Biomedical subjects

H Rensing

Publications and source records attributed to H Rensing.

6 recordsLinked to original sources

PubMed1999

Role of reactive oxygen species for hepatocellular injury and heme oxygenase-1 gene expression after hemorrhage and resuscitation.

Reactive oxygen species (ROS) generated during hemorrhage and subsequent resuscitation (H/R) may contribute to cellular injury but may also regulate an adaptive cellular response to stress. Heme oxygenase (HO)-1 has been recognized as an important stress-inducible gene conferring protection after H/R. The aim of this study was to determine the contribution of ROS to hepatocellular injury and to induction of HO-1 in parenchymal and nonparenchymal cells after H/R. Anesthetized Sprague-Dawley rats were subjected to reversible H/R with or without coadministration of the potent antioxidant Trolox (6 mg/kg body wt). HO-1 gene expression was determined at baseline, at the end of hemorrhagic hypotension, and after 1, 3, and 5 h of resuscitation on the messenger ribonucleic acid (mRNA) and protein level. Assessment of hepatocellular injury by alpha-glutathione-S-transferase serum levels showed a significant increase after H/R that was attenuated by Trolox (sham: 38 (26-42); H/R: 286 (150-696); Trolox: 14 (2-227) microg/L; median (25th/75th percentile) P<0.05). Injury correlated with induction of HO-1 mRNA (r2 = 0.97) on the whole organ level and with the expression pattern of HO-1-immunoreactive protein in pericentral hepatocytes after H/R. Trolox attenuated H/R-induced increase of HO-1 in hepatocytes. In contrast, nonparenchymal cells showed high constitutive levels of HO-1 mRNA and protein that were increased by sham operation and H/R to a similar extent. HO-1 steady-state transcripts in nonparenchymal cells were not modulated by Trolox. These results suggest a differential regulation of HO-1 gene expression in hepatocytes and nonparenchymal cells. ROS formation seems to contribute to early hepatocellular injury but also serves as an important trigger for HO-1 gene expression in parenchymal cells, which confers delayed protection after H/R.

Animals↗

PubMed1998

Expression pattern of heme oxygenase isoenzymes 1 and 2 in normal and stress-exposed rat liver.

Heme oxygenase (HO) catalyzes the oxidative cleavage of the alpha-mesocarbon of Fe-protoporphyrin-IX yielding equimolar amounts of biliverdin-IXa, iron, and carbon monoxide. The HO-system consists of two isoenzymes, namely HO-2 and the inducible isoform HO-1, also referred to as heat shock protein (hsp) 32. Although both parenchymal and non-parenchymal liver cells participate in heme metabolism, the expression pattern of the isoenzymes in normal and stress exposed liver is unknown. To study this, rats underwent either endotoxin (lipopolysaccharide [LPS]) challenge, hemorrhagic hypotension, glutathione (GSH) depletion, or cobalt chloride injection, all known to provoke oxidative stress. HO-2 messenger RNA (mRNA) and protein were constitutively expressed in hepatocytes, Kupffer/endothelial-, and stellate (Ito-) cell enriched fractions. Although both non-parenchymal cell fractions expressed HO-1 transcripts, HO-1 immunoreactive protein was restricted to Kupffer cells in the normal liver. In contrast to HO-2, a significant increase in HO-1 on the whole organ level was noted by hemorrhagic hypotension, GSH depletion, and cobalt chloride injection. However, the distinct stress models led to a strikingly different cell-type specific and sublobular expression pattern of HO-1 gene expression. HO-1 was inducible in sinusoidal lining cells (hemorrhagic hypotension, LPS challenge), in periportal (cobalt chloride), or pericentral (GSH depletion, hemorrhagic hypotension) hepatocytes. The blockade of protein translation before hemorrhage by cycloheximide reduced upregulation of HO-1/hsp32 mRNA significantly (65.4% reduction, P < .05), whereas the inducibility of hsp70 transcript was maintained. In addition to transcriptional regulation, HO-1 seems to be subject to posttranscriptional control in particular in non-parenchymal cells.

Animals↗

PubMed1998

[Anesthesia and perioperative immune function].

Innate and acquired immunity plays a pivotal role in the host defense response. Pain, stress, necrotic tissue and invading microorganisms are known modulators of the complex immune response of patients undergoing major surgery. Anaesthesia itself or perioperative interventions of the anaesthesiologist may substantially alter the immune function with potential impact on the postoperative course. For instance, transfusion of allogenic blood and administration of dopamine or metoclopramide may interfere with immunity. Stress and pain are associated with immune tolerance, increased susceptibility to infection and tumor spreading in animal models. Thus, anaesthesia may--through modulation of the neurohumoral stress response--indirectly affect immunity of the surgical patient. In particular epidural anaesthesia and/or administration of epidural or spinal opioids seem to attenuate the stress response with beneficial effects on cellular and humoral immunity. In addition, anaesthetics, such as etomidate, propofol, or thiopentone and opioid analgesics may directly affect function of immune competent cells. However, these actions may only be apparent with high or supraclinical concentrations and/or long-term exposure. Regarding the latter, evidence suggests that long-term sedation using thiopentone in neurosurgical patients is paralleled by infectious complications in a dose-dependent manner. At present, no data are available regarding the significance of the observed alterations associated with various anaesthetic procedures of the incidence of postoperative complications associated with impaired immunity, such as infection or metastatic spreading in oncological surgery.

Anesthesia↗

PubMed1997

[Organ specific expression pattern of a carbon monoxide generating stress protein (hemoxygenase-1/heatshock protein 32) following hemorrhagic shock].

OBJECTIVE: Recent evidence suggests a possible role for Haeme oxygenase (HO)-derived carbon monoxide (CO) in the regulation of vascular tone through elevation of cyclic 3'-5' guanosine monophosphate (cGMP). Previous work from our laboratory has shown that blockade of the HO pathway by tin-protoporphyrin-IX (SnPP) after resuscitation from hemorrhage leads to a specific and profound increase in portal resistance while neither systemic nor hepatic arterial resistance are affected. We therefore investigated the organ-specific expression pattern of the stress-inducible protein haeme oxygenase-1/heat shock protein 32 after haemorrhage and resuscitation. MATERIALS AND METHODS: After approval of the protocol by the local review board, male Sprague-Dawley rats (n = 6/group) were anaesthetised with pentobarbitone, instrumented for assessment of central haemodynamics and subjected to haemorrhagic hypotension (40 mm Hg for 1 h) followed by resuscitation with 60% shed blood and Ringer's solution or a time-matched sham protocol. Samples of liver, spleen, kidney intestine, aorta, and lungs were harvested 5 h after the onset of resuscitation and subjected to Western-blot analysis using a specific anti-rat HO-1/hsp 32 antibody (StressGen, Sidney, Canada). RESULTS: Resuscitation with shed blood/Ringer's solution restored central haemodynamics and acid-base status while significant haemodilution was observed. Haemorrhage and resuscitation led to strong induction of HO-1 in the liver and slight induction in aortic tissue, while no increase in steady-state protein levels was observed in the other organs studied. CONCLUSION: These results suggest a specific contribution of the HO/CO pathway to maintenance of low hepatic portal resistance in vivo in a clinically relevant model of haemorrhagic shock and adequate resuscitation.

Animals↗

PubMed1992

Alpha 2-adrenoceptor mediated inhibition of exocytotic noradrenaline release in the absence of extracellular Ca2+.

The effect of the alpha 2-adrenoceptor agonist clonidine on 3,4-diaminopyridine (3,4-DAP)-evoked [3H]noradrenaline ([32H]NA) release in rat hippocampus slices was studied in the presence or absence (+1 mM EGTA) of extracellular Ca2+. 3H overflow (consisting mainly of unmetabolized [3H]NA) was evoked by addition of 100 microM 3,4-DAP for 10 min to the medium, which always contained 1 microM desipramine. Ligands for L-type voltage-sensitive Ca2+ channels (VSCC) did not affect the evoked [3H]NA release, whereas the preferential N-type VSCC antagonist omega-conotoxin was inhibitory, both in the presence and even more potently in the absence of Ca2+, suggesting an involvement of N-type VSCC in the mechanism of 3,4-DAP-evoked [3H]NA release. In the absence of extracellular Ca2+ the initial Na+ influx, which has been previously proposed to liberate Ca2+ from intracellular stores for the exocytotic process, most probably occurs via N-type VSCC. Clonidine inhibited the 3,4-DAP-evoked [3H]NA release in a concentration-dependent manner, both in the presence and even more potently in the absence of Ca2+; its effects were antagonized by yohimbine. In the presence of extracellular Ca2+ the clonidine effect was not changed by addition of omega-conotoxin. Similar effects of clonidine were found in slices from the rabbit hippocampus. Since the availability of Ca2+ from intracellular stores seems to predominate in the present model, our results lend some support to the suggestion that alpha 2-adrenoceptor activation might affect intracellular mechanisms of Ca2+ homeostasis.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Aminopyridine↗

PubMed1991

Long-term survival of intrastriatal dopaminergic grafts: modulation of acetylcholine release by graft-derived dopamine.

The nigrostriatal dopaminergic system of rats was unilaterally lesioned with 6-hydroxydopamine. Part of the animals was grafted 2 weeks later with fetal dopaminergic cells on the lesioned side; untreated rats of the same strain served as controls. Both 3 and 12-14 months after surgery the striatal dopamine (DA) content and the in vivo rotational response following injection of D-amphetamine showed significant changes in grafted as compared to lesioned animals. At 12-14 months after transplantation, the electrically evoked release of tritiated DA and acetylcholine (ACh) in slices (preincubated with [3H]DA or [3H]choline, respectively) of striata of intact, lesioned, or grafted animals was also investigated. Electrical field stimulation of striatal slices of the lesioned side did not evoke any significant [3H]DA overflow, whereas a marked [3H]DA release was observed in slices of grafted and control striata. Moreover, both DL-amphetamine (3 microM) and nomifensine (10 microM) strongly enhanced basal 3H outflow in these slices. Electrically evoked [3H]ACh release was significantly reduced in slices from all striatal tissues by 0.01 microM apomorphine. In slices from denervated striata a clearcut hypersensitivity for this action of apomorphine was present, indicating supersensitivity of DA receptors on cholinergic terminals; this hypersensitivity was significantly reduced in graft-bearing striata. Furthermore, because this hypersensitivity was unchanged in slices of lesioned striata under stimulation conditions (four pulses/100 Hz) avoiding inhibition by endogenously released DA, it is concluded that lesion-induced DA receptor supersensitivity is caused by an increase in receptor density or efficacy rather than by a decreased competition between endogenous and exogenous agonists. Both reuptake blockade of DA with nomifensine (10 microM) and release of endogenous DA by DL-amphetamine (3 microM) potently reduced [3H]ACh release only in control and grafted but not in lesioned tissue. In experiments using potassium-evoked [3H]ACh release, tetrodotoxin had no effect on the inhibitory activity of amphetamine and nomifensine, indicating that the DA receptors involved in their indirect inhibitory action are located directly on the cholinergic terminals.

3,4-Dihydroxyphenylacetic Acid↗