Biomedical subjects

H Brasch

Publications and source records attributed to H Brasch.

At least 37 records · Page 2Linked to original sources

PubMed1990

Experimental studies on the acute cardiovascular toxicity of formalin and its antidotal treatment.

Rats anesthetized with pentobarbital and ventilated artificially were infused with 0.01 ml formalin (= 0.12 mmol formaldehyde)/kg.min. They exhibited a sharp decline of arterial blood pressure, heart rate and peripheral resistance and a slower one of cardiac output and died after 59.9 +/- 6.0 min of infusion. Sinus bradycardia and, in some cases, AV-arrhythmia occurred in the ECG. The additional infusion with cysteine attenuated the cardiovascular failure and more than doubled the survival time of formalin-infused rats. Infusion of N-acetylcysteine or correction of formalin-induced metabolic acidosis with sodium bicarbonate, on the other hand, did not exert antidotal activity. On isolated rat atria in vitro, formalin decreased the rate and the contractility and cysteine antagonized these effects of formalin. In conclusion, the severe and often lethal incidents observed following the therapeutic administration of formalin are due to the cardiovascular-depressive activity of formaldehyde and may be antagonized by cysteine.

Acetylcysteine↗

PubMed1989

No influence of enzyme inhibitors on the hydroxylation of methotrexate in rats.

In anaesthetized rats 50% of an infused dose of methotrexate (MTX) was excreted into the bile. About 3% was metabolized to 7-hydroxymethotrexate (7-OH-MTX), which appeared also in the bile. Pretreatment with allopurinol had no influence on the elimination of MTX or the production of 7-OH-MTX during a 3-h infusion of MTX. Cyanamide decreased the total MTX clearance, but increased the biliary elimination of 7-OH-MTX. Phorone decreased the biliary MTX-clearance, but not the biliary secretion of 7-OH-MTX. The results show that neither aldehyde oxidase nor xanthine oxidase is the predominant hydroxylating enzyme for MTX in the rat.

Aldehyde Oxidase↗

PubMed1989

Activation of alpha 2-adrenoceptors attenuates the inotropic effect of field stimulation in atria.

Guinea-pig left atria were driven to contract at a rate of 0.5 Hz by stimulation with punctate electrodes. For additional field stimulation, a train of one to eight field pulses (30 V; 0.05-0.4 ms duration) was applied during each refractory period. Cholinergic effects were blocked by atropine and thus the resulting increase of the contractile force was caused by noradrenaline released from sympathetic nerve endings. Trains of several short field pulses delivered in the refractory period after each contraction produced a significantly greater inotropic effect than one single pulse of the same total duration delivered in each refractory period. Phentolamine, rauwolscine and idazoxan, by blocking prejunctional alpha 2-adrenoceptors selectively increased the inotropic effect of single field pulses. Selective blockers of alpha 1-adrenoceptors (prazosin, corynanthine) were ineffective in this respect. The effect of alpha 2-adrenoceptor blockers persisted in the presence of noradrenaline uptake blockers (cocaine or desipramine plus corticosterone) or phenylephrine, but was overcome by the alpha 2-adrenoceptor agonists, clonidine and guanabenz. It is concluded that activation of presynaptic alpha 2-adrenoceptors limits the release of noradrenaline by long-lasting single field pulses. Autoinhibition of transmitter release was not seen with trains of short field pulses.

Adrenergic alpha-Agonists↗

PubMed1989

Pulse duration and alpha 2-adrenoceptors modify noradrenaline release from field-stimulated atria.

In guinea-pig atria preloaded with 10 muCi [3H]noradrenaline, field stimulation during the refractory period increased the release of radioactivity and the force of contraction. Both effects were dependent on the extracellular Ca2+ concentration and were abolished by 3 x 10(-8) mol/l tetrodotoxin. When applied during each refractory period, two short (0.05 ms) pulses released significantly more radioactivity than one pulse of 0.1 ms duration applied during each refractory period. Similarly, a train of four pulses (0.05 ms each) was more effective than one pulse lasting 0.2 ms. The radioactivity released by single, long-lasting pulses in each refractory period was increased by phentolamine, idazoxan and N-ethylmaleimide. A small increase was also obtained with prazosin. The effect of phentolamine was antagonized by clonidine but not by phenylephrine. Clonidine did not prevent the effect of N-ethylmaleimide (all drugs 3 x 10(-5) mol/l; atropine 10(-7) mol/l and cocaine 3 x 10(-6) mol/l present in all experiments). It is concluded that activation of prejunctional alpha 2-adrenoceptors reduces the amount of noradrenaline release by one long field pulse in each refractory period. In most experiments, the inotropic effect of the two stimulation protocols was not significantly different. However, when atria were stimulated with four pulses immediately before stimulation with one pulse, the autoinhibition thus caused was strong enough to also reduce the inotropic effect of this stimulation protocol.

Adrenergic alpha-Agonists↗

PubMed1989

[Combination of peritoneal dialysis and hemodialysis in the treatment of chronic renal insufficiency].

In case of 23 patients, who had been treated for 8.5 (2-10) months with intermittent peritoneal dialysis, the peritoneal dialysis was supplemented once or twice a week by haemodialysis for 8.5 months. This combined way of treatment was favourable in cases of hypervolemia and/or of increased level of substances of small molecular weight. The average duration of this kind of treatment was 4.1 (1.5-11) months. In the course of treatment the general condition of the patients improved. When they regained their optimal bodyweight, their blood pressure got normalized or their hypertony decreased or it could be regulated by drug therapy. At the effect of this treatment, the carbamid nitrate and serum creatinin significantly decreased and the serum total protein and albumin levels increased. Two of the patients underwent cadaver kidney transplantation, and 18 of them have been treated by hemodialysis, 3 of them are being treated in this combined way even now. The authors discuss the role of intermittent peritoneal dialysis and that of the combined treatment in the management of uremic patients.

Humans↗

PubMed1989

Pharmacokinetics of methotrexate (MTX) and 7-hydroxymethotrexate (7-OH-MTX) in rats and evidence for the metabolism of MTX to 7-OH-MTX.

In pentobarbital anesthetized rats that received 4 mg/kg i.v. methotrexate (MTX) or 7-hydroxymethotrexate (7-OH-MTX), the pharmacokinetics of the two drugs were similar. Plasma concentrations of both drugs declined biexponentially, with terminal half-lives of 90.6 min for MTX and 97.2 min for 7-OH-MTX. The total clearance values were 9.2 and 9.6 ml x kg-1 x min-1, respectively. With MTX, 48.2% of the dose was excreted in the urine within 200 min and another 31.6% was recovered from the bile; 5.8% was metabolized to 7-OH-MTX and appeared in the bile. Plasma concentrations of the metabolite 7-OH-MTX after MTX administration were below the detection limit. Injected 7-OH-MTX was predominantly excreted into the bile (72.8% of the dose); only 11.2% could be recovered from the urine. Differences between the physicochemical properties of MTX and 7-OH-MTX or different affinities for active transport systems may account for the unequal importance of these two excretion pathways for the two compounds.

Animals↗

PubMed1989

No evidence for an increased lipid peroxidation during reoxygenation in Langendorff hearts and isolated atria of rats.

Rat left atria or Langendorff hearts were kept at 37 degrees C and stimulated at a rate of 3.33 Hz. They were subjected to hypoxia (deprivation of oxygen) or ischemia (deprivation of oxygen and glucose + acidosis + increased extracellular potassium concentration) for 15 min or 1 h and subsequent reoxygenation for 5 or 15 min. Tissue concentrations of proteins, reduced and oxidized glutathione and conjugated dienes were measured at the end of the experiment. Hypoxia and ischemia decreased the excitability and contractility of the preparations and caused contracture. These effects were partly reversible during reoxygenation. However, in Langendorff hearts reoxygenation caused an increased release of CPK, LDH and glutathione into the perfusion fluid. Ischemia and reoxygenation in atria lowered the tissue concentration of reduced glutathione and increased its oxidized form. Similar changes were seen in atria and Langendorff hearts when oxygen radical production was accelerated by hypoxanthine and xanthine oxidase. No treatment raised significantly the concentration of conjugated dienes. These results seem to exclude an important role of an increased lipid peroxidation for reperfusion injury of isolated heart preparations.

Animals↗

PubMed1988

The effects of antibiotics and uricosuric drugs on the renal elimination of methotrexate and 7-hydroxymethotrexate in rabbits.

In anesthetized rabbits, continuous infusion of methotrexate (MTX; 30 micrograms kg-1 min-1) established steady-state plasma concentrations for MTX and the metabolite 7-hydroxymethotrexate (7-OH-MTX) within 40 min. Fifty percent of the infused dose was eliminated unchanged by the kidneys and the renal MTX clearance was slightly higher than the inulin clearance. Another 15%-30% was metabolized and excreted as 7-OH-MTX in the urine. Infusions of 7-OH-MTX, furosemide or benzarone had no influence on the clearance of MTX or 7-OH-MTX. Infusions of probenecid or piperacillin decreased the renal clearance of MTX and 7-OH-MTX mainly by reducing the tubular secretion of both compounds. In contrast, infusions of the antibiotics ceftriaxone and sulfamethoxazole increased the renal elimination of MTX and 7-OH-MTX. An increase was also observed during the infusion of the uricosuric drugs sulfinpyrazone and benzbromarone. These results are consistent with competition for tubular reabsorption between MTX, ceftriaxone and sulfamethoxazole. The pharmacokinetic drug interactions observed occurred with therapeutic drug concentrations and thus may be clinically relevant.

Animals↗

PubMed1988

Electrophysiologic effects of saterinone and milrinone in the isolated guinea pig myocardium.

The positive inotropic agent milrinone and the newly synthesized compound saterinone [+/-)-1,2-dihydro-5-[4-[2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl] propoxy]phenyl]-6-methyl-2-oxo-3-pyridine-carbonitrile, BDF 8634) dose-dependently increased the contractile force of guinea pig left atria. During a 90-min exposure, 10(-4) mol/l saterinone caused a continuous increase of the functional refractory period (FRP), while the initial positive inotropic effect faded gradually. No change of the FRP was observed with milrinone. Saterinone (10(-4) mol/l) also increased the action potential duration and the FRP of guinea pig papillary muscles, while milrinone had no influence on either parameter. Both milrinone and saterinone increased the amplitude, depolarization velocity and duration of slow response action potentials in K+-depolarized muscles. These effects appeared in the presence of tetrodotoxin or propranolol and could be reversed by carbachol. It is concluded that saterinone increases the force of contraction and the slow inward current by inhibiting cardiac phosphodiesterase. The increase of the FRP may be attributed to a decrease of the membrane K+ conductance.

Action Potentials↗

PubMed1986

Influence of the antibiotics piperacillin, doxycycline, and tobramycin on the pharmacokinetics of methotrexate in rabbits.

In rabbits methotrexate (MTX) plasma concentrations showed a triexponential decline after short-term infusion (12 mg/kg in 10 min). Probenecid (50 mg/kg PO 1 h before MTX) and piperacillin (100 mg/kg SC 10 min before MTX plus 50 mg/kg SC 4 h later) increased the plasma concentrations of MTX and its metabolite 7-hydroxy-methotrexate (7-OH-MTX) 40 min to 6 h after the end of MTX infusion. The total body clearance of MTX was reduced, while the elimination half-life and the drug distribution to the peripheral body compartments were unchanged. Doxycycline (5 mg/kg PO 30 min before MTX) had no influence on the pharmacokinetics of MTX. Tobramycin was ineffective when given either only on the day of MTX infusion (2 mg/kg SC, 5 min before MTX and 2 mg/kg SC 4 h later) or as a 5-day pretreatment (2 X 2 mg/kg SC daily). The influence of probenecid and piperacillin can be explained by a reduction of the renal elimination of MTX via the tubular transport mechanism for organic acids. This interaction occurred with therapeutic drug concentrations and thus may be clinically relevant.

Animals↗

PubMed1986

Influence of the optical isomers (+)- and (-)-naloxone on beating frequency, contractile force and action potentials of guinea-pig isolated cardiac preparations.

Naloxone in concentrations ranging from 7.5 to 120 mumol l-1 reduced the beating frequency of guinea-pig isolated atria. The ED50 was 7.9 mumol l-1 for the (-)-isomer and 10.8 mumol l-1 for the (+)-isomer. Concentrations up to 120 mumol l-1 of either (-)- or (+)-naloxone did not affect the force of contraction of left atria stimulated at 1 Hz. In concentrations from 30 to 120 mumol l-1 (-)-naloxone increased the action potential (AP) duration and the functional refractory period (FRP) of papillary muscles. The resting membrane potential and the AP amplitude remained unchanged, while a small decrease of Vmax was seen with the larger drug concentrations. The influence of (+)-naloxone (120 mumol l-1) was comparable to that of the (-)-isomer. The influence of morphine (120 mumol l-1) on papillary muscle AP was small. AP duration and FRP showed a marginal prolongation while Vmax was slightly decreased. (-)-Naloxone 60 mumol l-1 had no effect on slow-response APs of K+-depolarized papillary muscles. Slow-response APs were abolished by verapamil (1 mumol l-1). In left atrial strips the prolongation of the AP duration produced by 120 mumol l-1 of either (-)- or (+)-naloxone resembled the drug effect in papillary muscles. Most of the observed changes can be explained by an inhibition of the time-dependent membrane K+ outward current, an effect of naloxone that may be classified as a Class III antiarrhythmic action. Apparently this effect is not mediated by stereospecific opioid receptors.

Action Potentials↗

PubMed1985

Effects of salicylate and two benzoates on contractions of the field-stimulated guinea-pig vas deferens and atrium.

Na salicylate (3.75-30 mmol/l), Na benzoate (10.5-84 mmol/l) and Na metaiodobenzoate (0.375-0.8 mmol/l) concentration dependently reduced the contractile force of the field-stimulated guinea-pig vas deferens. Contractions elicited by either noradrenaline (0.5 mmol/l) or direct muscle stimulation were also reduced while the maximum twitch response induced by KCl (160 mmol/l) was unaffected. The twitch-inhibiting potency of salicylate and the benzoates correlated to their lipophilicity. The positive inotropic effect of field stimulation of the atrium during the refractory period was not altered by the two benzoates but was reduced by Na salicylate. It is concluded that salicylate and benzoate anions are incorporated into smooth muscle cell membranes of the vas and reduce excitability. No binding seems to occur in membranes of the atrial myocardium or the sympathetic neuron terminals and salicylate or benzoate compounds do not interfere with the liberation of neurotransmitters. In addition to its influence on the cell membrane Na salicylate can diminish contractions by uncoupling oxidative phosphorylation. The use of benzoates can help to distinguish between the two effects.

Animals↗

PubMed1985

Pharmacokinetics of methotrexate and 7-hydroxy-methotrexate in rabbits.

In rabbits the IV kinetics of MTX (1.33, 4 and 12 mg/kg) could be described by a linear three-compartment model with a terminal half-life between 2.4 and 3.6 h. During 8 h 50% of the dose was excreted into urine in unchanged form and 15% as the metabolite 7-OH-MTX. These fractions remained constant with increasing dose. In continuous infusion experiments (9-900 micrograms/kg X min MTX IV) a decrease of the renal MTX clearance with increasing plasma concentration was observed. This effect was nearly compensated by an increase of the extrarenal MTX clearance. After short-term infusion of 7-OH-MTX (4 mg/kg) a biexponential decline of 7-OH-MTX plasma concentrations was observed with a terminal half-life of 0.45 h. About 80% of the dose was regained from urine during 5 h. From the combined pharmacokinetic data a linear model was constructed for the calculation of 7-OH-MTX plasma concentrations after short-term MTX infusion. For the first 4 h after MTX application the predicted values were in good accordance with the 7-OH-MTX concentrations actually measured.

Animals↗

PubMed1984

Protective effects of Na salicylate against digoxin- and BaCl2-induced arrhythmias in guinea-pigs.

In pentobarbital-anaesthetized (60 mg/kg i.p.) guinea-pigs injections of Na salicylate (50 and 100 mg/kg i.v.) had a protective effect against arrhythmias induced by digoxin or BaCl2. A lower (25 mg/kg) and a higher (200 mg/kg) dose exerted no clearcut antiarrhythmic effect. Plasma concentrations of Na salicylate up to 1 mg/ml influenced neither the heart rate nor the ECG parameters. The antiarrhythmic effect of the drug may be explained by an inhibition of cardiac cyclooxygenase.

Animals↗

PubMed1984

Influence of Tris (hydroxymethyl) aminomethane on plasma insulin and glucose concentration of normal and streptozotocin-diabetic rats.

The influence of Tris buffer on plasma glucose and insulin concentrations was investigated in pentobarbital-anesthetized (60 mg/kg i.p.) Wistar rats. A bolus injection of neutralized Tris (5 mmol/kg; pH 7.4) caused a transient increase of plasma insulin concentration (+ 130 +/- 20 microU/ml; means +/- S means, n = 6) but did not change the glucose concentration. A continuous infusion of Tris (0.5 mmol/kg X min for 90 min) reduced the plasma glucose concentration from 8.7 +/- 0.42 to 5.1 +/- 0.33 mmol/l after 30 min. The plasma insulin concentration was elevated during the first 20 min (maximum +122 +/- 21 microU/ml after 10 min). In streptozotocin-diabetic rats (75 mg/kg i.v., 48 h prior to the experiments) an infusion of Tris changed neither glucose nor insulin concentration in plasma. The results indicate that in the rat Tris-induced hypoglycemia is always associated with a transient stimulation of insulin secretion.

Animals↗

PubMed1984

IgA glomerulonephritis: light microscopic and immunohistological studies.

Renal biopsy material of 50 patients suffering from IgA glomerulonephritis was studied by light microscopy, immunofluorescence and occasionally electron microscopy. Associated with a uniform immunohistological pattern mainly focal or diffuse mesangial proliferative glomerulonephritis was found. In addition to the glomerular changes the importance of frequent extraglomerular, mainly vascular and interstitial, alterations is stressed. In arterioles and arteries, deposition of a hyalinous substance was observed. Immunohistology revealed the presence of immunoglobulins and/or C3 in the vessels. In the interstitium fibrinogen/fibrin was often seen, accompanied by chronic inflammatory infiltration and fibrosis.

Arteries↗

PubMed1983

Lack of direct antiarrhythmic electrophysiological effects of salicylate on isolated guinea-pig myocardium.

Conventional microelectrode techniques were used to study the influence of Na-salicylate, Na-benzoate, Na-2,6-dihydroxybenzoate and 2,4-dinitrophenol (2,4-DNP) on the action potential (AP) of guinea-pig papillary muscles and atria. In papillary muscles, Na-salicylate (0.19-1.87 mmol/l) concentration-dependently shortened the AP duration and the functional refractory period. The AP amplitude decreased slightly with the largest concentration, while the resting potential and the maximum depolarisation velocity (Vmax) were not affected. A concentration-dependent negative inotropic effect was also seen. All drug effects were reversible after washout. In atria, 6.24 mmol/l Na-salicylate induced a slight shortening of the AP duration, a decrease of the AP amplitude and Vmax, but no decrease of the contractile force. The effects of the uncoupling agent, 2,4-DNP (10 mumol/l), were similar to those of the largest concentration of Na-salicylate in papillary muscles and in atria. Na-benzoate and Na-2,6-dihydroxybenzoate had no significant influence on AP duration, AP amplitude, resting potential, Vmax, refractory period or force of contraction of either papillary muscles or atria. These results suggest that Na-salicylate exerts its effects on isolated guinea-pig myocardium by uncoupling the oxidative phosphorylation, whereas two other possible mechanisms of action, namely an increase of membrane surface charge and an inhibition of prostaglandin synthesis, seem to be of minor importance.

2,4-Dinitrophenol↗

PubMed1983

Negative inotropic effects of Na-salicylate and three congeners on the guinea-pig Langendorff heart.

In guinea-pig Langendorff hearts, Na-salicylate (1.9, 3.8 and 7.6 mmol/l) concentration-dependently reduced the contractile force (--9.1, --51.0 and --75.1%, respectively) and the coronary resistance. The influence of the uncoupling agent 2.4-dinitrophenol (0.02 mmol/l) was comparable to that of the largest concentration of Na-salicylate. From the three congeners of Na-salicylate that were tested, only 3.5-diiodosalicylate (0.03 mmol/l) reduced the contractility whereas Na-benzoate (42 mmol/l) and m-iodobenzoate (1.2 mmol/l) were inactive. These results suggest that the cardiac effects of salicylate-like compounds in vitro are caused by an uncoupling of the oxidative phosphorylation.

2,4-Dinitrophenol↗