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Biomedical subjects

H H Klein

Publications and source records attributed to H H Klein.

At least 109 records · Page 6Linked to original sources
PubMed1986

Regulation of epidermal growth factor receptor number and phosphorylation by fasting in rat liver.

The binding of 125I-epidermal growth factor (EGF) to microsomal membrane preparations from the livers of rats fasted for 72 h or fed control or high carbohydrate diets was examined to determine whether alterations in nutrient intake could affect the EGF receptor system. Fasted rats had 40-50% less membrane binding than did control or carbohydrate-fed rats. Scatchard analysis of the binding data indicated that the decrease in EGF binding in fasted rats was due to a decrease in receptor number with no change in receptor affinity. Cross-linking of 125I-EGF to EGF receptors with disuccinimidyl suberate revealed specific binding of a Mr 170,000 protein, which was diminished by approximately 75% in fasting, and a Mr = 150,000 protein, which accounted for 40-50% of the total labeling in the control and carbohydrate-fed rats and which was relatively unchanged by fasting. The sum of the labeling of the 2 bands was reduced by approximately 40% in fasting and is consistent with the reduction in EGF binding detected by Scatchard analysis. EGF stimulated a 1.5-3-fold increase in 32P incorporation into one major protein of 170 kDa in all 3 groups. Basal and EGF-stimulated autophosphorylation of 170 kDa, when normalized for protein, was 75% lower in membranes from fasted animals, compared to those from control or carbohydrate-fed rats. The comparable reduction of 125I-EGF binding to, and 32P incorporation into, the 170-kDa EGF receptor protein suggested that kinase activity/receptor was unaffected by fasting. Moreover, EGF receptor kinase activity in the 3 groups was comparable for an exogenous substrate, as judged by equal basal and EGF-stimulated phosphorylation of Val5-angiotensin II, when normalized for total EGF-binding capacity. These results suggest that fasting regulates EGF receptor kinase activity primarily by regulation of the number of hepatic EGF receptors. The possibility exists that some in vivo effects of fasting may be mediated by a reduction in EGF receptor levels.

Animals↗
PubMed1986

Comparative analysis of myocardial enzyme activities of the energy-supplying metabolism in patients with dilative cardiomyopathies and valve diseases.

We determined representative enzyme activities of glycogenolysis (glycogen phosphorylase) glycolysis (d-glyceraldehyde-3-phosphate dehydrogenase, GAPDH), beta oxidation of free fatty acids (1-3-hydroxyacyl CoA dehydrogenase, HADH), citric acid cycle (citrate synthase, CS), lactate fermentation (lactate dehydrogenase LDH), and creatine phosphate metabolism (creatine kinase, CK) in left ventricular samples of 36 patients to investigate if the metabolic capacities of the energy-supplying pathways are differently affected in different heart diseases. There were 17 patients with mitral valve diseases (MVD), 8 patients with aortic valve diseases (AVD), and 11 patients who suffered from dilative cardiomyopathies (DCM). The main metabolic characteristic on the level of enzymatic organization in patients with DCM was an increased ratio of GAPDH/HADH activities and a decreased ratio of HADH/CS activities compared to the valve-diseased patients. This result indicates that the capacity of glucose oxidation is enhanced at the expense of fatty acid metabolism in patients with DCM. Furthermore, we determined significantly lower myocardial CK activities in this group of patients, most probably reflecting a diminished content of myofibrils. Citrate synthase activity was lowest in patients with AVD. Although we cannot rule out that the impaired left ventricular function is in part responsible for the shift of the capacities of the energy-supplying metabolism in patients with DCM, we favor the assumption that it is a specific feature of this myocardial disease.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1985

Insulin receptor kinase activity in rat liver. Regulation by fasting and high carbohydrate feeding.

Insulin receptor kinase activity was measured in partially purified receptor preparations from livers of rats fed a standard diet or subjected to either prolonged fasting or a high carbohydrate (CHO) diet, conditions known to decrease (fasting) and increase (CHO) insulin action. Basal and insulin-stimulated phosphorylation of the beta subunit of the insulin receptor was comparable in all groups with a half-maximal effect at approximately 2.0 ng/ml free insulin and a 10-12-fold maximal effect. The kinase activity of insulin receptors from the three groups was further examined using the synthetic polypeptide Glu 4:Tyr 1. Basal and insulin-stimulated rates of Glu 4:Tyr 1 phosphorylation were highest in the CHO-fed and lowest in the fasted group. The magnitude of these differences was the same in the absence or presence of insulin; thus, the alterations in receptor kinase activity in fasting and CHO feeding were entirely expressed in the basal rate of peptide phosphorylation. Antireceptor antibody immunoprecipitated 70-80% of the basal Glu 4:Tyr 1 kinase activity in each group; the remaining 20-30% showed minor group differences when normalized for the amount of protein present in the receptor preparations. These results indicate that the group differences in basal kinase were intrinsic to the insulin receptor. Insulin increased the Vmax of Glu 4:Tyr 1 phosphorylation by approximately 30 fmol of phosphorus/fmol of binding activity/30 min in all three groups; however, the absolute Vmax was highest in the CHO-fed and lowest in the fasted group. The Km of Glu 4:Tyr 1 phosphorylation was unaffected by insulin and was comparable (approximately 0.25 mg/ml) in the three groups. These findings indicate that fasting and CHO feeding produce changes in receptor kinase activity which are regulated by mechanisms independent of insulin and that the alterations show substrate specificity so that differences are detected with one substrate (Glu 4:Tyr 1) but not another (the beta subunit).

Adenosine Triphosphatases↗
PubMed1985

[Experiences with telemetry-supported pacemaker controls in patients with VVI pacemakers].

Investigations on telemetry-supported pacemaker control were carried out in 55 patients with the VVI-pacemaker Quantum (Intermedics). The investigations were done at least once during the 6-24 month period after implantation. The telemetry function was utilised for pacemaker programming, for clarifying pacemaker defects and for characterising the type of pacemaker electrode used. It could be shown that the Osypka spiral electrode VY (Dr. Osypka) had a lower impedance, and greater pulse width and charge threshold in comparison with the two other electrodes used (Encor, Cordis; Polyflex, Intermedics). In 38 of the 55 patients (69%) a pulse amplitude of 2.7 V could be chosen, whereas an amplitude of 5.4 V was programmed in the rest. Pacemaker sensing threshold was set to values between 2.4 and 3.0 mV. Pacemaker problems appeared in three patients; in one patient due to programming too economically and in the other two due to pacemaker defects.

Adult↗
PubMed1985

Substrate specificities of insulin and epidermal growth factor receptor kinases.

The abilities of insulin and EGF stimulated protein kinases to phosphorylate a series of exogenous substrates were compared using wheat germ lectin purified preparations of solubilized rat liver membranes. Three different kinds of substrates were found: substrates phosphorylated primarily by insulin stimulated kinase, substrates phosphorylated primarily by EGF stimulated kinase and substrates phosphorylated by both kinases to a similar extent. These results indicate that the insulin and the EGF receptor kinase have different, but overlapping, substrate specificities. In vivo, phosphorylation of cellular proteins by various hormone receptor kinases may be part of the signal transmission process for actions of the hormones. Different substrate specificities of kinases of different hormone receptors may therefore represent an important mechanism to preserve the specificity of the hormonal signal at the post receptor level.

Angiotensin II↗
PubMed1984

The effect of two different diltiazem treatments on infarct size in ischemic, reperfused porcine hearts.

The effect of diltiazem on the development of infarcts was investigated in porcine hearts. The left anterior descending coronary artery was occluded in each of 32 anesthetized pigs for 75 min and was reperfused for 4 hr. Diltiazem (15 micrograms/kg X min) was infused in 11 pigs for 30 min before occlusion (therapy A) and in another eight pigs before reperfusion (therapy B). Eleven pigs served as controls. Tissue concentrations of adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NAD) were determined in transmural needle biopsy samples taken from the ischemic apex after 70 min of ischemia. The infarct size, expressed as the ratio of the infarcted tissue over the area at risk of necrosis multiplied by 100, amounted to 79 +/- 20% in the control group. Although there was no significant difference between hemodynamics in the control and the treated groups, pretreatment with diltiazem significantly reduced infarct size (53 +/- 26%; p = .025). Reduction of infarct size by therapy B did not reach the required level of significance (66 +/- 33%). The ischemic loss of ATP and NAD was significantly lower in the pretreated group, which further indicates that the beneficial effect of diltiazem was exerted primarily during ischemia and not during reperfusion.

Adenosine Triphosphate↗
PubMed1984

Temporal and spatial development of myocardial infarcts in porcine hearts without significant collateral blood flow.

To evaluate the time-dependent beneficial effect of reperfusion on infarct size, we investigated the temporal and spatial development of infarcts in porcine hearts. The left anterior descending coronary artery was occluded in 17 pigs for different periods of time. Ischemia was always followed by 4 hours of reperfusion. After 60 minutes of ischemia, transmural needle biopsies subdivided into subendocardial and subepicardial halves were removed from the ischemic apex to determine the tissue concentrations of adenosine triphosphate and nicotinamide adenine dinucleotide. The myocardium at risk was determined with a fluorescent dye, and the infarcted tissue with nitroblue tetrazolium stain. Infarct size was expressed as the ratio of the infarcted myocardium over the risk region. Ischemic cell death began in the jeopardized left ventricular subendocardial septum after about 30 minutes of ischemia. Further progress involved the right subendocardial septum and the subendocardium of the left anterior free wall. After 75 minutes of ischemia, most of the myocytes were already irreversibly injured. Tissue damage from the infarctions was complete after 90 to 120 minutes of ischemia. These results indicate that in hearts without a significant collateral blood flow, reperfusion can only reduce infarct size if initiated within 60 to 75 minutes of ischemia. As in canine hearts, infarctions in porcine hearts progress from the ischemic subendocardium toward the outer layers.

Journal Article↗
PubMed1984

Effect of nisoldipine on electrophysiological parameters in patients pretreated with beta-blockers.

The effect of the new 1,4-dihydropyridine calcium antagonist nisoldipine on electrophysiological parameters was investigated in 10 patients who were pretreated with a beta-blocker. 9 patients received atenolol (75 mg/d) and 1 patient pindolol (15 mg/d) at least for three days prior to the electro-physiological study. Before and after the intravenous injection of nisoldipine (1.5 micrograms/kg body weight) the sinus node function (spontaneous sinus node cycle length, sinus node recovery time, rate corrected sinus node recovery time), the conduction times from the high right atrium to the apex of the right ventricle, and the refractoriness of the different compartments of the heart were assessed. Arterial blood pressure was measured with the cuff method. Nisoldipine induced a slight but significant increase of the heart rate without effecting the blood pressure significantly. All other measured electrophysiological parameters remained unaltered, especially the conduction time of the av node. It is concluded that concerning electrophysiology nisoldipine can safely be combined with beta-blockers because this calcium antagonist does not exert an electrophysiological effect.

Adrenergic beta-Antagonists↗
PubMed1983

[Effect of the calcium antagonist nisoldipine on electrophysiologic parameters in the human].

We investigated the influence of nisoldipine, a new calcium antagonist, on sinus node function, intracardiac conduction times, and the refractoriness of different compartments of the heart. Three catheters were placed in the right heart: a quadripolar one in the high right atrium, a bipolar one in the His position, and one in the apex of the right ventricle. Nisoldipine given i.v. in a dose of 1.5 microgram/kg body weight shortened the sinus node cycle length and the sinus node recovery time by 10%. The rate corrected sinus node recovery time, the sinoatrial conduction time, and the intracardiac conduction times remained unaffected. The effective refractory period of the right ventricle decreased slightly but significantly. The refractoriness of the other compartments did not change significantly. Systolic blood pressure decreased by 6%, whereas diastolic blood pressure remained constant. Nisoldipine thus exhibits no major effects on electrophysiological parameters in man. The increase in heart rate is regarded as a sympathetic reflex mechanism due to the decrease of systemic resistance.

Aged↗
PubMedDate not supplied

Postischemic cell death in reperfused porcine hearts is not attenuated by the spin trap agent PBN during early reperfusion.

Ischemic, reperfused porcine hearts were used to investigate whether the spin trap agent PBN (N-tert-butyl-alpha-phenylnitrone) attenuates postischemic cell death by scavenging of free radicals. The left anterior descending coronary artery (LAD) was ligated distally in 16 pigs for 45 min and then reperfused for 3 h. PBN (coronary concentration approximately 1 mM) was infused into the LAD of eight pigs during the first 45 min of reperfusion. Electron spin resonance spectroscopy (ESR) was performed to identify free radical adducts in the reperfused coronary venous blood. Regional systolic shortening (SS%) was determined by sonomicrometry. Infarct size was evaluated as the percentage of infarcted (tetrazolium stain) to ischemic (dye technique) myocardium. The transmural ultrastructural degree of myocardial injury as well as myocardial ATP levels were assessed at the end of the experiment. Intracoronary treatment with PBN during early reperfusion did not attenuate myocardial damage. Infarct sizes (control group 59 +/- 19%, treated group 55 +/- 14%), transmural ultrastructural alterations, myocardial ATP concentrations (control group 1.8 +/- 0.3 mumol/mg frozen weight, treated group 1.7 +/- 0.4 mumol/mg) and regional systolic shortening at the end of the experiments (control group -1 +/- 5%, treated group -2 +/- 6% did not differ significantly. Furthermore, under various experimental conditions of spin trapping, free radical adducts could not be identified in coronary venous blood during early reperfusion. The results suggest that the spin trap agent PBN (1 mM) does not affect postischemic cell death in porcine hearts.

Adenosine Triphosphate↗
PubMedDate not supplied

Cell death in ischemic, reperfused porcine hearts: a histochemical and functional study.

The temporal development of infarcts was histochemically and functionally determined in porcine hearts. In one series of experiments (22 pigs), the distal third of the left anterior descending coronary artery (LAD) was transiently occluded for periods between 20 and 90 min and was reperfused for another 24 h. At the end of the experiments, the infarcted myocardium of four tissue slices was determined with a tetrazolium stain and related to the risk region which was delineated by a fluorescent dye. Infarcts started to develop in the ischemic septum and the subendocardial layer of the free anterior wall between 20 and 35 min of ischemia. Thereafter, infarctions progressed rapidly from the inner towards the outer layer at risk. The jeopardized anterior left ventricular wall became almost completely infarcted within 60 min of ischemia. In a second series of experiments (10 pigs) recovery of systolic shortening was studied with implanted ultrasonic crystals over 3 weeks of reperfusion. At the end of the experiments, systolic shortening was about 75% of baseline level when ischemia had lasted between 20 and 35 min. Almost no recovery was observed when the occlusion time lasted 45 to 60 min. This study suggests that the assessment of myocardial infarction with a tetrazolium stain after 24 h of reperfusion corresponds very well with functional recovery after 3 weeks of reperfusion. Furthermore, determination of regional myocardial function of the ischemic, reperfused segment in the chronic stage may be considered an additional tool to evaluate therapeutic effects on infarct size in this model.

Animals↗
PubMedDate not supplied

Intracoronary superoxide dismutase for the treatment of "reperfusion injury", A blind randomized placebo-controlled trial in ischemic, reperfused porcine hearts.

The effect of recombinant human superoxide dismutase (rh-SOD) on infarct size was investigated in porcine hearts. The left anterior descending coronary artery was occluded in each of 24 anesthetized pigs for 45 min and reperfused for 24 h. The animals were randomly assigned to either rh-SOD (n = 12) or placebo treatment (n = 12). 2 min before reperfusion, an intracoronary (i.c.) infusion of rh-SOD (total dose: 2000 U/kg) or placebo was started which lasted for up to 45 min reperfusion. At the end of the experiment, the infarcted myocardium was assessed using a tetrazolium stain (NBT) and related to the risk region which was determined with a fluorescent dye. Two pigs of the SOD group and one of the control group died before the end of the experiments. Except for a lower calculated myocardial oxygen consumption and a lower dp/dtmax in the SOD group during ischemia, hemodynamic parameters of the two groups did not differ significantly. rh-SOD i.c. treatment during reperfusion did not reduce infarct size significantly. Infarct size amounted to 74 +/- 13% in the control group and to 66 +/- 19% in the treated group. The incidence of reperfusion arrhythmias was not affected by rh-SOD treatment. It is concluded that i.c. rh-SOD treatment at the beginning of reperfusion neither significantly reduces infarct size nor diminishes the incidence of reperfusion arrhythmias in this preparation.

Animals↗
PubMedDate not supplied

A modified regionally ischemic porcine heart preparation with eligible residual blood flows.

The left anterior descending coronary artery was occluded in each of 28 thoracotomized pigs around an intracoronary catheter for periods between 30 and 240 min followed by 90 min of reperfusion. The catheter was connected via an external pump with another arterial catheter. The pump rate was set to deliver 1.5 ml (group I), 3 ml (group II), or 6 ml blood/min (group III) respectively during ischemia. The distribution of the residual blood flow during ischemia was determined in group II with non-radioactive microspheres. We delineated the risk region by a fluorescent dye and the infarcted tissue with a tetrazolium stain. The higher residual blood flow in groups II and III reduced the incidence of ventricular fibrillation during ischemia from 70% (group I) to 28%, suggesting that the amount of residual blood flow is one important determinant for this rhythm disturbance. The subendocardial-subepicardial blood flow ratio in the risk region of the anterior wall was 41%. Infarcts started to develop after 30 min of ischemia (groups I and II). In all groups necrosis progressed most rapidly within the first 90 min of ischemia indicating that besides the beneficial effect of a high residual blood flow only early reperfusion is able to salvage a substantial amount of jeopardized myocardium. Compared to conventional regionally ischemic canine and porcine heart preparations the described model offers the following advantages: Accurate delineation of the risk region, eligible residual blood flow, reduction of ventricular fibrillation with higher residual blood flows, and the possibility to selectively test the metabolic influence of drugs on ischemic injury while avoiding systemic effects.

Animals↗
PubMedDate not supplied

Intracoronary hyperosmotic mannitol during reperfusion does not affect infarct size in ischemic, reperfused porcine hearts.

We investigated the effect of reperfusion with hyperosmotic mannitol on the infarct size in porcine hearts. The distal half of the left anterior descending coronary artery was occluded in each of 21 anesthetized pigs for 75 min and was reperfused for 2 h. During reperfusion mannitol (1075 mosmol/kg) was intracoronarily infused at a dose of 0.5 ml/min in 6 pigs ("low" mannitol group), at a dose of 1.5 ml/min in another 6 pigs ("high" mannitol group), and at a dose of 5 ml/min in 3 pigs for the first 8 min of reperfusion ("very high" mannitol group). 6 pigs served as controls. Although mannitol infusion increased plasma osmolality in the ischemic, reperfused myocardium in all experiments, the infarct size expressed as the ratio of the infarcted tissue over the area at risk of necrosis was not significantly influenced. Infarct size amounted to 72 +/- 25% in the control group, to 75 +/- 14% in the "low" mannitol group, to 78 +/- 18% in the "high" mannitol group, and to 93 +/- 8% in the "very high" mannitol group. These results clearly indicate that reperfusion with hyperosmotic mannitol after 75 min of ischemia does not exert any beneficial effect on the infarct size.

Animals↗