PubMed Health⌕ Search

Biomedical subjects

E Gerlach

Publications and source records attributed to E Gerlach.

At least 19 recordsLinked to original sources
PubMed1992

Different endothelial mechanisms involved in coronary responses to known vasodilators.

The role of the endothelium in mediating flow responses to acetylcholine (ACh), bradykinin (BK), adenosine (Ado), and the poorly hydrolyzable ATP-derivative beta,gamma-methylene-ATP (MeATP) was evaluated in the intact coronary system of the isolated perfused guinea pig heart. In the presence of superoxide anions, known to inactivate the endothelium-derived relaxing factor nitric oxide (NO), only steady-state dilatation induced by ACh (1 microM) was fully inhibited and that of BK (0.1 nM) attenuated. Similar effects were obtained with methylene blue and N omega-nitro-L-arginine; however, the latter also reduced the actions of Ado (0.1 microM) and MeATP (0.5 microM). Conversely, perfusion with the NO precursor L-arginine (10 microM) resulted in a potentiated relaxation by ACh, whereas steady-state responses to BK and Ado remained unchanged. Pretreatment of hearts with hydroxyl radicals (.OH) elevated vascular permeability. Under this condition, flow increases induced by ACh, BK, and Ado were enhanced by 130, 89, and 47%, respectively, whereas the effect of MeATP (0.5 microM) was reduced by 45%. Preexposure of hearts to the oxidant hypochlorous acid (HOCl) prevented dilatations by ACh, BK, MeATP and Ado (0.1 microM), and the response to Ado (5 microM) was reduced by 68%; postischemic hyperemia was attenuated. Glyburide, an inhibitor of ATP-sensitive K+ channels, halved the flow response to infused Ado (0.1 and 5 microM), inhibited MeATP, and abolished reactive hyperemia. We conclude that in the guinea pig coronary system ACh, BK, MeATP, and Ado (0.1 microM) induce endothelium-dependent vasodilatation, some step(s) of the signal transmission being vulnerable to oxidative attack by HOCl.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

No evidence for the existence of preformed antibodies against hydroxyethyl starch in man.

Using the highly sensitive ELISA technique for detecting anti-hydroxyethyl starch (HES) antibodies in man sera from 1,056 patients were analyzed. Patients of both sex, who had never had any prior contact with HES, were included in the study. In none of the cases could any titer of HES-reactive antibodies be detected. These data suggest that in man preformed HES-reactive antibodies do not exist or are extremely rare. In any case, unlike dextran-reactive antibodies, they should not have a high clinical importance. The mechanism behind the very rarely observed anaphylactoid reactions after HES application is still unknown.

Adult↗
PubMed1991

[Are the radical scavenging properties of ACE inhibitors with sulfhydryl groups in therapeutically effective concentrations of quantitative significance?].

The chemiluminescence reaction elicited from luminol in the presence of hydroxyl radicals was concentration-dependently suppressed by captopril, indicating efficacious radical scavenging. As to be expected, ACE inhibitors lacking free sulfhydryl groups (ramipril, enalapril) were inactive. However, the endogenous scavenger and anti-oxidant uric acid proved to be far superior to captopril, when concentrations of both were compared that are realized in vivo. A substantial augmentation of endogenous scavenging ability during therapy with captopril thus seems unlikely. In a model of standardized myocardial hypoxia (isolated working heart of the guinea pig with 30 min low flow perfusion) captopril, ramiprilat and uric acid equally improved post-hypoxic heart function. There was no cardioprotective action of captopril in excess of that accountable for by inhibition of ACE. It seems possible that ACE (kininase II) inhibitors exert cardioprotection via elevated tissue levels of kinins: bradykinin also improved heart performance after low flow perfusion and bradykinin-induced coronary dilatation was markedly enhanced in the presence of ramiprilate, reflecting attenuated degradation by endothelial kininase II.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Uric acid as radical scavenger and antioxidant in the heart.

Uric acid (UA) is released from the heart of many species, including man, and its site of formation has been shown to be the microvascular endothelium. Since UA reacts with oxygen radicals in vitro, experiments were conducted on guinea pig hearts perfused with Krebs-Henseleit buffer (KHB) to evaluate whether the formation of UA could afford protection from damage by radicals and oxidants. The following results were obtained: (1) Upon addition of the hydroxyl radical scavenger DMSO to the perfusate, the coronary rate of release of endogenous uric acid was increased relative to the precursor purines. (2) UA was degraded during passage through the coronary system and also in KHB in vitro after addition of substances generating hydroxyl radicals or hypochlorite. Superoxide (O2-) radicals did not seem to react directly with UA, though UA concentration-dependently quenched the chemiluminescence generated from luminol in the presence of O2- and OH radicals. (3) Coronary dilation by acetylcholine (Ach) and sub-microM concentrations of adenosine, induced by both via endothelial mechanisms, was attenuated after prolonged inhibition of endothelial UA formation by allopurinol. Furthermore, the effect of Ach but not of adenosine proved acutely sensitive to methylene blue and O2-, substances known to inactivate EDRF. This finding suggests involvement of EDRF in Ach-mediated, but not in adenosine-induced dilatation of the intact coronary system. Exogenously applied UA prevented the impairment of vascular responses to Ach and adenosine caused by allopurinol, and to Ach upon generation of O2-. (4) Hearts performed more pressure-volume work and exhibited greater functional stability when perfused with KHB supplemented with UA in a physiological concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1989

Effects of chronic treatment with adrenaline or propranolol on platelet function and c-AMP levels in the rat.

Most of our knowledge about the modulation of platelet function by catecholamines is based on observations of acute in vitro actions. Little is known about the effects of chronically elevated or reduced adrenergic stimulation of the platelets. We therefore treated rats for 8 weeks with either adrenaline or the beta-blocker propranolol. Adrenaline (0.5 mg.kg-1.d-1) continuously administered from subcutaneously implanted osmotic mini pumps caused an increase in the sensitivity of the platelets towards ADP as stimulating agent. In contrast, chronic application of propranolol (10 mg.kg-1.d-1) via the drinking water led to a reduction in platelet aggregability. For animals treated with adrenaline, in accordance with the results of the aggregation experiments, the levels of c-AMP found in platelet rich plasma were reduced, both basally (by 33%) and after stimulation of platelet adenylate cyclase with prostaglandin E1 (by 39%). For the propranolol treated animals, the basal c-AMP concentrations remained unchanged. The levels of c-AMP attained after stimulation with prostaglandin E1 were diminished to a similar extent as for the adrenaline treated animals (by 38%). Although the in vitro addition of adrenaline to platelet rich plasma causes a beta-adrenoceptor mediated inhibition of platelet aggregation in the rat, the simulation seen after chronic adrenaline exposure in vivo, which is associated with decreases in both basal and stimulated c-AMP levels, suggests a functional preponderance of alpha-adrenoceptors over beta-adrenoceptors on the rat platelets. Although intraplatelet metabolic changes (blockade of stimulated c-AMP formation) after chronic application of propranolol should have resulted in enhancement of platelet aggregability, an inhibition of aggregation was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1989

Inhibition of platelet aggregation following chronic in vivo treatment of rats with nicotine: prevention by simultaneous application of propranolol.

Platelet aggregability is known to be enhanced and platelet-survival time shortened in smokers when compared with nonsmokers. Up to now it is unknown which of the substances in tobacco smoke are responsible for these effects. To evaluate a possible role of nicotine, rats were chronically treated with the alkaloid (10 mg/kg/day), continuously released from subcutaneously implanted osmotic minipumps. Surprisingly, after 8 weeks, platelet sensitivity toward the aggregating stimulus adenosine 5'-diphosphate (ADP) was markedly reduced. The mean ADP concentration required to induce half the maximum rate of aggregation (EC50) was 0.88 mumol/L in nicotine-treated animals, as compared with 0.67 mumol/L in controls (p less than 0.002). Platelet aggregability remained normal when the rats were treated simultaneously with nicotine and the beta blocker propranolol (3.5 mg/kg/day); for these animals, the mean EC50 for ADP was 0.73 mumol/L. These results are suggestive of a catecholamine-mediated action of nicotine. However, neither the basal levels of cAMP in platelet-rich plasma, nor the cAMP levels attained after stimulation of platelet adenylate cyclase with prostaglandin E1 (PGE1), were affected by 8 weeks of treatment with nicotine or nicotine plus propranolol. No effect on platelet aggregation was observed when the rats were treated with nicotine for only 2 weeks, or when nicotine or nicotine plus cotinine were added to platelet-rich plasma in vitro in concentrations equal to those attained in vivo after 8 weeks. Thus, prolonged application of nicotine in vivo caused an inhibition of ADP-induced rat platelet aggregation presumably mediated by beta-catecholaminergic stimulation of platelets.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1989

Purine metabolism in cultured aortic and coronary endothelial cells.

Purine salvage pathways in cultured endothelial cells of macrovascular (pig aorta) and microvascular (guinea pig coronary system) origin were investigated by measuring the incorporation of radioactive purine bases (adenine or hypoxanthine) or nucleosides (adenosine or inosine) into purine nucleotides. These precursors were used at initial extracellular concentrations of 0.1, 5, and 500 microM. In both types of endothelial cells, purine nucleotide synthesis occurred with all four substrates. Aortic endothelial cells salvaged adenine best among purines and nucleosides when applied at 0.1 microM. At 5 and 500 microM, adenosine was the best precursor. In contrast, microvascular endothelial cells from the coronary system used adenosine most efficiently at all concentrations studied. The synthetic capacity of salvage pathways was greater than that of the de novo pathway. As measured using radioactive formate or glycine, de novo synthesis of purine nucleotides was barely detectable in aortic endothelial cells, whereas it readily occurred in coronary endothelial cells. Purine de novo synthesis in coronary endothelial cells was inhibited by physiological concentrations of purine bases and nucleosides, and by ribose or isoproterenol. The isoproterenol-induced inhibition was prevented by the beta-adrenergic receptor antagonist propranolol. The end product of purine catabolism in aortic endothelial cells was found to be hypoxanthine, whereas coronary endothelial cells degraded hypoxanthine further to xanthine and uric acid, a reaction catalyzed by the enzyme xanthine dehydrogenase.

Animals↗
PubMed1988

Endothelium-mediated coronary dilatation by adenosine does not depend on endothelial adenylate cyclase activation: studies in isolated guinea pig hearts.

Adenosine, applied to the coronary system of guinea pigs at up to 10(-6) M, elicits dilatation solely via an endothelium-mediated process. We investigated the role of coronary A2 receptors in this dilation, since the coronary endothelium possesses adenosine A2-receptors with a stimulatory action on the adenylate cyclase. In situ, A2 receptor stimulation can be assessed by prelabeling the coronary endothelial adenine nucleotide pool with 3H-adenosine and subsequently determining the rate of release of radiolabeled cAMP induced by A2 agonists. Thus, perfusion of isolated hearts with 5'-N-ethylcarboxamidoadenosine (NECA) dose-dependently increased coronary flow and the release of 3H-cAMP from the endothelium. In the presence of 50 microM 2',5'-dideoxyadenosine (ddA), a P-site agonist which inhibits the catalytic activity of adenylate cyclase, coronary flow increases induced by both adenosine and NECA were unaffected. In contrast, ddA reduced the release of labeled cAMP in response to NECA by about 60%. In cultured endothelial cells, ddA likewise inhibited cAMP accumulation due to NECA by about 70%. Moreover, ddA antagonized the adenylate cyclase mediated flow response due to the PGI2 analogue, iloprost, as well as the positive chronotropic and inotropic actions of isoproterenol. The dissociation elicited by ddA between the coronary flow response and the release of cAMP strongly indicates that the endothelial A2 receptors which are linked to adenylate cyclase are not causally involved in endothelium-dependent coronary dilatation induced by adenosine.

Adenosine↗
PubMed1979

Purine metabolism in cultured coronary endothelial cells.

Endothelial cells from coronary vessels of guinea pig hearts were isolated, cultivated and morphologically characterized. --Cells from confluent cultures contained adenine nucleotides and their dephosphorylated degradatives in exceptionally high amounts. --Adenine nucleotide levels were only slightly influenced by the growth state of the cultures and remained stable during incubation for three days in purine-free medium. In contrast, brief incubation of endothelial cells under anoxic conditions resulted in a substantial breakdown of adenine nucleotides associated with an enhanced formation and release of adenosine. --Measurements of specific activities of enzymes involved in adenine nucleotide synthesis and degradation lend additional support to the view that a very active adenine nucleotide metabolism is a typical feature of cultured coronary endothelial cells.

Adenine Nucleotides↗
PubMed1979

Functional and metabolic features of an isolated perfused guinea pig heart performing pressure-volume work.

Cardiac performance and some parameters of glycolytic and oxidative metabolism were analyzed in isolated perfused guinea pig hearts performing pressure-volume work. Perfusion medium was an oxygenated Krebs-Henseleit bicarbonate buffer (pH 7.4) which contained glucose and physiological concentrations of pyruvate and insulin. The pressure-flow relationship in the coronary vascular bed indicated autoregulation of coronary flow. Left ventricular function was influenced by aortic pressure (Pa) and venous filling pressure (Pv) in accordance with the Frank-Starling principle, i.e. stroke work increased as a function of Pa or Pv to a certain maximum and then decreased. Myocardial oxygen consumption (MVO2), on the other hand, was linearly correlated with Pa and Pv, respectively, over the entire pressure range. Efficiency of the left ventricle, therefore, increased to an optimum (16%) and decreased at higher pressures. Myocardial contents of glycogen, ATP and creatine phosphate were not markedly influenced by a change in Pa or Pv. L-Noradrenaline (0.08 micrometer, NA) stimulated stroke work and MVO2 at a all Pv tested; efficiencies reached physiologic values (21%) at high volume loads. The increased MVO2 was associated with an acceleration of pyruvate decarboxylation and lactate release up to 10- and 15-fold, respectively, at elevated but physiological NA concentrations (0.2 micrometer). Our results demonstrate that the isolated perfused working guinea pig heart compares favourably with the non-failing Starling heart-lung preparation and hearts in situ, as far as coronary function, left ventricular performance and oxidative metabolism are concerned.

Animals↗
PubMed1978

Radioimmunoassay for adenosine in biological samples.

A sensitive and specific radioimmunoassay for adenosine has been developed. Antibodies directed against adenosine (titer 1:400--1:700) were obtained by immunizing rabbits with adenosine, conjugated via its vicinal hydroxyl groups to bovine serum albumin (periodate oxidation). Interfering adenosine deaminase activity was removed from the antisera by treatment with DEAE-cellulose. Free and antibody bound 3H-adenosine was separated by either the "second antibody" precipitation method or by a simple filtration step. The sensitivity and assay range for adenosine was 1--100 pmoles per assay tube. Structurally related purine compounds (adenine nucleotides, adenine) crossreacted with adenosine binding and were removed by a single chromatographic step. Analysis of the adenosine content in normoxic guinea pig hearts yielded 2.53 nmoles/g, a value which was confirmed by spectrophotometric analysis.

Adenosine↗
PubMed1978

Stimulation of myocardial adenine nucleotide biosynthesis by pentoses and pentitols.

In rats, pentoses and pentitols, intravenously injected in a single dose of 100 mg/kg, induced a considerable enhancement of the available pool of 5-phosphoribosyl-1-pyrophosphate and of the rate of adenine nucleotide biosynthesis in the heart, but not in liver and kidney. De novo synthesis of adenine nucleotides not detectable in skeletal muscle of normal rats became measurable after application of ribose. The stimulatory effect of isoproterenol on myocardial adenine nucleotide biosynthesis could be further potentiated by ribose and xylitol, but not by glucose. The isoproterenol-induced decrease of cardiac adenine nucleotide concentrations could be almost completely prevented by repeated administrations of ribose. Thus, pentoses and pentitols in combination with beta-receptor stimulation markedly and quite specifically enhance adenine nucleotide biosynthesis in the rat heart. The results indicate that the increase in the available pool of 5-phosphoribosyl-1-pyrophosphate is an important factor for the enhancement of cardiac adenine nucleotide biosynthesis. Moreover, the availability of 5-phosphoribosyl-1-pyrophosphate and the rate of de novo synthesis of adenine nucleotides in the heart seem to be limited by the flow through the hexose monophosphate shunt.

Adenine Nucleotides↗
PubMed1977

Adenosine as inhibitor of myocardial effects of catecholamines.

Infusion of adenosine into the coronary arteries of isolated guinea pig hearts produced a dose-dependent inhibition of dP/dtmax caused by bolus injections of isoproterenol (4 X 10(-11) moles). Threshold concentration of adenosine was 10(-7) M and maximal inhibition (90%) occurred at 10(-5) M. Coronary dilation induced by papaverine did not influence the contractile response to catecholamines. In addition to its influence on cardiac performance, adenosine (10(-5) M) effectively inhibited the isoproterenol (10(-7)M) induced initial rise in myocardial levels of cyclic 3'5'-AMP, glucose-1-phosphate and glucose-6-phosphate. Adenosine also antagonized the effect of isoproterenol on adenylate cyclase activity in a crude membrane preparation from guinea pig ventricles; it was without effect on the activity of the membrane phosphodiesterase. Theophylline inhibited the actions of adenosine both on adenylate cyclase activity and on contractile force development. Upon infusion of isoproterenol (3 X 10(-7)M) into the coronary arteries of the isolated heart (perfusion at constant pressure), the adenosine concentration in the effluent perfusate increased within 45 s from 10(-8) M to about 10(-6) M. It thus appears conceivable that in ventricular myocardium endogenously formed adenosine may serve 2 functions: dilation of the coronary arteries and limitation of the inotropic and metabolic effects of catecholamines.

Adenosine↗
PubMed1977

Release of adenosine, inosine and hypoxanthine from the isolated guinea pig heart during hypoxia, flow-autoregulation and reactive hyperemia.

In an attempt to test the hypothesis whether adenosine is involved in the regulation of coronary flow adenosine, inosine and hypoxanthine were measured in the effluent perfusate and in the tissue of isolated guinea pig hearts under various experimental conditions. In addition, the release of 14C-adenosine, 14C-inosine and 14C-hypoxanthine was determined after prelabeling cardiac adenine nucleotides with 14C-adenine. The decrease in coronary resistance induced by hypoxic perfusion (30% and 20% in the gas phase) and during autoregulation was associated with a considerable increase in the release of adenosine and hypoxanthine. Under both conditions the concentrations of adenosine in the effluent perfusate were clearly within the coronary vasodilating range of exogenously administered adenosine. The tissue content of adenosine also increased significantly when the perfusion pressure was reduced. The release of 14C-adenosine closely paralleled the changes in coronary resistance during hypoxic perfusion, autoregulation and during reactive hyperemia. The specific activity of adenosine in the effluent perfusate, however, decreased substantially upon reduction of the oxygen supply to the heart, indicating that the release of 14C-adenosine does not provide an absolute measure of total adenosine release by the heart. Our data indicate that the greater part of the adaptive changes of vascular resistance during hypoxia and autoregulation can be attributed to adenosine which is formed at an enhanced rate under these conditions. However, other factors might be involved as well.

Adenosine↗
PubMed1977

Studies on the regulation of the biosynthesis of myocardial adenine nucleotides.

1) Changes in the rates of biosynthesis of adenine nucleotides in rat hearts under various experimental conditions are paralleled by corresponding alterations in the concentration of cyclic AMP. 2) Pentoses and pentitols cause an acceleration of the de novo synthesis of adenine nucleotides in the normal heart and a further amplification of the increase of adenine nucleotide synthesis in isoproterenol-stimulated hearts. 3) The enhancement of de novo synthesis of adenine and nucleotides induced by isoproterenol as well as by pentoses and pentitols appears to be causally related to a greater availability of 5-phos-phoribosyl-1-pyrophosphate.

Adenine↗