[On the method of action of new types of coronary dilatators with simultaneous oxygen-saving myocardial effects, prenylamine and iproveratril. 2].
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Angina Pectoris↗
Biomedical subjects
H Kammermeier
Publications and source records attributed to H Kammermeier.
Is fatty acid uptake in cardiomyocytes determined by physicochemical fatty acid partition between albumin and membranes?
Palmitate uptake by isolated, calcium-resistant cardiomyocytes was measured by using a stimulation chamber in which cell contraction can be evoked electrically. Experiments were performed in a medium containing physiological interstitial concentration of albumin (2%) and palmitate/albumin (P/A) ratios ranging from 0.03 to 2.5, and were compared to experiments with fixed P/A ratio (= 1). Initial rate of uptake (Vi) was calculated from fitted uptake vs. time curves as measured by accumulation of radioactivity in the cells from 14C-labelled palmitate. Vi-vs.-concentration curves exhibited a saturable component, if albumin concentration was kept constant. Almost no change in Vi was observed in experiments performed at constant P/A. This is in contrast to the albumin receptor hypothesis. The 14C-palmitate content of the myocytes as estimated by thin-layer-chromatography did reach a plateau at less than or equal to 30s and had the same value at 30 min after administration. The cellular content of labelled palmitate could be attributed to the membrane compartment as calculated from partition coefficient (Kc) of fatty acids (FA) between albumin and membranes. With electrical stimulation Vi-vs.-palmitate concentration kinetics showed a shift in apparent Km from 62 microM (P/A = 0.22) to 23 microM (P/A = 0.08), and presence of 2,4-dinitrophenol increases Vi. Our results suggest that FA-transfer across the sarcolemmal membranes is determined by a physicochemical equilibrium between the compartments of extracellular FA-albumin complex, the membrane lipid phase, intracellular FA binding proteins and the respective aqueous phases.(ABSTRACT TRUNCATED AT 250 WORDS)
2,4-Dinitrophenol↗
Interstitial noradrenaline concentration of rat hearts as influenced by cellular catecholamine uptake mechanisms.
Marked concentration differences of noradrenaline (NA) between the vascular and the interstitial compartment were detected by sampling interstitial transudate from isolated perfused rat hearts. The ratios of vascular/interstitial concentration amounted to 7.4 to 1.3 depending on the concentration of NA administered (3 x 10(-9) to 10(-6) M). These concentration differences were abolished by inhibitors of uptake1 [desipramine (DMI)] and uptake2 (O-methyl-isoprenaline (OMI)). Neuronal uptake1 was characterized by a Km of 0.22 mumol/l and a Vmax of 370 pmol x min-1 x gWWT-1, extraneuronal uptake2 by a KUPTAKE of = 0.313 min-1. The apparent permeability surface area (P x S)-product calculated from uptake rate and transcapillary concentration difference was significantly decreased by administrating 100 mumol/l (NA) in presence of DMI. A presumed endothelial uptake mechanism contributing to catecholamine translocation was investigated in endothelial cells in culture. These cells showed a specific noradrenaline uptake with a K(m) of 4.35 mumol/l and a Vmax of about 75 pmol x min-1 x gWWT-1. Any inhibition by inhibitors of both of the two noradrenaline uptakes was lacking. The uptake rate of this mechanism is insufficient to contribute to the diffusive conductivity of the capillary wall (P x S-product). We conclude from our investigations on interstitial concentrations of catecholamines and transcapillary concentration differences, that the capillary wall, owing to its metabolic and diffusional characteristics, influences the exchange of catecholamines to a substantial and physiologically relevant extent.
Animals↗
Characterization of catecholamine uptake2 in isolated cardiac myocytes.
Extraneuronal catecholamine uptake was investigated in isolated quiescent rat myocardial cells. By administration of (3H-)(-)-noradrenaline concentration of 22 nmol/l up to 1000 mumol/l the following data were obtained: (1) The KM of the uptake process amounted to 260 mumol/l, the Vmax to 4.24 nmol/ (10 min x mg Protein) corresponding to 179 nmol/(min x gWWt)(WWT = Wet Weight). (2) The uptake was largely inhibited by the uptake2-inhibitors corticosterone (100 mumol/l), isoprenaline (IC50 = 30.6 mumol/l), and O-methylisoprenaline (IC50 = 2.1 mumol/l), but not by the uptake1-inhibitors cocaine (100 mumol/l) and desipramine (10 mumol/l). (3) The 'affinity'-values KM and IC50 closely agreed with those already known, but the Vmax-value was higher than those obtained in whole rat hearts by a factor of at least 1.79. This is caused presumably by the voltage dependence of the uptake mechanism and the resulting inhibition of uptake2 during the periods of depolarisation in beating hearts of other studies.
Animals↗
Catecholamine-induced cardiac necroses: protective effect of leucocytopenia, influence of an S2 antagonist, thromboxanesynthetase inhibitor and prostacycline analogue.
The influence of various drugs and leucocytopenia (induced by cyclosphamid) on isoproterenol(40 mg/kg, s.c.)-induced cardiac necroses was investigated in female SPF Sprague Dawley rats. The influence of fibrinogen reduction was investigated in spontaneously hypertensive rats (SHR). 8-15% of the area of 15 cross-sections were evaluated with a computer-aided morphometric device allowing classification of number and area of necroses. The reduction of number and area of necroses amounted to approximately: 50% by prostacyclin analogue, 25% by S2 inhibition (ketanserin). Inhibition of thromboxane synthesis and fibrinogen reduction from elevated values (200 mg/dl) below the limit of detection by infusion of 35 U/kg Ancrod in SHR had no significant effects, where in SHR only 10 mg/kg isoproterenol were tolerated with a higher extent of necrosis formation. Leucocytopenia caused a reduction of necroses of over 90%. The condition of mismatch of oxygen consumption and supply induced by high doses of isoproterenol can be considered a model of angina pectoris. The effect of leucocytopenia indicates an essential role of leucocytes in necrosis formation in both situations.
Animals↗
Isolated, (Langendorff) hearts perfused with an aqueous buffer (should) have excess oxygen availability.
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Animals↗
Alteration of vascular endothelium and endothelium smooth muscle interaction after carbogen gas perfusion of isolated rat and guinea pig heart.
The aim of the study was to alter the vascular endothelium of the mammalian myocardium with respect to coronary flow regulation and vascular permeability. For this purpose, carbogen gas perfusion (GP) of Langendorff-type isolated rat and guinea pig heart was chosen. Perfusion of the hearts with carbogen gas was possible, as well as replacement of the GP by fluid perfusion. The energetic and mechanical state, the creatine kinase release, and the electron microscopic examination of the rat heart indicated only a moderate to minimal alteration of the cardiomyocytes after GP. As a result of GP a massive alteration of the vascular endothelium could be demonstrated in the rat heart, based on the release of the cytosolic endothelial marker enzyme, purine nucleoside phosphorylase, the partly altered vascular permeability and the morphologically detected endothelial damage to arterioles, capillaries and venules. Moreover, the reduced coronary flow response to short periods of anoxia (rat, guinea pig) and the inverted flow response to serotonin administration with maintained response to sodium nitroprusside (rat) in the post-gas perfusion period reflected an alteration of endothelial smooth muscular interaction in the rat and guinea pig heart. Furthermore, the distensibility of the coronary vasculature was increased in the rat and guinea pig heart in the post-gas perfusion period, where a relative autoregulatory behavior was maintained (rat) or partly maintained (guinea pig) in passively predilated vessels. In conclusion, carbogen gas perfusion of isolated hearts allows to induce preferred alteration of endothelium and endothelium-smooth muscle interaction.
Animals↗
Meaning of energetic parameters.
High energy phosphates (HEP: ATP & phosphocreatine (PCr)) are to be considered under qualitative (free energy of hydrolysis) and quantitative (concentration) aspects. Energy charge is also a (normalized) concentration related parameter. Owing to high turnover rates concentration (HEP stores) provides sufficient energy only for 10 to 20 s in the case of interruption of supply. Utilization (without immediate supply) leads to rapid drop of free energy which--owing to the CK reaction--is indicated by rapid drop of PCr and the respective ratios. Critical reduction of free energy appears to be prevented by various protective mechanisms reflected in phenomena of early hypoxic failure, hibernating and stunning.
Adenosine Diphosphate↗
Time dependent partial loss of the effects of isoproterenol on function and energy metabolism of isolated rat hearts.
In isolated perfused rat hearts (medium: Krebs-Ringer solution containing about 15% bovine red cells) the following parameters were estimated: heart rate (F), left intraventricular peak pressure (P), dP/dt, oxygen consumption (VO2); myocardial tissue content of glycogen, ATP, ADP, AMP, cAMP, phosphocreatin (PC) and inorganic phosphate (Pi). Isoproterenol (ISO) was administered to the non circulating system in the concentration range of 5 x 10(-10) to 5 x 10(-5) M for 4 min and 1 hour respectively by infusion into the perfusate close to the aortic canula. After administration period of 4 min dependent on the concentration of ISO, P, dP/dt, VO2 and the content of cAMP are increased. The ratios of PC/Pi and ATP/ADP as well as glycogen content are reduced. For an administration period of 1 hour at a level of 5 x 10(-9) M the effects of isoproterenol are maintained. At ISO concentration higher than 5 x 10(-9) M the effects on mechanical parameters and VO2 fall to the level of those values which are produced at 5 x 10(-9) M ISO. In contrast, high energy phosphates and glycogen content remain reduced while that of cAMP is elevated.
Adenine Nucleotides↗
Myocardial high energy phosphates and function as influenced by di- or trivalent cations and isoproterenol or DBcAMP.
The effects of Mn++, La+++ and Co++ (2 mM) with and without ISO or DBcAMP were investigated in isolated perfused rat hearts concerning mechanical and metabolic parameters. Mn++ and La+++ produce cardiac arrest accompanied by unchanged content of high energy phosphates. ISO or DBcAMP resp. administered together with these cations do not exhibit characteristic effects. Co++ induces cardiac arrest as well, but in addition severe reduction of high energy phosphate stores and O2-consumption. The effects of Co++ can be partly prevented by administration of ISO and elevated extracellular Ca++ concentration concerning mechanical parameters and oxygen consumption, whereas high energy phosphate stores remain low. The results obtained demonstrated that the Ca++ antagonistic ions studied show the expected metabolic consequences of EC-uncoupling only in the case of Mn++ and La+++. Co++ ions induce in additions to cardiac arrest and low O2-consumption severe reduction of high energy phosphate stores indicating disturbance of respiratory control of mitochondria.
Adenosine Diphosphate↗
Function and energy metabolism of isolated rats hearts as influenced by Sr++.
Effects of Sr++ and isoproterenol were studied in rat hearts perfused with red cell containing media. Sr++ in the presence of Ca++ causes a positive inotropic effect without corresponding metabolic changes. Without Ca++ 0.5 mM Sr++ causes an immediate arrest, 2 mM Sr++ a complete contracture (14 min) and 5 mM a contracture after about 44 min. At a level of 10 mM Sr++ phasic contractions are maintained (60 min). Occurring phasic contractions are prolonged 3 to 6fold. Administration of isoproterenol (ISO) at a level of 0.5 mM Sr++ causes a delayed occurrence of cardiac arrest and incomplete contracture. At a concentration of 2 and 5 mM Sr++ positive inotropic responses proceed to a contracture (7 min, 50 min resp.). VO2 is reduced by 0.5 mM Sr++ initially by 2 mM Sr++ with delay. 5 and 10 mM Sr++ induce an initial increase. Subsequent decrease is smallest at 10 mM Sr++ ISO at all Sr++ concentrations induces an increase in VO2 initially and strong reduction finally. During 10 min administration, high energy phosphate stores (HEP) are reduced at all Sr++ concentrations, but to the smallest extent at 10 mM Sr++, ISO at levels of 0.5 and 2 mM Sr++ induces a partial recovery of HEP, but at 5 and 10 mM a further reduction. Finally, under the influence of ISO the metabolic state is similar to that without ISO. Sr++ at high concentrations in absence of Ca++ seems to be capable of substituting in principle for Ca++ also concerning metabolism. Severe metabolic disturbances at low Sr++ concentrations indicate a failure of regulation of oxidative phosphorylation.
Adenosine Diphosphate↗
Are isolated cardiomyocytes a suitable experimental model in all lines of investigation in basic cardiology?
Isolated cardiac myocytes of adult rats resemble the intact myocardium in many respects. Thus, use of isolated cells has been established in many lines of basic cardiological research. In electrophysiology, ionic channels can apparently be characterized more accurately than in intact tissue. The transport of metabolites across the sarcolemma can be studied independently of the influence of other types of cells and transport barriers. However, most reports about metabolism deal with quiescent cells, which obviously have a very low metabolic rate, provided they are intact, and their oxidative phosphorylation is not uncoupled. Thus, their application as a model of a working heart appears to be restricted. But using electrical stimulation, the metabolic activity of the cells can be gradually enhanced up to those values observed in beating hearts. In this case, the measurement of mechanical parameters as the myocytes respond to the electrical stimulation is of interest. The combination of the measurements of both metabolic and mechanical parameters in a physical model, led us to investigate the possibility of measuring inotropic effects as well as the relationship between mechanical changes and changes in oxygen consumption, e.g. as a result of the utilization of different substrates. This expands the application of the model to pharmacology, in which the influence of the mechanical action of the heart and its oxygen consumption is of major interest. If the model of isolated cardiomyocytes is employed in screening studies, a reduction in the number of experimental animals required for this line of research will inevitably result.
Animals↗
Biomechanics of valvular plane displacement of the heart.
There has been no consensus concerning the particular movement of the valvular plane of the heart (VPM). As shown in this study involving a mathematical model based upon the momentum equation and experiments on a specially designed artificial heart pump, the VPM not only results from the shortening of the heart, but also from blood flow within the heart and large blood vessels, from the forces caused by the muscle movements, and from the elastic properties of the heart's suspension. The results of the calculations and the experiments confirm the effect of the so-called valve mechanism and its influence on the economic beating action of the heart.
Aortic Valve↗
Quantification of horseradish peroxidase delivery into the arterial wall in vivo as a model of local drug treatment: comparison between a porous and a gel-coated balloon catheter.
PURPOSE: To quantify horseradish peroxidase (HRP) delivery into the arterial wall, as a model of local drug delivery, and to compare two different percutaneous delivery balloons. METHODS: Perforated and hydrophilic hydrogel-coated balloon catheters were used to deliver HRP in aqueous solution into the wall of porcine iliac arteries in vivo. HRP solutions of 1 mg/ml were used together with both perforated and hydrophilic hydrogel-coated balloon catheters and 40 mg/ml HRP solutions were used with the hydrogel-coated balloon only. The amount of HRP deposited in the arterial wall was then determined photospectrometrically. RESULTS: Using the 1 mg/ml HRP solution, the hydrogel-coated balloon absorbed 0.047 mg HRP into the coating. Treatment with this balloon resulted in a mean vessel wall concentration of 7.4 microg HRP/g tissue +/- 93% (standard deviation) (n = 7). Treatment with the hydrogel-coated balloon that had absorbed 1.88 mg HRP into the coating (using the 40 mg/ml HRP solution) led to a mean vessel wall concentration of 69.5 microg HRP/g tissue +/- 74% (n = 7). Treatment with the perforated balloon using 1 mg/ml aqueous HRP solution led to a mean vessel wall concentration of 174 microg/g +/- 81% (n = 7). Differences between the hydrogel-coated and perforated balloons (1 mg/g solutions of HRP) and between hydrogel-coated balloons (0.047 mg vs 1.88 mg absorbed into the balloon coating) were significant (p < 0.05; two-sided Wilcoxon test). CONCLUSIONS: The use of a perforated balloon catheter allowed the delivery of a higher total amount of HRP compared with the hydrogel-coated balloon, but at the cost of a higher systemic HRP application. To deliver 174 microg HRP per gram of vessel wall with the perforated balloon, 6.5 +/- 1.5 mg HRP were lost into the arterial blood (delivery efficiency range = 0.2%-0.3%). With 0.047 mg HRP loaded into the coating of the hydrogel balloon, 7.4 microg HRP could be applied to 1 g of vessel wall (delivery efficiency 1.7%), and with 1.88 mg HRP loaded into the coating of the hydrogel balloon, 69.5 microg HRP could be applied per gram of vessel wall (delivery efficiency 0.6%).
Animals↗