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Biomedical subjects

R Schulz

Publications and source records attributed to R Schulz.

At least 199 records · Page 11Linked to original sources
PubMed1998

Effect of chronic GH overproduction on cardiac ANP expression and circulating ANP levels.

Sodium and water retention are common in acromegaly and upon GH administration. The underlying mechanisms, however, have not been clearly characterized as yet. Therefore, the aim of this study was to examine possible alterations of atrial natriuretic peptide (ANP), an endogenous regulator of volume homeostasis, in response to chronic elevated GH. We used GH-transgenic mice (GH-TM) as a model for chronic hypersomatotropinemia and moreover investigated 7 and 27 week old animals, respectively, in order to discriminate between short and long term effects of GH overexpression. Hematocrit values were reduced in GH-TM compared to control animals and it is known that plasma volume is increased in these animals. Structural lesions of the kidney were found in the GH-TM, however, in the animals studied there were no signs of renal insufficiency as evidenced by serum creatinine and urea levels. The serum concentration of immunoreactive ANP (IR-ANP) determined by RIA was significantly (P < 0.005) elevated in the young GH-TM as compared to control littermates (81.7+/-13.3 vs. 50.9+/-10.8 fmol/ml). The increase in serum IR-ANP of 27 week old GH-TM, however did not reach the level of significance (57.13+/-16.3 vs. 50.25+/-16.4 fmol/ml). Serum samples of control mice as well as of the 7 week old animals mainly contained ANP 99-126, known to be the circulating form of ANP. In contrast, serum of 27 week old GH-TM predominantly showed the cardiac storage form of ANP, ANP 1-126. Cardiac expression of ANP was quantified by Northern blot analysis. mRNA coding for ANP was found 1.2- and 2-fold increased in the atria of 7 and 27 week old GH-TM, respectively. In parallel, a 2.2-fold (7 week) and 2-fold (27 week) increase of IR-ANP was observed in transgenic atria compared to tissue of control animals. In contrast, no significant difference of ANP mRNA expression or of content of IR-ANP was observed in the ventricles of both groups of animals. In conclusion, GH-TM show various alterations in their ANP status suggesting an influence of the peptide on the effect of GH in fluid retention.

Aging↗
PubMed1998

Ischemic preconditioning in pigs: a graded phenomenon: its relation to adenosine and bradykinin.

BACKGROUND: A threshold concept for ischemic preconditioning (IPc) has been proposed. It is unclear, however, whether IPc, above a certain threshold, is an all-or-nothing or a graded phenomenon. METHODS AND RESULTS: In 71 enflurane-anesthetized swine, severe left anterior descending coronary artery hypoperfusion for 90 minutes followed by 2 hours of reperfusion resulted in an infarct size (IS, by triphenyltetrazolium chloride) of 16.7+/-3.4% (SEM) of the area at risk. IPc by 2 minutes of low-flow ischemia and 15 minutes of reperfusion before the 90-minute target ischemia did not reduce IS (21.9+/-7.0%). IS was decreased to 9.0+/-2.6% (P<0.05) by 3 minutes of IPc and reduced further to 1.9+/-0.9% (P<0.05) by 10 minutes of IPc. The interstitial adenosine concentration (microdialysis, high-performance liquid chromatography) was unchanged with 2 and 3 minutes of IPc but increased with 10 minutes of IPc (by 573+/-144%). The interstitial bradykinin concentration (microdialysis, radioimmunoassay) remained unchanged with 2 minutes of IPc but increased to a similar extent with 3 minutes (by 198+/-32%) and 10 minutes (by 224+/-30%) of IPc. The IS reduction by 3 minutes of IPc was abolished by blockade of the bradykinin B2 receptor with intracoronary HOE 140 (16.6+/-4.3%) but not with intracoronary infusion of adenosine deaminase (8.4+/-2.5%, P<0.05). HOE 140, however, did not affect the IS reduction (3.5+/- 1.1%, P<0.05) by 10 minutes of IPc. Combined infusion of HOE 140 and adenosine deaminase abolished the IS reduction by 10 minutes of IPc (15.4+/-6.7%). CONCLUSIONS: IS reduction by IPc is a graded phenomenon. Whereas bradykinin is essential during preconditioning ischemia of shorter duration, adenosine is more important during preconditioning ischemia of longer duration.

Adenosine↗
PubMed1998

Beta-blocker therapy of severe congestive heart failure in infants with left to right shunts.

We report on the clinical and neurohumoral effects of adding low-dose propranolol to conventional therapy with digoxin and diuretics in 6 infants with severe congestive heart failure due to large left-to-right shunts. A significant decrease in heart failure scores and a decrease of the highly activated renin-angiotensin-1 aldosterone system by approximately 70% strongly suggests a beneficial effect of this new therapeutic approach.

Adrenergic beta-Antagonists↗
PubMed1998

Translocation of phosducin in living neuroblastoma x glioma hybrid cells (NG 108-15) monitored by red-shifted green fluorescent protein.

Activation of G protein-coupled receptors triggers translocation of certain proteins from cytoplasm to cell membrane located targets. One of these cytosolic proteins is phosducin (Phd) which has been described to compete with G protein-coupled receptor kinases for Gbetagamma dimers attached to the cell membrane, thereby attenuating desensitization of activated receptors. These features of protein redistribution prompted us to examine whether stimulation of membrane associated E-prostaglandin receptors coupled to Gs causes Phd to migrate towards the plasma membrane. We made use of enhanced green fluorescence protein (EGFP), a reporter protein, to follow redistribution of Phd both by means of confocal microscopy and biochemical techniques in living neuronal NG 108-15 hybrid cells challenged with prostaglandin E1 (PGE1). The cells were transiently transfected to express Phd fused to the C-terminus of EGFP, or to express EGFP only. Overexpression of the proteins is implied by FACS analysis as well as by western blot technique, and the functional integrity of EGFP-tagged Phd was confirmed by its ability to elevate cAMP accumulation. Time-lapse imaging of single living cells by means of confocal microscopy revealed that exposure to prostaglandin causes EGFP/Phd, which is evenly spread throughout the cell, to relocate towards the membrane within few minutes. Fluorescence associated with the cell nucleus displayed little rearrangement. The principle finding that prostaglandin triggers translocation of Phd from cytosol to the cell periphery was verified with membranes prepared from EGFP/Phd expressing cells. We found maximal concentrations of membrane associated fluorescent material 5 to 7 min upon prostaglandin exposure. The present study reports for living NG 108-15 hybrid cells that PGE1 stimulation causes cytosolic Phd to translocate towards the membrane, where it is believed to bind to G protein subunits such as Gbetagamma and Galphas.

Alprostadil↗
PubMed1998

Positron emission tomography analysis of [1-(11)C] acetate kinetics in short-term hibernating myocardium.

BACKGROUND: Modeling of the time-[1-(11)C]acetate activity curve assumes a constant concentration of labeled tricarboxylic acid cycle intermediates and associated metabolites, such as glutamate and aspartate, which may, however, decrease in short-term hibernating myocardium. METHODS AND RESULTS: In 12 anesthetized pigs, [1-(11)C]acetate was injected as a bolus into the cannulated left anterior descending coronary artery during normoperfusion, inotropic stimulation, and early (5 to 45 minutes) and prolonged ischemia (60 to 90 minutes). Regional myocardial oxygen consumption (MVO2, microliters per minute per gram) was measured, and the absence of necrosis was verified by triphenyl tetrazolium chloride staining. Inotropic stimulation increased MVO2 from 52.5+/-7.4 to 195.4+/-36.2 (mean+/-SD) and the rate constant (kmono, minutes[-1]) of [1-(11)C]acetate clearance from 0.094+/-0.018 to 0.322+/-0.076. During early ischemia, MVO2 and kmono were decreased to 24.3+/-8.5 and 0.061+/-0.011, respectively. Kmono closely correlated to MVO2 during normoperfusion, inotropic stimulation, and early ischemia. In short-term hibernating myocardium, however, at an unchanged MVO2, kmono increased toward control values (0.080+/-0.014). Myocardial glutamate and aspartate concentrations (biopsies) decreased to 47+/-26% and 77+/-18%; the peak count rate decreased to 66+/-22% of its respective control value. After correction for the decreases in glutamate and aspartate or in peak count rate, kmono was again decreased (0.050+/-0.016 or 0.052+/-0.014, respectively), and a close relationship to MVO2 was restored. CONCLUSIONS: Kmono correlates to MVO2 in short-term hibernating myocardium when the decreases in aspartate and glutamate or in peak count rate are considered.

Acetates↗
PubMed1998

Thiols protect the inhibition of myocardial aconitase by peroxynitrite.

Peroxynitrite (ONOO-) is a potent inhibitor of myocardial aconitase. Because ONOO- reacts with sulfhydryl moieties, we investigated whether thiols protect against ONOO(-)-mediated inhibition of aconitase. Aconitase activity was examined in ventricular homogenates prepared from freshly isolated rat hearts. Peroxynitrite, but not the nitric oxide donor S-nitroso-N-acetyl-d,l-penicillamine (0.03-300 microM), inhibited aconitase activity (IC50 = 47 +/- 6 microM). L-Cysteine (0.03-3 mM), glutathione (0.03-3 mM), and N-(2-mercaptoproprionyl)-glycine (MPG, 0.1-3 mM) protected against the inhibitory effect of ONOO- (100 microM) with the rank order of potency of MPG > glutathione > L-cysteine. D-Cysteine (3 mM) had a protective effect similar to L-cysteine, but L-cystine, the oxidized form of L-cysteine, offered no protection. Ferrous ammonium sulfate (1 mM) markedly enhanced the protection provided by L-cysteine, but not by glutathione or MPG. Thiols protect myocardial aconitase against inhibition by ONOO- in a manner which is sulfhydryl group dependent and not stereospecific. The protection is related to the maintenance of the redox state of the iron-sulfur cubane cluster and cysteine residues at the active site of the enzyme. Both naturally occurring thiols and thiol-based drugs may be useful to protect the heart during ischemia-reperfusion injury where there is an excessive production of ONOO-.

Aconitate Hydratase↗
PubMed1998

Rat beta-adrenergic receptor kinases 1 and 2 in mouse neuroblastoma X rat glioma NG 108-15 hybrid cells.

Beta-adrenergic receptor kinase (betaARK, EC 2.7.1.-) has been implicated in the phosphorylation of G protein-coupled receptors, including opioid receptors. Since delta-opioid receptors of mouse neuroblastoma x rat glioma hybrid cells (NG 108-15) desensitize upon activation, this investigation was designed to find out whether NG 108-15 cells contain betaARK activity. Using the reverse transcription polymerase chain reaction technique, we identified two mRNAs, one coding for rat betaARK1 and the other for rat betaARK2. No hint was found for the presence of mouse betaARK. Examining the cytosolic betaARK activity in these hybrid cells using rhodopsin as substrate, we found a strict functional dependence on the presence of exogenous G protein subunit Gbetagamma. This relationship reflects a characteristic for betaARK1 and 2 out of the known G protein-coupled receptor kinases. Finally, highly purified recombinant betaARK1 proved active to phosphorylate enriched delta-opioid receptor preparations in an opioid agonist-dependent manner. The results reported here provide the basis to study more closely the molecular function of G protein-coupled receptor kinases in a cell line (NG 108-15) most frequently used to investigate acute and chronic opioid actions.

Animals↗
PubMed1998

Prevention of ischemic preconditioning only by combined inhibition of protein kinase C and protein tyrosine kinase in pigs.

In rabbits, inhibition of either protein kinase C or protein tyrosine kinase abolishes the infarct size reduction achieved by ischemic preconditioning. In pigs, however, inhibition of protein kinase C does not attenuate ischemic preconditioning. The present study tested whether inhibition of protein tyrosine kinase alone or in combination with inhibition of protein kinase C interferes with ischemic preconditioning in pigs. In 29 enflurane-anesthetized pigs, the LAD was cannulated and perfused from an extracorporeal circuit. Protein tyrosine kinase and protein kinase C were inhibited by continuous intracoronary infusion of genistein (5x10(-6) mol/l) and staurosporine (10(-7) mol/l), respectively. Subendocardial blood flow (ENDO) was measured with microspheres. Infarct size was analysed by TTC staining (% of LV area at risk) following 90 min low-flow ischemia and 120 min reperfusion. In the presence of genistein, 90 min ischemia at an ENDO of 0.06+/-0.01 (+/-s.e.m.) ml/min/g resulted in an infarct size of 16.7+/-4.2% (n=8). With genistein, ischemic preconditioning by 10 min ischemia and 15 min reperfusion still reduced infarct size to 6.5+/-2.7% (ENDO: 0.05+/-0. 01 ml/min/g, n=7, P<0.05). In the presence of both genistein and staurosporine, infarct size following 90 min ischemia was 14.1+/-3. 6% (ENDO: 0.06+/-0.01 ml/min/g, n=7). With genistein and staurosporine, ischemic preconditioning no longer reduced infarct size significantly (11.5+/-3.1%, ENDO: 0.06+/-0.01 ml/min/g, n=7). The effective attenuation of ischemic preconditioning only by simultaneous inhibition of both, protein kinase C and protein tyrosine kinase, suggests a complex signal cascade involving both protein kinases.

Animals↗
PubMed1998

Impact of resting and ischemic blood flow on infarct probability in ischemic preconditioning--a new approach to infarct size-blood flow data by logistic regression.

The linear regression analysis of infarct size (IS) v ischemic myocardial blood flow (MBF) does not account for the heterogeneity of MBF and infarcted tissue; moreover, it cannot assess a blood flow threshold for infarction (MBFT) accurately, as with ischemic preconditioning (IP) the close relationship between ischemic MBF and IS otherwise observed is lost. Finally, the impact of resting blood flow on myocardial infarction cannot be considered in such analysis. Therefore, in a retrospective data analysis of 32 enflurane-anaesthetized swine undergoing 90 min severe ischemia and 120 min reperfusion without (CON, n = 12) or with IP induced by either 3 (IP3, n = 8) or 10 min ischemia (IP10, n = 12) and 15 min reperfusion, a MBFT was assessed by logistic regression (LR) in individual tissue pieces. MBFT was arbitrarily defined as that ischemic MBF (microspheres) at which infarct probability was 0.2, derived from the ratio of infarcted (n = 141, TTC) to all tissue samples (n = 684). The duration of the preconditioning ischemia and MBF both at rest and during the sustained ischemia were significant predictors of infarct probability. Ischemic MBFT at an infarct probability of 0.2, was 0.089 +/- 0.023 ml/min/g in CON. MBFT was decreased to 0.051 +/- 0.03 ml/min/g with IP3 (P < 0.05 v CON) and further to 0.004 +/- 0.037 ml/min/g with IP10 (P < 0.05 v CON, IP3). Corresponding to the leftward shift of MBFT, the relationships between infarct probability and MBF were shifted in parallel by IP with no change in their slopes.

Animals↗
PubMed1998

[Short-term hibernating myocardium: circulation, function and metabolism in sustained regional myocardial ischemia].

During moderate prolonged myocardial ischemia, the myocardium is dysfuctional but can remain viable. In such ischemic and dysfunctional myocardium, contractile function is reduced in proportion to the reduction in regional myocardial blood flow, i.e., a state of "perfusion-contraction matching" exists. The metabolic status of such myocardium improves over the first few hours, as myocardial lactate production is attenuated and creatine phosphate, after an initial reduction, returns to control values. Ischemic myocardium, characterized by perfusion-contraction matching, metabolic recovery and lack of necrosis, has been termed "short-term hibernating myocardium". "Short-term hibernating" myocardium can respond to an inotropic stimulation with increased contractile function, however, at the expense of a renewed worsening of the metabolic status. A role for endogenous adenosine in the development of hibernation has been excluded, since neither contractile function, metabolic parameters, nor viability are altered by increased catabolism of endogenous adenosine by infusion of adenosine deaminase. Also activation of ATP-dependent potassium channels is not responsible for "short-term hibernation". "Short-term hibernating" myocardium has, however, reduced calcium responsiveness.

Animals↗
PubMed1998

The relationship between regional blood flow and contractile function in normal, ischemic, and reperfused myocardium.

During normoperfusion, both myocardial blood flow and contractile function are heterogeneously distributed throughout the left ventricle, in that midwall segment shortening is higher at the apex than at the base of the left ventricle, and greater in the anterior than in the posterior wall. Also, transmural heterogeneity of myocardial deformation exists with greater segment shortening and wall thickening occurring in inner than in outer myocardial layers. A transmural heterogeneity of myocardial blood flow-with greater inner as compared to outer wall perfusion-exists which is not simply related to temporal fluctuations since the heterogeneous flow pattern is stable over at least a few minutes. While an increase in myocardial contractile function will lead to a metabolically mediated increase in myocardial blood flow, an increase in regional coronary perfusion within or above the autoregulatory range does not increase regional myocardial contractile function. During hypoperfusion, the reduction in subendocardial blood flow is more pronounced than that in subepicardial blood flow, and contractile function in the inner myocardial layers ceases more rapidly than in the outer myocardial layers. The reduced regional myocardial contractile function is closely matched to the reduced regional myocardial blood flow; however, such a coupling between reduced flow and function is lost when ischemia is prolonged for several hours in that function for a given flow is further reduced. During reperfusion, regional myocardial contractile function remains depressed for a prolonged period of time, depending on the severity, duration, and location of the preceding ischemic episode, while regional myocardial blood flow is restored to almost normal. Recovery of contractile function in the outer myocardial layers is faster than in the inner myocardial layers.

Animals↗
PubMed1998

AT1 receptor blockade in experimental myocardial ischemia/reperfusion.

The renin-angiotensin system is activated during myocardial ischemia, and local angiotensin II formation occurs in ischemic hearts. At least two angiotensin II receptor subtypes, the AT1 and AT2 receptor, have been identified. The cardiovascular effects of angiotensin II have been largely attributed to activation of AT1 receptors. In ventricular preparations from normal rat and pig hearts, the density of AT1 receptors is higher than that of AT2 receptors, whereas data on the AT receptor subtype density and its distribution in human hearts remain controversial. AT1 receptor blockade increases coronary blood flow during ischemia in dogs and during reperfusion in rats. It also reduces the incidence of ischemia-related arrhythmias in rats and guinea pigs, limits infarct size in pigs, improves functional and metabolic recovery following myocardial ischemia, and attenuates ventricular remodelling post-myocardial infarction in rats. The potential mechanisms responsible for the cardioprotection by AT1 receptor blockade remain to be elucidated in detail, but appear to involve AT2 receptor activation and the subsequent action of bradykinin, prostaglandins, and/or nitric oxide. Patients under treatment with AT1 receptor antagonists for indications such as hypertension and ventricular dilatation after myocardial infarction are likely to have improved prognosis when suffering an acute myocardial infarction.

Angiotensin Receptor Antagonists↗
PubMed1998

Expression of calcium regulatory proteins in short-term hibernation and stunning in the in situ porcine heart.

BACKGROUND: Myocardial hibernation and stunning are characterised by a reversible contractile dysfunction during and after ischaemia, respectively. Calcium homeostasis might be disturbed in hibernation and stunning due to altered expression of cardiac proteins involved in calcium handling. METHODS: In enflurane-anaesthetised swine the coronary blood flow through the left anterior descending coronary artery was decreased to reduce regional contractile function (microsonometry) by approximately 50%. In transmural biopsies obtained during ischaemia and reperfusion creatine phosphate as well as the expression of sarcoplasmic reticulum calcium ATPase (SERCA), phospholamban (PLB), calsequestrin (CSQ), and troponin inhibitor (TnI) were determined. RESULTS: During ischaemia creatine phosphate, after an initial reduction, recovered back to control values, and necrosis was absent (hibernation). After 90 min of ischaemia the myocardium was reperfused for 120 min but regional contractile function continued to be depressed (stunning). PLB, SERCA, CSQ, and TnI proteins were unchanged during ischaemia as well as reperfusion. Likewise, levels of PLB and SERCA mRNAs were unchanged. CONCLUSION: It is concluded that other mechanisms than altered expression of these regulating proteins underlie the contractile dysfunction observed during acute ischaemia, short-term hibernation and stunning.

Animals↗
PubMed1998

Inorganic phosphate content and free energy change of ATP hydrolysis in regional short-term hibernating myocardium.

OBJECTIVE: Short-term myocardial hibernation is characterized by an adaptation of contractile function to the reduced blood flow, the recovery of creatine phosphate content and lactate balance back towards normal, whereas ATP content remains reduced at a constant level. We examined the hypothesis that, despite the absence of ATP recovery, the short-term hibernating myocardium regains an energetic balance. METHODS: An enzymatic method was modified for the measurement of inorganic phosphate (Pi) in transmural myocardial drill biopsies (about 5 mg). In 12 anaesthetized swine, moderate ischemia was induced by reduction of coronary inflow into the cannulated left anterior descending coronary artery to decrease regional myocardial function (sonomicrometry) by 50%. RESULTS: The development of short-term hibernation was verified by the recovery of creatine phosphate content, the persistence of inotropic reserve in response to dobutamine and the absence of necrosis (triphenyl tetrazolium chloride). At 5-min ischemia, Pi was increased from 3.6 +/- 0.3 (SD) to 8.1 +/- 1.1 mumol/gwet wt (p < 0.05). The free energy of ATP hydrolysis (delta GATP) was decreased from -57.8 +/- 0.8 to -52.2 +/- 1.4 kJ/mol (p < 0.05). The relationships between function and Pi (r = -0.81) and delta GATP (r = -0.83), respectively, during control and at 5-min ischemia became invalid at 90-min ischemia, as myocardial blood flow and function remained reduced at a constant level, but Pi decreased back to 4.9 +/- 0.9 mumol/g (p < 0.05 vs. control and 5-min ischemia), and delta GATP fully recovered back to -57.2 +/- 1.3 kJ/mol (p < 0.05 vs. 5-min ischemia). CONCLUSIONS: In short-term hibernating myocardium, myocardial inorganic phosphate content recovers partially and the free energy change of ATP hydrolysis returns to control values. Contractile function remains reduced by mechanisms other than an energetic deficit.

Adenosine Triphosphate↗