vitro system, we show that phosphorylation by different kinases alters ER action through distinct mechanisms. Phosphorylation by Src and protein kinase A increases affinity for estradiol (E2), whereas ER phosphorylation by MAPK decreases trans-hydroxytamoxifen (TOT) binding. Affinity of ER for the consensus estrogen response element is also altered by phosphorylation in a ligand-specific manner, with decrease in affinity of MAPK- and Src-phosphorylated ER in the presence of TOT. ER phosphorylation by MAPK, AKT, or protein kinase A increases recruitment of steroid receptor coactivator 3 receptor interaction domain to the DNA-bound receptor in the presence of E2. Taken together, these results suggest that ER phosphorylation alters receptor functions (ligand, DNA, and coactivator binding), effecting changes that could lead to an increase in E2 agonism and a decrease in TOT antagonistic activity, reflecting changes encountered in tamoxifen resistance in endocrine therapy of breast cancer.

Breast Neoplasms↗
PubMed1980

Somatostatin: an endogenous peptide in the toad urinary bladder inhibits vasopressin-stimulated water flow.

Somatostatin (somatotropin release-inhibiting factor; SRIF) is a tetradecapeptide present in brain, pancreas, gastrointestinal tract, and thyroid that inhibits the secretion or action of several hormones in these tissues. We observed that the toad urinary bladder contains concentrations of endogenous somatostatin (8.0 pg/micrograms of protein) comparable to those found in the mammalian pancreas and gastrointestinal tract. To determine if somatostatin directly alter the action of vasopressinn we studied the effects of this polypeptide on vasopressin-stimulated transport processes in the toad urinary bladder in vitro. Somatostatin produced a dose-dependent, reversible inhibition of vasopressin-stimulated osmotic water flow; it inhibited theophylline-stimulated osmotic water flow but not the water flow stimulated by 8-p-chlorophenylthioadenosine 3',5'-cyclic monophosphate. These data are consistent with an inhibition of both basal and hormone-stimulated adenylate cyclase. Vasopressin-stimulated short circuit current was not inhibited by somatostatin. These studies provide direct evidence for an effect of somatostatin on hormone-modulated epithelial transport in tissues other than the gastrointestinal tract. We propose that endogenous somatostatin may function as a local regulator of the cellular action of vasopressin on osmotic water flow.

Animals↗
PubMed2001

Drug transfer through mucus.

Mucus is a complex aqueous mixture of glycoprotein, lipid, salts and cellular debris covering many epithelial surfaces in the human body. It affords protection for the underlying tissues from various environmental insults and the effects of enzymes or other chemical agents. In performing its functions, mucus may adversely affect the absorption or action of drugs administered by the oral, pulmonary, vaginal, nasal or other routes. The nature of mucous in normal and diseased states is summarized and discussed in this review. The study of the permeability of native or purified mucous gels is also important to understanding how it may alter the action or absorption of drugs that come in contact with epithelial surfaces. Various methods for studying mucous permeability and models for analyzing permeation data are discussed. A compilation of drug permeability data through various types of mucus is included. Drug binding to mucus is also important to understanding the relative importance of hindered diffusion versus drug binding to altered permeability through mucous layers. This is discussed with methods for and results of drug-mucus binding studies.

Absorption↗
PubMed1990

Cardiac electrophysiologic properties of bupivacaine and lidocaine compared with those of ropivacaine, a new amide local anesthetic.

Ropivacaine is a new amino-amide local anesthetic whose anesthetic profile appears similar to that of bupivacaine. Moreover, in intact animals ropivacaine was reportedly less arrhythmogenic than bupivacaine. These experiments evaluated the cardiac transmembrane electrophysiologic effects of ropivacaine compared with those of lidocaine and bupivacaine in an isolated rabbit Purkinje fiberventricular muscle preparation. Only bupivacaine (3-5 micrograms/ml, 0.92-1.5 x 10(-5) m) significantly decreased Purkinje fiber maximum diastolic potential. Action potential amplitude and maximal rate of depolarization (Vmax) were significantly decreased by all agents in the following order: bupivacaine, ropivacaine, lidocaine. High concentrations of bupivacaine and ropivacaine caused premature depolarizations during phase 3 in some preparations. In addition, bupivacaine altered the action potential configuration by producing "notching" not seen with either ropivacaine or lidocaine. This may reflect effects caused by changes in Ca2+, K+, or electrotonic effects. Ropivacaine and bupivacaine (30 micrograms/ml, 9.2 x 10(-5) m) and lidocaine (100 micrograms/ml, 3.74 x 10(-4) m) caused Purkinje fiber inexcitability and Purkinje fiber-ventricular muscle conduction block. However, the duration of PF inexcitability following exposure to ropivacaine and lidocaine was significantly shorter than in bupivacaine-treated preparation. Duration of PF-VM conduction block also tended to be shorter for ropivacaine than bupivacaine, but significantly longer than lidocaine. In general, ropivacaine is less potent than bupivacaine but more potent than lidocaine in terms of its depressant effect on cardiac excitation and conduction.

Action Potentials↗
PubMed1995

Immunoresponsiveness in endometriosis: implications of estrogenic toxicants.

Endometriosis is a reproductive disease characterized by the growth of endometrial cells at sites outside the uterus. This disease is a serious disorder associated with chronic pain and infertility, which may be present in 6 million women in this country. Traditional medical therapy has consisted of hormonal regimens that limit the action of endogenous estrogen. The etiology of endometriosis is unknown, but studies suggest that soluble factors known as cytokines play a role in disease pathogenesis. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD or dioxin) is an environmental toxicant that alters the action of estrogen in reproductive organs and adversely affects immunocompetence. The incidence of endometriosis was determined in rhesus monkeys that were chronically exposed to dioxin for a period of approximately 4 years. Ten years after termination of dioxin treatment, the presence and severity of endometriosis was assessed by surgical laparoscopy. The incidence of endometriosis correlated with dioxin exposure and disease severity was dependent upon the dose administered. Moderate to severe endometriosis was not found in control animals but was documented in three of seven animals exposed to 5 ppt dioxin (43%) and in five of seven animals exposed to 25 ppt dioxin (71%). The frequency of spontaneous disease in the control group was 33%, similar to an overall prevalence of 30% in 304 rhesus monkeys with no history of dioxin exposure. This study indicates that endometriosis may be associated with dioxin exposure in the rhesus. In view of overwhelming evidence that cytokines participate in the mediation of reproductive-endocrine phenomena and regulation of endometrial growth, future assessment of the effects of environmental toxicants on reproductive health may depend upon our understanding of the bidirectional cytokine network between the immune and endocrine systems.

Animals↗
PubMed1997

Modulation of L-type calcium current by internal potassium in guinea pig ventricular myocytes.

OBJECTIVES: The early phase of myocardial ischemia is characterized by a considerable K+ efflux from cardiac myocytes, causing decreasing internal ([K+]i) and increasing external ([K+]o) K+ concentrations. The change in [K+]i and [K+]o is one of the factors thought to initiate the ischemia-induced changes in electrical activity. Nevertheless, little is known about the influence of [K+]i and [K+]o on the L-type calcium current. METHODS: The whole-cell patch-clamp technique combined with an internal perfusion system was used to test possible actions of altered [K+]i and [K+]o on L-type current carried by Ca2+ and Ba2+ in isolated guinea pig ventricular myocytes. RESULTS: Changing the [K+]i in the range of 110-170 mM revealed a sigmoidal concentration-response relationship between the L-type current and [K+]i. The maximum change in current amplitude was more than 40% with a half-saturation concentration of 136 mM which is near the physiological [K+]i. Ca2+ influx during action potential clamp increased by approximately 42% after raising [K+]i from 130 to 170 mM. Internal perfusion with Cs+ demonstrated that Cs+ is less effective than K+ in regulating the L-type current. By using ATP-analogues, [K+]i was shown to affect the L-type channel in a phosphorylation-independent way. Changes in [K+]o only modulated the L-type current via alterations in [K+]i. CONCLUSIONS: The decrease in [K+]i during early ischemia is, per se, sufficient to reduce the L-type current by up to 15%, thereby decreasing the action potential duration, and Ca2+ influx into the cells. This may act in addition to well-known mechanisms such as changes in internal pH and falling ATP levels, which influence the L-type current. Moreover, the phenomenon may complicate the interpretation of electrophysiological measurements of L-type current under conditions where [K+]i is not precisely controlled.

Animals↗
PubMed1995

Lusitropic effects of a Ca2+ sensitization with a new cardiotonic agent, MCI-154, on diseased human hearts.

OBJECTIVES: Recognition of the problems of conventional cardiotonic agents has led to an interest in drugs that produce a positive inotropic action by altering the responsiveness of myofilament to Ca2+ (i.e., Ca2+ sensitizing agents). The importance of the effects of these compounds on left ventricular (LV) systolic function has been emphasized, whereas the effect of them on LV diastolic function is still problematic. To investigate the lusitropic action of a novel Ca2+ sensitizing agent, MCI-154, we compared the effects of MCI-154 on LV relaxation and filling dynamics with those of dobutamine in diseased human hearts. METHODS: We assessed the slope of the end-systolic pressure-volume relation (Emax), the time constant of LV pressure decay (Tw) and the maximum rate of LV early filling (dV/dtmax) before and after the infusion of dobutamine (n = 10) or MCI-154 (n = 9). LV volume and pressure were measured by a conductance catheter and a micro-tip catheter pressure transducer. RESULTS: When both agents increased Emax comparably, dobutamine decreased Tw from 51 to 37 ms and MCI-154 decreased Tw from 54 to 44 ms. The decrease of Tw with MCI-154 was less than that with dobutamine (17 vs. 29%, P < 0.05). At the same time, dobutamine increased dV/dtmax per end-diastolic volume (dV/dtmax/V) from 2.84 to 3.88 s-1, whereas MCI-154 did not. CONCLUSIONS: Diastolic properties were not compromised by MCI-154, though the alteration in them with MCI-154 was less than that with dobutamine when MCI-154 increased LV contractile state to the same extent as dobutamine. The present results suggest that MCI-154 would be an ideal Ca2+ sensitizing agent that enhances force during systole without impairing diastolic function.

Adult↗
PubMed1992

Emerging role of lipids of Candida albicans, a pathogenic dimorphic yeast.

It is clear that C. albicans lipids have gained tremendous importance in recent years. In addition to being a barrier for entrance of various metabolites, it also provides the site of action for the synthesis of enzyme(s) involved in cell wall morphogenesis and antifungal action. While alterations in lipid composition during a yeast to mycelia transition have been observed, in most of the studies, lipid fluctuations reported could have been due to various environmental factors involved in the induction of morphogenesis [4,5]. A clear understanding of lipid biosynthesis and metabolic blocks due to antifungal action is likely to shed further light on selective interactions of antifungals. Despite the multifacet role of lipids in various functions of this pathogenic yeast, their exact involvement is poorly understood. The situation is little better with regard to ergosterol and its metabolism. Ergosterol is, indeed, important for anti-candidal activity and appears to be involved in the morphogenesis of C. albicans. The fluctuation in phospholipid composition have led to altered properties of plasma membrane namely, membrane fluidity, transport activities and drug sensitivity, which suggest that-a critical level of individual phospholipid is important for proper functioning of the plasma membrane. What the exact role is of individual phospholipid is far from clear. Many unanswered questions relating to the role of PI and sphingomyelin in signal transduction, involvement of phospholipases in the maintenance of phospholipid composition, and role of lipid transfer proteins in assembly and asymmetry of lipids are some aspects which merit further work.

Candida albicans↗
PubMed1992

Platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and EGF and PDGF beta-receptors in human endometrial tissue: localization and in vitro action.

Human endometrial tissue and primary stromal cell culture contain immunoreactive epidermal growth factor (EGF), platelet-derived growth factor (PDGF)-AB as well as EGF and PDGF-beta receptors. The immunostaining for EGF, EGF receptor, and PDGF beta-receptor were associated with endometrial luminal and glandular epithelial and stromal cells, whereas only the stromal cells contain immunoreactive PDGF-AB. The immunostaining intensity of EGF, EGF receptor, and PDGF-AB was similar in both phases of the menstrual cycle, whereas, PDGF-beta receptor immunostaining was highest in proliferative phase and considerably reduced, particularly in luminal and glandular epithelial cells in the secretory phase. In addition primary stromal cell cultures express EGF, PDGF-AB, and contain EGF and PDGF-beta receptors, and very low levels of PDGF-alpha receptor. 3H-Thymidine incorporation indicate that after 48 h of incubation in serum-free medium approximately 75-80% of stromal cells are quiescent. Incubation of quiescent stromal cells with 10% fetal bovine serum stimulate 3H-thymidine incorporation in a time-dependent manner reaching maximal after 30-48 h, with a doubling time of 38.2 h. EGF (1.5-15 ng/ml) stimulates 3H-thymidine incorporation by quiescent stromal cells (P less than 0.001). This effect was significantly reduced at concentrations above 15 ng/ml (P less than 0.005). PDGF-AB (3-10 ng/ml) and PDGF-BB (0.5-10 ng/ml) also stimulate 3H-thymidine incorporation in quiescent stromal cells compared to controls (P less than 0.005). The action of EGF (15 ng/ml) and PDGF-AB (10 ng/ml) was time dependent, reaching maximal after 36 and 48 h of incubation (P less than 0.002). Addition of PDGF-AB (10 ng/ml) to EGF (15 ng/ml) significantly enhanced the action of EGF or PDGF-AB used individually (P less than 0.001). 17 beta-estradiol or progesterone at 1 microM did not stimulate 3H-thymidine incorporation, although they were stimulatory in combination (P less than 0.001), they did not alter the action of EGF or PDGF when added in combination. These observations provide further evidence that human endometrial tissue contains specific immunoreactive EGF receptors. It also demonstrates the presence of immunoreactive EGF, PDGF-AB, and PDGF-beta receptors in endometrial tissue as well as stromal cells in primary culture. Both EGF and PDGF are mitogenic for endometrial stromal cells, suggesting an autocrine/paracrine role in modulation of endometrial cell growth and differentiation.

Cell Division↗
PubMed1977

Regulation of amino acid transport activity and growth rate of animal cells in culture.

Balb/3T3 mouse cells grown in cell culture contain the A and L systems for neutral amino acid transport. L-Alanine was used as a test amino acid for the A system and L-leucine for the L system. Transport activities for both transport systems are altered as the growth conditions for the cells are altered. When cell growth was arrested by allowing cells to approach confluency, or by the removal of serum or by the addition of protein synthesis inhibitors, System A transport activity decreased and System L activity increased significantly. The content of the cellular amino acids increased 2- to 3-fold whenever cell growth was arrested by the conditions stated above. Increased cellular amino acids, therefore, are associated with decreased transport activity of System A and increased activity of System L. Altering cellular amino acids by loading or depleting the cells produced the predicted responses for the rapidly exchanging L-system but System A was less responsive. It is possible that regulatory mechanisms operate for the A system other than the direct action of alterations in cellular amino acid levels. The implications of the amino acid transport activity changes observed here on various studies on the role of transport in cell growth regulation and malignant transformation are discussed.

Alanine↗
PubMed1999

Pharmacokinetic and pharmacodynamic interactions between dehydroepiandrosterone and prednisolone in the rat.

The effects of multiple-dosing with dehydroepiandrosterone sulfate (DHEA-SO4) on the pharmacokinetics and pharmacodynamics of prednisolone were examined. Prednisolone (25 mg/kg i.v.) was administered to male and female Sprague-Dawley rats (250-350 g) alone and following DHEA-SO4 (4 mg/kg i.v., every 8 h for 4 days). Male control rats cleared prednisolone faster [3.68 +/- 1.30 (males) vs 1.01 +/- 0.7 l/h/kg; p < 0.05] and had larger Vss (1.38 +/- 0.459 vs 0.394 +/- 0.500 l/kg; p < 0.05) than females both due largely to lesser plasma protein binding. Prednisolone clearance and Vss were not altered by DHEA-SO4 in males or females. The net effect of prednisolone on basophils and plasma corticosterone did not differ with gender. DHEA-SO4 had no effect on plasma corticosterone and did not alter prednisolone action. DHEA-SO4 inhibited basophil trafficking in males, but to a lesser extent than prednisolone, and antagonized the effect of prednisolone on basophil trafficking in both sexes. The steroid-sparing effect observed with DHEA clinically may not be due to an alteration of corticosteroid pharmacokinetics but partly to its ability to affect immune functions.

Adjuvants, Immunologic↗
PubMed1992

[The anesthetic site of action: from the intact brain to the isolated protein. An overview].

To the present day there is no consensus of opinion as to which molecular events lead to the complex clinical state generally referred to as anaesthesia. The multitude of simultaneous physiological changes are also responsible for this lack of consensus. During anaesthesia, for example, consciousness, perception, memory, pain, and muscle relaxation are altered. The actions of anaesthetics correlate very well with their partitioning into lipophilic phases. Lipophilic interactions are non-specific. Therefore, it is likely that anaesthetics act at many different sites. Cell membranes are not the only possible sites but also membrane proteins and the various hydrophobic domains they contain. The multitude of clinical anaesthetic effects is paralleled by the complexity of molecular interactions. A better understanding of anaesthesia requires an integrated view of anaesthetic effects at the various systemic levels, beginning with the molecular domain and ending with the intact central nervous system. Anaesthesia research could be directed more towards man because it has now become possible to conduct molecular in-vitro studies with human cells as well as non-invasive studies of the intact human central nervous system.

Anesthetics↗
PubMed2001

Ischemic tolerance of the heart by adaptation to chronic hypoxia is suppressed by high subchronic carbon monoxide exposure.

This study was designed to investigate whether exposure to carbon monoxide (CO) could alter the ischemic tolerance induced by chronic hypoxia. We aimed to determine whether chronic hypoxia-induced cardiovascular adaptation was modified during the return to normoxia or by subchronic CO exposure. The degree of resistance to an in vitro transient ischemia was measured, using the Langendorff method, in hearts from rats previously exposed to chronic hypoxic hypoxia and/or subchronic CO exposure to 600 ppm. Chronic hypoxia decreased ischemic contracture (15.6 +/- 04.9 vs. 60.8 +/- 07.7%) and improved both contractile recovery (59.6 +/- 07.3 vs. 21.8 +/- 06.8%) and ventricular arrhythmia during reperfusion (0 vs. 45%) compared to a control normoxic group. However, in our chronic hypoxia regression model many parameters returned near to control values except for the persistence of cardiomegaly, a significant decrease in both ischemic contracture (22.0 +/- 04.9 vs. 60.8 +/- 07.7%), and ventricular tachycardia (25 vs. 45%). CO exposure alone increased the coronary flow and improved both contractile recovery (42.6 +/- 7.2 vs. 21.8 +/- 6.8%) and ventricular arrhythmia (16.7 vs. 45%) without altering the action potential shape. These two models causing tissue hypoxia induced the same degree of polycythemia or cardiomegaly and provided similar ischemic tolerance. CO exposure after chronic hypoxia exacerbated ischemic contracture (69.3 +/- 10.5 vs. 22.0 +/- 14.5%) and ventricular tachycardia incidence (100 vs. 50%) but with significant alteration in contractile recovery (12.7 +/- 10.5%) compared to the chronic hypoxia or CO exposure. Thus, CO exposure completely suppressed the chronic hypoxia-induced ischemic tolerance.

Animals↗
PubMed1989

Cytosolic sodium concentration regulates contractility of cardiac muscle.

The present chapter provides experimental evidence to show that intracellular Na+ concentration regulates cardiac contractility effectively by altering intracellular Ca2+ concentration via the Na-Ca exchange. This steep coupling between the Na+ and Ca2+ electrochemical gradients implies that a change in intracellular Na+ concentration is accompanied by a concomitant change in intracellular Ca2+ concentration (and, therefore, contractility). Under the physiologic conditions, each cardiac action potential alters intracellular Na+ concentration in a dynamic manner. Therefore, Na-Ca exchange can regulate cardiac contraction from a beat-to-beat basis.

Animals↗