[Heart surgery interventions in risk patients. New possibilities for improving therapeutic results]. / Herzchirurgische Eingriffe bei Risikopatienten. Neue Möglichkeiten zur Verbesserung der Therapieergebnisse.

Perioperative therapy in conjunction with cardiac surgery had so far been guided by functional, paraclinical, and clinical parameters which only conditionally enabled objective appraisal of the present condition of the myocardium. Perioperative recording of the arterio-coronary-venous concentration difference of lactate (acDL) has now enabled the use of an objectivated parameter for accurate description of the metabolic-energetic situation of the myocardium. This will be helpful in metabolic-energetic condition monitoring (MESM) to optimise perioperative cardiotonic therapy. Stabilisation of the metabolic-energetic situation of the myocardium, objectivated by MESM, has proved to be superior to premature cardiac support, using catecholamines. It has been associated with improved restitution with high significance (p less than 0.005).

Perioperative assessment of cardiac energy metabolism by means of arterio-coronary venous difference in lactate concentration (acDL). A parameter for optimizing ventricular function of the postcardioplegic myocardium.

Fourty-three patients undergoing open heart surgery were subjected to extended hemodynamic and metabolic monitoring (arterial and coronary sinus (CS) lactate concentration). In 95% of patients investigated, a significant increase in CS lactate concentration above the arterial lactate concentration was established at the beginning of reperfusion (RPT). In these cases, a decrease in the CS lactate below the arterial concentration occurs within the RPT creating a cross-over point (COP) from negative to positive lactate extraction values. Whereas the initial rise in CS lactate is an expression of the expected ischemia-induced acceleration of anaerobic glycolysis, the onset of a positive lactate extraction can be related to reconsolidation of mitrochondrial oxidative phosphorylation. We found two groups with an early and late COP at 7.2 +/- 0.8 min (ECOP) and 42.5 +/- 5.2 min (LCOP) (P less than 0.005). Whereas a short cross-over time was associated with a normal postoperative outcome, cardiac recovery was delayed in the LCOP group. With the aid of metabolic monitoring it is possible to identify the COP and cardiac overload situations and so to optimize the perioperative outcome, especially in selected patients (NYHA stage III/IV, re-operation, high-risk operation).

[Arterio-coronary venous difference in lactate concentration--a new objective and topical available parameter for the estimation of the energy metabolism status of the heart]. / Die arterio-koronarvenöse Differenz der Laktatkonzentration--ein neuer objektiver und aktuell verfügbarer Parameter zur Einschätzung der metabolisch-energetischen Situation des Herzens.

Cardiosurgical operations were tested experimentally by means of a perioperative metabolic-energetic monitoring and by the conventional method of the hemodynamic monitoring (Swan-Ganz-catheter). By that could be shown that a perioperative monitoring by means of the arterio-coronary venous difference of the lactate level is possible. Intraoperative information about the topical metabolic-energetic condition of the myocardium is to receive as the decisive advantage of this method. An improvement of the therapy results is possible in that way by an optimum of the treatment. A metabolic recovery of the heart during the operation was substantial more favourable for the postoperative myocardial restitution than an early application of catecholamins. This method for perioperative observation should be used specially in risk operations (NYHA-stadium III-IV, reoperations, etc.).

Binding of several phenothiazine neuroleptics to a common binding site of alpha 1-acid glycoprotein, orosomucoid.

The interaction of several phenothiazine neuroleptics with alpha 1-acid glycoprotein was investigated using circular dichroism and equilibrium dialysis techniques. For chlorpromazine only, one high-affinity binding site of the protein was found. The binding of the drug to this single site generated typical polyphasic extrinsic Cotton effects. Since several other phenothiazine neuroleptics gave qualitatively comparable extrinsic Cotton effects in the presence of alpha 1-acid glycoprotein and potently inhibited the binding of chlorpromazine to the single site, it was concluded that all phenothiazine derivatives investigated bound preferentially to only one common binding site of the alpha 1-acid glycoprotein molecule.

Beta-carboline binding indicates the presence of benzodiazepine receptor subclasses in the bovine central nervous system.

Receptor binding studies were performed with tritiated propyl beta-carboline-3-carboxylate ( [3H]PrCC), tritiated ethyl beta-carboline-3-carboxylate ( [3H]ECC), and tritiated flunitrazepam ( [3H]FNT) in membrane preparations from different regions of the bovine brain and retina. Specific binding in all regions investigated was associated with benzodiazepine receptor sites. However, not all benzodiazepine receptors in the regions investigated as determined by the specific binding of tritiated flunitrazepam ( [3H]FNT) are available for [3H]PrCC suggesting that specific [3H]PrCC binding labels only one subclass or subpopulation of the benzodiazepine receptor. This benzodiazepine receptor subclass is sensitive to GABAergic modulation and amounts for about 60% of the benzodiazepine receptors in bovine cortex, hippocampus, and retina but for about 80% of the benzodiazepine receptors in the bovine cerebellum. By contrast, specific [3H]ECC binding in the cerebellum and the hippocampus labeled the same number of benzodiazepine receptors as [3H]FNT, giving no evidence for a benzodiazepine receptor subclass specificity of this compound in the bovine CNS.

Characterization of an important drug binding area on human serum albumin including the high-affinity binding sites of warfarin and azapropazone.

This paper reports a variety of experimental observations which strongly support the assumption that the warfarin binding site, or site I of human serum albumin, is better described as the warfarin-azapropazone binding area, consisting of the overlapping binding sites for warfarin and azapropazone. In general, drugs interacting with one of the two sites will also displace drugs bound to the other site, although their displacing potencies for both sites may vary considerably. This is most pronounced in the case of glibenclamide, which strongly inhibits the binding of drugs to the azapropazone site with only minor effects on drugs bound to the warfarin site. The lone tryptophan residue of human serum albumin, previously shown to be part of the warfarin binding site, is obviously located in the not-overlapping part of the warfarin site, so that its modification affects only the binding of drugs to the warfarin and not to the azapropazone site of this large binding area. The observation of different but overlapping binding sites might explain the fact that the albumin binding of drugs which seem to be bound to similar sites because of their mutual displacement can be affected differently during several disease states.

Optical studies on the specific interaction of dipyridamole with alpha 1-acid glycoprotein (orosomucoid).

The interaction of dipyridamole with alpha 1-acid glycoprotein was investigated by circular dichroism and ultraviolet absorbance measurements as well as by equilibrium dialysis experiments. Dipyridamole is bound to the protein via one site of extremely high affinity and by at least one site of considerably lower affinity. Only the association of dipyridamole with the high affinity site produces typical extrinsic Cotton effects. As a result of experimental observations it is concluded that the high affinity site is located in a hydrophobic protein structure of the glycoprotein.

Benzodiazepine antagonism by harmane and other beta-carbolines in vitro and in vivo.

Harmane and other related beta-carbolines are putative endogenous ligands of the benzodiazepine receptor. Since the compounds are potent convulsants they may have agonist activities at the benzodiazepine receptor while the benzodiazepines may be antagonists. This hypothesis was proved by comparing the in vivo and in vitro antagonism of benzodiazepines by harmane and other beta-carbolines. Harmane is clearly a competitive inhibitor of benzodiazepine receptor binding in vitro. Moreover, harmane-induced convulsions can be inhibited reversibly by diazepam in a manner which is consistent with the assumption of competitive antagonism in vivo. For some beta-carboline derivatives a correlation was found between the affinity for the benzodiazepine receptor in vitro and the convulsive potency in vivo. Thus, the data reported suggest that harmane or other related beta-carbolines are putative endogenous agonists of the benzodiazepine receptor. This suggestion is further supported by the observation that diazepam is equally potent in inhibiting harmane- or picrotoxin-induced convulsions, indicating a convulsive mechanism within the GABA receptor-benzodiazepine receptor system.

Specific [3H]strychnine binding associated with glycine receptors in bovine retina.

Saturable, specific [3H]strychnine binding can be demonstrated in homogenates of bovine retina. Scatchard plots revealed only one set of binding sites with a dissociation constant (Kd) of about 60 nM and a maximal number of binding sites of about 1.5 pmol/mg protein. The structural specificity of [3H]strychnine binding sites in bovine retina parallels the properties found for [3H]strychnine binding sites in the spinal cord of several vertebrates. Thus, the data do not give any evidence that specific [3H]strychnine binding in bovine retina labels taurine rather than glycine receptors and favors glycine rather than taurine as inhibitory neurotransmitter in bovine retina. The subcellular distribution of specific [3H]strychnine binding in bovine retina parallels that of sodium-dependent, high-affinity uptake of glycine and taurine. All 3 parameters are mainly found in the P2 fractions of bovine retina homogenates, containing conventional synaptosomes, most abundant in the inner plexiform layer, but can also be found in the P1 fractions, containing large synaptosomes from the photoreceptor cell layer.

1-Methyl-beta-carboline (harmane), a potent endogenous inhibitor of benzodiazepine receptor binding.

The interaction of several beta-carbolines with specific [3H]-flunitrazepam binding to benzodiazepine receptors in rat brain membranes was investigated. Out of the investigated compounds, harmane and norharmane were the most potent inhibitors of specific [3H]-flunitrazepam binding, with IC50-values in the micromolar range. All other derivatives, including harmine, harmaline, and several tetrahydroderivatives were at least ten times less potent. Harmane has been previously found in rat brain and human urine, so it is the most potent endogenous inhibitor of specific [3H]-flunitrazepam binding known so far, with a several fold higher affinity for the benzodiazepine receptor than inosine and hypoxanthine. Thus, we suggest that harmane or other related beta-carbolines could be potential candidates as endogenous ligands of the benzodiazepine receptor.

Inhibition of GABA and benzodiazepine receptor binding by penicillins.

Penicillins are thought to be GABA receptor antagonists. In order to determine the affinities of various penicillin derivatives for the GABA receptor, their potencies as inhibitors of specific [3H]GABA binding to rat brain membranes were investigated. All investigated penicillins inhibit specific [3H]GABA binding, with IC50 values ranging from 2 to 60 mM. The results are consistent with the assumption that penicillins are weak GABA receptor antagonists.

Benzodiazepine receptor interactions may be involved in the neurotoxicity of various penicillin derivatives.

The interaction of seven penicillin derivatives with specific [3H]flunitrazepam binding to benzodiazepine receptors was investigated. The affinities of the penicillins for benzodiazepine receptor seemed to depend on the lipophilia of the derivatives. The concentrations of the penicillins which inhibit specific [3H]flunitrazepam binding are consistent with penicillin levels found in the central nervous system of patients developing penicillin induced convulsions. The results suggest that penicillins inhibit GABAergic transmission not only at the GABA receptor, but also at the benzodiazepine receptor, which is thought to be part of a neuronal system facilitating GABAergic transmission. Both mechanisms may account at least in part for the convulsive not neurotoxic properties of penicillins.