Biomedical subjects

G Stark

Publications and source records attributed to G Stark.

At least 73 records · Page 4Linked to original sources

PubMed1996

The antiarrhythmic effect of verapamil on atrioventricular re-entry in the Wolff-Parkinson-White syndrome: a computer model study.

Verapamil is supposed to suppress the initiation of circus movement supraventricular tachycardia by affecting the atrioventricular node. In electrophysiological tests, programmed stimulation is usually performed by using the same location for pacing and premature stimulus. Spontaneous ectopic activity starts from a different location than the sinus node and can therefore find altered re-entry conditions. In this study a 3D computer model based on Huygen's principle is used for simulation of the spread of excitation in the human heart in combination with a posterobasal, right or left lateral accessory pathway (AP). The effect of verapamil on properties of the atrioventricular node were modelled by prolonging the effective refractory period and basal conduction time. For each of the three APs, ectopic foci at the atrial base and between sinus node and AP were modelled at various coupling intervals for investigating re-entrant activation. In the control state (without verapamil) only orthodromic echoes were found. The maximum echo zone (EZ) range was found near the AP. If stimuli were selected further away from the AP on the atrial basis, the EZ range decreased until no EZ was found. The EZ range decreased from it's maximum value near the AP, towards the difference of the effective refractory periods between AP and AV-node near the sinus node Verapamil abolished the EZ in case of a posteroseptal AP. For a lateral AP the administration of verapamil resulted in an orthodromic and antidromic EZ depending on the atrial premature activation site. A maximum orthodromic EZ was found for premature stimuli near the AP. As stimulus site moved away from the AP, the EZ range first decreased continuously to zero leading eventually to an antidromic EZ. These findings suggest the important influence of the site of premature stimuli with respect to the accessory pathway and AV-node on the inducibility of atrial re-entry.

Anti-Arrhythmia Agents↗

PubMed1996

Effects of verapamil and diltiazem on the ventricular rate during simulated atrial flutter in isolated guinea pig hearts.

To compare the direct effects of verapamil and diltiazem on the ventricular rate during atrial flutter, we developed an atrial flutter model in guinea pig isolated hearts. Atrial flutter was simulated by rapid atrial pacing (cycle length = 50 ms). At this atrial pacing cycle length, the shape of the frequency of distribution of the ventricular cycle lengths was comparable to that during spontaneous atrial flutter. Verapamil (0.01, 0.03 microM) and diltiazem (0.03, 0.09 microM) caused a comparable prolongation of the atrioventricular conduction time and atrioventricular refractoriness. Also, the anterograde Wenckebach cycle length was increased to a comparable degree by both substances. The mean ventricular cycle length during atrial flutter was comparable prolonged by both substances. The prolongation of the maximal ventricular cycle length was significantly more pronounced in the presence of verapamil. The time dependence of drug-induced alterations in atrioventricular conduction time during abrupt changes of heart rate is significantly more pronounced in the presence of verapamil compared to diltiazem. In conclusion, the more pronounced effect of verapamil on the maximal ventricular cycle length compared to the action of diltiazem may be explained by the slow binding kinetic of this drug to the Ca2+ channel resulting in a longlasting blockade of the Ca2+ channel.

Animals↗

PubMed1996

Quantification of rate-dependent effects of verapamil, diltiazem, and digoxin on atrioventricular conduction.

The calcium channel blocking agents, verapamil and diltiazem, and the digitalis compound, digoxin, caused drug specific rate-dependent changes of the atrioventricular conduction time (AVCT). The purpose of this study was to investigate this rate adaptation of the AVCT in isolated guinea pig hearts perfused by the method of Langendorff to get an insight in drug-specific binding kinetic to the respective channel. In the presence of 10 nM verapamil, 30 nM diltiazem, or 0.6 nM digoxin, the atrioventricular conduction time was prolonged to a comparable degree during sinus rhythm. The drug-specific time constant, characterizing the rate-dependent adaptation of the AVCT, in the presence of a substance was comparable if evaluated after abruptly changing the heart rate from the pacing cycle length of 240 ms to 180 ms (tau-on) or from 180 to 240 ms (tau-off). The adaptation of the AVCT in the presence of verapamil (tau-on = 178 +/- 45 beats, tau-off = 125 +/- 33 beats, mean +/- SEM) was more pronounced than in the presence of digoxin (tau-on = 144 +/- 24 beats, tau-off = 98 +/- 15 beats) or diltiazem (tau-on = 70 +/- 11 beats, tau-off = 98 +/- 15 beats). In conclusion, the differences in the rate adaptation of the AVCT may be explained by the drug-specific association and dissociation kinetic to the calcium channel, slow in the case of verapamil, and fast in the case of dilitiazem, whereas this phenomenon in the presence of digoxin may be explained by its direct effects on passive membrane properties.

Adaptation, Physiological↗

PubMed1996

Rate-dependent effects of detajmium and propafenone on ventricular conduction and refractoriness in isolated guinea pig hearts.

Detajmium (4--3'-diethylamino-2'-hydroxypropyl--ajmalin) is an Na(+)-channel-blocking drug with an extremely long recovery from use-dependent sodium channel block. The aim of the present study was to investigate the rate-dependent effects of detajmium on the intraventricular conduction of isolated, spontaneously beating, guinea pig hearts in comparison with the effects of propafenone. Detajmium (0.3 microM) and propafenone (0.3 microM) caused comparable prolongations of the intraventricular conduction time during sinus rhythm. The time to steady state of the rate-dependent QRS prolongation during rapid ventricular pacing follows an exponential function of the beat number after an abrupt change of frequency and is characterized by a drug-specific time constant. This time constant was significantly longer for detajmium (tau = 265 +/- 165 beats; mean +/- SEM; n = 6) than for propafenone (tau = 31 +/- 4 beats; n = 11; p < 0.01). In the presence of propafenone, QRS duration peaked initially before decreasing to a steady state. Detajmium, in contrast, progressively broadened the QRS complex. Both substances caused the greatest increase in the ventricular effective refractory period (V-ERP) when the number of conditioning stimuli (interstimulus interval, 120 ms) was in the range of the time constant. However, when the number of conditioning stimuli was further increased, the V-ERP for propafenone diminished progressively. In conclusion, propafenone displayed, in comparison with detajmium, only a transient rate-dependent effect on intraventricular conduction and V-ERP.

Ajmaline↗

PubMed1996

Involvement of the L-arginine-nitric oxide pathway in hyperglycaemia-induced coronary artery dysfunction of isolated guinea pig hearts.

The effects of hyperglycaemia and L-arginine on flow-induced reduction of coronary artery resistance were investigated in isolated guinea pig hearts. In the presence of indomethacin, hyperglycaemia caused an increase in flow-induced vasodilatation (P < 0.05). Hyperosmotic controls failed to mimic this effect. Addition of L-arginine strongly enhanced this effect. Addition of D-arginine failed to mimic the effects of L-arginine. The effect of L-arginine was abolished by co-administration of NG-nitro-L-arginine. In the absence of indomethacin and L-arginine, the effect of hyperglycaemia was blunted, suggesting the formation of vasoconstrictive prostanoids. Addition of L-arginine again resulted in a significant increase in flow-induced vasodilatation. In conclusion our results suggest that increased flow-induced vasodilatation under hyperglycaemic conditions depends on an adequate supply of L-arginine to maintain sufficient formation of nitric oxide.

Animals↗

PubMed1996

How to measure AV nodal refractoriness in the presence of verapamil, amiodarone, digoxin, and diltiazem.

On the AV node the negative dromotropic action of verapamil, amiodarone, digoxin, and diltiazem is known to be rate dependent. The effective refractory period of the AV node (AV-ERP) at a short cycle length is related to the AV conduction at that cycle length. We investigated how the number of stimuli during the conditioning train (S1) (during measurement of refractoriness at a high pacing rate [cycle length = 180 ms]) might influence the AV-ERP in isolated guinea pig hearts in a Langendorff preparation. Verapamil (10 nM), amiodarone (10 microM), digoxin (0.6 nM), and diltiazem (30 nM) caused a comparable prolongation of the AV conduction time (AVCT). All four drugs caused a significant prolongation of the AV-ERP when evaluated by a standard stimulation protocol with a conditioning train of 10 stimuli (10 S1) at a pacing cycle length of 180 ms followed by the test stimulus (S2). When the number of stimuli during the conditioning train (S1) was increased (> 10), until the prolongation of AVCT reached steady state, the AV-ERP in the presence of verapamil (132 +/- 4 vs 141 +/- 3 ms; P < 0.05, mean +/- S.E.M.) and diltiazem (143 +/- 3 vs 151 +/- 3 ms; P < 0.05) was prolonged significantly further. These results indicate that the effect of drugs on AV-ERP should be measured with a modified stimulation protocol, whereby the number of conditioning stimuli is comparable to the time constant characterizing the prolongation of AVCT at fast pacing rates.

Amiodarone↗

PubMed1996

Effects of propafenone on the median frequency of ventricular fibrillation in Langendorff perfused guinea-pig hearts.

OBJECTIVE: The aim was to investigate the antifibrillatory effects of two concentrations of propafenone by means of signal analysis of epicardial ECG recordings in isolated, Langendorff-perfused guinea-pig hearts. METHODS: Isolated Langendorff-perfused guinea-pig hearts were used as a model for sustained ventricular fibrillation (VF) during reperfusion after global ischaemia. ECG signals were recorded for the first 20 min of reperfusion. The recording was divided into episodes of 1 s and the median frequency (FM) of the dynamic power spectrum was computed for each episode. Cardiac electrical activity was monitored for an additional 10 min. Additionally steady state conditions (i.e. constant FM values for the remaining observation period) were analysed and the effects of 0.1 microM and 1.0 microM propafenone added at reperfusion on the FM were examined. RESULTS: After initial irregularities, FM remained on a high steady state level in the control group. The addition of propafenone altered the steady state value of FM in a dose-dependent and significant manner but had no effects on the time until steady state was reached. During reperfusion without propafenone, 1 out of 6 hearts spontaneously converted to a stable sinus rhythm. Reperfusion with 0.1 microM propafenone caused spontaneous conversion to stable sinus rhythm in 1 out of 6 hearts and intermittent periods of sinus rhythms in 2 additional hearts. During the first 30 min of reperfusion with 1.0 microM propafenone, 5 out of 6 hearts spontaneously converted to stable sinus rhythm. The sixth heart showed repeated switching between VF and periods of non-sustained sinus rhythm. CONCLUSION: Propafenone caused a dose-dependent decrease of FM at steady state conditions. The rate of spontaneous termination of VF appeared to be dose dependent and the stability of the sinus rhythm was correlated inversely with the FM immediately before spontaneous defibrillation. Therefore, in this model the FM value prior to spontaneous termination of VF may be useful in the estimation of defibrillation success.

Animals↗

PubMed1996

[Effects of adenosine on the heart--therapeutic and diagnostic possibilities].

Adenosine is a substance with many different actions on the heart. The most important effects is its action on the conduction system, causing a marked prolongation of atrioventricular conduction time and atrioventricular refractoriness. Since the half life of adenosine is only a few seconds it is a very safe antiarrhythmic drug for the treatment of supraventricular tachyarrhythmias caused by a reentry mechanism via the atrioventricular node. Adenosine is also a potent coronary vasodilator. This effect enables adenosine to be used diagnostically for stress echocardiography and as a pharmacological stress test for thallium-201 single-photon emission computed tomography myocardial perfusion imaging. Adenosine also protects myocardial cells under conditions of raised oxygen requirement of the heart or during ischemia. In addition to assessing the importance of the effect, the underlying mechanism requires further investigation. The manifold actions of adenosine on the heart have led to growing scientific interest in this substance, especially in the field of antiarrhythmic therapy, where adenosine represents a new generation of drugs.

Adenosine↗

PubMed1996

Carotid artery aneurysm as a rare cause for aspiration pneumonia. A case report.

A now 92-year-old patient presented in 1990 with a massive 6 x 4 x 4 cm aneurysm of the left internal carotid artery which completely occluded the left oro- and nasopharynx. The main complaint of dysphagia was not only a consequence of the narrowed pharynx but was also due to a palsy of the glosso-pharyngeal nerve and caused one to two episodes of aspiration pneumonia per year. The patient could not be operated on because the aneurysm extended to the base of the skull. Remarkably the patient never experienced a cerebral ischemic event and during a follow-up of five years the aneurysm did not increase in size and partial thrombosis of the aneurysm was never detected. Thus conservative management seems feasible, when partial thrombosis of the aneurysm can be ruled by CT-examination.

Aged↗

PubMed1995

Effects of semotiadil, a novel Ca2+ channel antagonist, on the electrical activity of Langendorff-perfused guinea pig hearts in comparison with diltiazem, amlodipine and nifedipine.

Semotiadil, a new Ca2+ antagonist with a high vasoselectivity, in high concentrations depresses AV nodal conduction in a frequency-dependent manner. The aim of the present study was to investigate the effects of semotiadil on intact cardiac conduction and the pacemaker system in comparison with diltiazem, amlodipine and nifedipine. The effects were studied in isolated guinea pig hearts perfused by the method of Langendorff. Both semotiadil and diltiazem decreased markedly the sinus rate in a concentration-dependent manner whereas this was not the case in the presence of amlodipine and nifedipine. Semotiadil (10 microM) markedly prolonged sinus node recovery time and in the presence of diltiazem (10 microM) in 5 out of 7 experiments an intermittent sinus node arrest occurred. Atrioventricular conduction and the effective refractory period of the AV node were most affected by diltiazem and semotiadil. The Ca2+ channel blocking compound semotiadil showed the most pronounced rate-dependent effects on the AV node. In the presence of diltiazem the QT interval became even shorter than in untreated hearts. In contrast, semotiadil did not act on the QT interval. In conclusion, as semotiadil exerts a clear rate-dependent effect on AV nodal conduction with a long time constant, it mimics the electrophysiological behavior of a substance of the verapamil type.

Amlodipine↗

PubMed1995

Photodynamic and radiolytic inactivation of ion channels formed by gramicidin A: oxidation and fragmentation.

Ion channels formed by the peptide gramicidin A in planar lipid membranes have been reported to react very sensitively upon irradiation of the membrane by ionizing radiation (radiolysis), by UV light (photolysis), or by visible light in the presence of appropriate photosensitizers (photodynamic inactivation). In all three cases the effect is due to the presence of the four tryptophan residues of the pentadecapeptide. Modifications of these amino acids--due to an interaction with free radicals formed upon water radiolysis or due to light absorption--have been found to reduce the membrane conductance by many orders of magnitude. The present study was intended to correlate functional changes, observed at the level of single ion channels, with changes of the molecular structure identified by mass spectrometry. About 98% of the inactivated channels showed a single-channel conductance of virtually zero, while about 2% of the channels present before irradiation are converted to a state of reduced conductance (and reduced lifetime). On the structural level, irradiation in the presence of the photosensitizer Rose Bengal was found to produce oxidation and fragmentation of the peptide at the positions of the tryptophan residues. Our results provide evidence that the main effect of radiolysis, or of photodynamic treatment, is the cleavage of the peptide backbone leading to immediate closure of an open ion channel.

Amino Acid Sequence↗

PubMed1995

Application of a fast charge-pulse technique to study the effect of the dipolar substance 2,4-dichlorophenoxyacetic acid on the kinetics of valinomycin mediated K(+)-transport across monoolein membranes.

We report on a modified charge-pulse relaxation technique applied at planar lipid membranes. The method has an improved time resolution of 20-30 ns. It is based on the capacitive coupling of a voltage-jump to the membrane. The method was used to study the fast relaxation processes induced by valinomycin/K+ in the presence of 2,4-dichlorophenoxyacetic acid (2,4-D). The change of the rate constants of the ion carrier valinomycin was analysed as a consequence of the adsorption of the dipolar substance 2,4-D to the membrane/water interface of monoolein membranes. The effect of 2,4-D can be explained solely via the influence of the introduced dipole potential, VD. The latter was found to act (primarily) on the inner membrane barrier experienced by the positively charged carrier-ion complex and on the interfacial barriers responsible for complex formation and dissociation. No evidence for a change of the microviscosity of the membrane interior was obtained.

2,4-Dichlorophenoxyacetic Acid↗

PubMed1995

Radiation-induced and free radical-mediated inactivation of ion channels formed by the polyene antibiotic amphotericin B in lipid membranes: effect of radical scavengers and single-channel analysis.

This paper is part of a study on the effect of ionizing radiation on ion channels in biological membranes. Ion channels formed by polyene antibiotics amphotericin B or nystatin represent clusters of conjugated double bonds. As a consequence of this structural peculiarity, the conductance of lipid membranes--in the presence of polyene channels--has been found to decrease by several orders of magnitude at comparatively small doses of ionizing radiation. The phenomenon shows an inverse dose-rate behaviour similar to that of radiation-induced lipid peroxidation. We report on experiments performed in the presence of various radical scavengers, at varying cholesterol concentrations, and with different lipids. They support the view that channel inactivation is due to free radical-induced peroxidation of the polyenes leading to a destabilization of the barrel-like structure of the ion channels. Radiation-induced channel closing is shown for the first time at the level of single-ion channels.

Amphotericin B↗

PubMed1995

Comparison of the frequency-dependent effects on the atrioventricular node of verapamil, amiodarone, digoxin, and diltiazem in isolated guinea pig hearts.

To slow ventricular rate during supraventricular tachycardia, a drug must have a strong rate-dependent depressant effect on atrioventricular (AV) conduction. We investigated the frequency-dependent effects of verapamil, amiodarone, digoxin, and diltiazem on AV conduction time (AVCT) in isolated guinea pig heart perfused by Langendorff method. Verapamil (0.01 microM), amiodarone (10 microM), digoxin (0.6 nM), and diltiazem (0.03 microM) caused comparable prolongation of AVCT and also a comparable reduction in sinus rate. To evaluate the time dependence of drug-induced alterations in AVCT, we abruptly increased the atrial pacing rate and shortened the pacing cycle length (CL) from 240 to 180 ms. The resulting time constant was longest in the presence of verapamil (tau = 194 +/- 45 beats, mean +/- SEM) and the shortest during perfusion with diltiazem (tau = 89 +/- 9 beats). The magnitude of AVCT prolongation after abrupt increase in pacing rate was significantly greater for digoxin as compared with all other drugs tested. The calculated beat-to-beat increase in AVCT evaluated by dividing the magnitude of AVCT prolongation by the time constant tau was greatest with diltiazem, which may explain the high efficacy of diltiazem in controlling ventricular rate during atrial fibrillation.

Amiodarone↗

PubMed1995

Elevation of D-glucose impairs coronary artery autoregulation after slight reduction of coronary flow.

Diabetes mellitus is thought to increase the susceptibility of tissue to hypoxic injury through D-glucose-induced alterations of intracellular metabolism. Therefore the effects of hyperglycaemia on coronary artery autoregulation under slight reduction of coronary flow were investigated in isolated perfused guinea-pig hearts. Under normal (10 mM) D-glucose concentrations coronary autoregulation was intact in response to a slight reduction of coronary flow (from 6 to 4.5 mL min-1) when L-arginine as a precursor of the endothelium-derived relaxing factor (EDRF/NO) was available and formation of prostaglandines was intact. Under high (44 mM) D-glucose concentrations on the other hand, a sustained vasodilatation dependent on the availability of L-arginine was observed, when formation of prostaglandins was blocked. This effect was partially reduced in the presence of prostaglandin synthesis. Furthermore, the effect of L-arginine under both conditions could be antagonized by the L-arginine-analogue NG-nitro-L-arginine-methyl-ester (100 microM). Our results suggest that hyperglycaemia impairs coronary artery autoregulation by reducing the threshold for hypoxic vasodilatation in an EDRF/NO-dependent manner. Concomitantly a shift from the formation of vasodilatatory to vasoconstrictive prostaglandines was observed. These results might be of particular interest in patients with diabetes mellitus and ischaemic heart disease.

Animals↗

PubMed1995

Direct cardiac electrophysiologic effects of sufentanil and vecuronium in isolated guinea-pig hearts.

Sufentanil and vecuronium are commonly used simultaneously in anaesthesia. Bradycardia and asystole have been described immediately after the administration of these two compounds. Therefore, the purpose of the present study was to evaluate the direct cardiac effects of sufentanil and vecuronium in all parts of the cardiac pacemaker and conduction system. The electrophysiological effects of sufentanil and vecuronium were studied in isolated spontaneously beating guinea-pig hearts perfused by the method of Langendorff. At a concentration of 0.1 mumol/l sufentanil a significant reduction of the spontaneous sinus rate, prolongation of atrioventricular, intraventricular and His' bundle conduction could be observed. The highest concentration of 10 mumol/l of sufentanil led to an overall slowing of conduction velocity and to an profound showing of spontaneous sinus rate. AV nodal as well as atrial and ventricular refractoriness were markedly prolonged at this high concentration of sufentanil. In contrast, during perfusion with vecuronium at a concentration of 0.1 mumol/l up to 10 mumol/l no significant effects on cardiac conduction and pacemaker activity could be observed. In conclusion, the electrophysiological effects of sufentanil are comparable to that of unspecific calcium antagonists. Therefore, especially in patients with a preexisting damage of the cardiac conduction system, the indirect effect of the combination of sufentanil and vecuronium which is predominantly responsible for bradycardia and asystole may be worsened by the direct effects of sufentanil.

Animals↗

PubMed1994

Inactivation of the Na, K-ATPase by radiation-induced free radicals. Evidence for a radical-chain mechanism.

Free radicals produced by water radiolysis were used to study the inactivation of the enzymatic activity of the Na,K-ATPase. A decrease of the activity to virtually zero with a mono-exponential dependence on the radiation dose was observed. The inactivation process is initiated by hydroxyl radicals. This was shown by the effect of appropriate radical scavengers such as t-butanol, formate and vitamin C. In all cases a significant increase in the characteristic D37 dose of inactivation was observed. Inactivation was found to show a so-called inverse dose-rate effect, i.e., the sensitivity of the enzyme to radical attack is increased if the dose rate is reduced. The data were found to agree with the relationship 1/D37 approximately 1/D1/2, which is known to be a strong indicator of a radical chain mechanism. This means that the inactivation, after initiation by single radicals, is amplified by a subsequent chain mechanism.

Cell Membrane↗

PubMed1994

Mice devoid of interferon regulatory factor 1 (IRF-1) show normal expression of type I interferon genes.

The transcription factor interferon regulatory factor 1 (IRF-1) binds tightly to the interferon (IFN)-beta promoter and has been implicated in the induction of type I IFNs. We generated mice devoid of functional IRF-1 by targeted gene disruption. As reported by others, IRF-1-deficient mice showed a discrete phenotype: the CD4/CD8 ratio was increased and IFN-gamma-induced levels of macrophage iNO synthase mRNA were strongly diminished. However, type I IFN induction in vivo by virus or double-stranded RNA was unimpaired, as evidenced by serum IFN titers and IFN mRNA levels in spleen, liver and lung. There was also no impairment in the response of type I IFN-inducible genes. Therefore, IRF-1 is not essential for these processes in vivo.

Animals↗