A pivotal role for serotonin (5HT) in the regulation of beta adrenoceptors by antidepressants: reversibility of the action of parachlorophenylalanine by 5-hydroxytroptophan

Summary An acute reduction in the synaptic availability of serotonin (5HT) by p-chlorophenlalanine (PCPA) nullifies the decrease in the density of cortical beta adrenoceptors caused by desipramine (DMI) but does not appreciably alter the attenuation of the norepinephrine (NE) sensitive adenylate cyclase. The analysis of competition-binding curves of [³H]-dihydroalprenolol shows that the affinity of the agonist (–)-isoproterenol for cortical beta adrenoceptors is profoundly reduced following PCPA. This reduction in agonist affinity is enhanced by DMI. Resupplying 5HT by by-passing trptophan hydroxylase inhibition, by administering 5-hydroxytryptophan, converts a DMI non-responsive to a DMI responsive beta adrenoceptor population and shifts the markedly decreased agonist affinity towards the affinity values found in control preparations. The results demonstrate the pivotal role of 5HT in the regulation of the density and agonist affinity characteristics of cortical beta adrenoceptors and contribute to the scientific basis of the serotonin-norepinephrine link hypothesis of affective disorders.Acknowledgments. This work was supported by USPHS grant MH-29228 and the Tennessee Department of Mental Health and Mental Retardation. Present address of L. R. Sterank: NOVA Pharmaceutical Corporation, Baltimore (MD 21228, USA).     

The localization of [3H]-desipramine in central nerve terminals studied with electron microscope autoradiography and subcellular fractionation.

The cellular and subcellular distribution of [3H]-desipramine (DMI) in rat brain was studied by electron microscope (EM) autoradiography and by subcellular fractionation. A considerable proportion of label was found to be bound to the membranes of presynaptic nerve terminals, as well as to sites inside those terminals.     

The localization of [3H]-desipramine in central nerve terminals studied with electron microscope autoradiography and subcellular fractionation

Summary The cellular and subcellular distribution of [³H]-desipramine (DMI) in rat brain was studied by electron microscope (EM) autoradiography and by subcellular fractionation. A considerable proportion of label was found to be bound to the membranes of presynaptic nerve terminals, as well as to sites inside those terminals.Acknowledgment. The authors are most grateful to Mr and Mrs Gudelsky for their generous support.     

Electrophysiological actions of chlorimipramine on guinea-pig ventricular fibres.

Chlorimipramine (CMI, 1 x 10(-5)M to 7 X 10(-5)M) decreased the amplitude, overshoot and rate of rise of ventricular action potentials and abolished the Ca-mediated action potentials elicited in guinea-pig papillary muscles. These results indicates that CMI inhibits the rise in sodium and calcium conductances during the cardiac action potential.     

The site of gating in the ventricular conducting system of rabbit, dog and monkey hearts

The longest action potential durations of the ventricular conducting system were found at about two thirds of the distance along each false tendon in dog and monkey hearts. In the rabbit heart, this area which corresponds to the gating mechanism - was found in the middle part of the bundle branches; therefore the number of gates is much smaller in the rabbit than in other 2 species.     

Tetrodotoxin slightly shortens action potential duration in ventricular but not in atrial heart muscle

Tetrodotoxin (TTX), at concentrations significantly decreasing maximal upstroke velocity (dV/dtmax) of the action potential, exerted variable effects on action potential duration (APD) in different myocardial preparations. APD was virtually unchanged by tetrodotoxin in the guinea pig atrium, but slightly shortened in the guinea pig ventricle at maximally effective concentrations. In the human ventricle, both dV/dtmax and APD were reduced in the same concentration range of TTX. These results suggest that a TTX-sensitive sodium current significantly contributes to the repolarization phase of the action potential in ventricular but not in atrial heart muscle.     

Contributions of cellular electrophysiology to the understanding of the electrocardiogram

The understanding of cardiac action potential and membrane currents has broadened the theoretical foundation and enhanced the clinical usefulness of the electrocardiogram. An improved understanding of the morphology of the electrocardiographic waveform has resulted from: correlations between Vmax of depolarization and QRS complex, plateau of the ventricular action potential and S-T segment, terminal repolarization and T-wave, from definitions of action potential differences responsible for the T-wave, and recordings of action potential alternans. Cellular electrophysiology has contributed to the understanding of certain mechanisms of cardiac standstill. Many disturbances of conduction and refractoriness associated with ventricular arrhythmias can be attributed to the following derangements at the cellular level: slowing of terminal repolarization, development of diastolic depolarization in fibers with stable resting membrane potential, after-depolarizations, currents of injury resulting from non-uniform polarization, increased dispersion of action potential durations, and co-existence of slow conduction and short premature action potentials.     

Contributions of cellular electrophysiology to the understanding of the electrocardiogram

Summary The understanding of cardiac action potential and membrane currents has broadened the theoretical foundation and enhanced the clinical usefulness of the electrocardiogram. An improved understanding of the morphology of the electrocardiographic waveform has resulted from: correlations between V_max of depolarization and QRS complex, plateau of the ventricular action potential and S-T segment, terminal repolarization and T-wave, from definitions of action potential differences responsible for the T-wave, and recordings of action potential alternans. Cellular electrophysiology has contributed to the understanding of certain mechanisms of cardiac standstill. Many disturbances of conduction and refractoriness associated with ventricular arrhythmias can be attributed to the following derangements at the cellular level: slowing of terminal repolarization, development of diastolic depolarization in fibers with stable resting membrane potential, afterdepolarizations, currents of injury resulting from non-uniform polarization, increased dispersion of action potential durations, and co-existence of slow conduction and short premature action potentials.     

Ein Beweis für das Vorhandensein des Knotpunktpotentials am Herzmuskel

Summary After administration of methoxamine, a synthetic sympathomimetic amine, a change in the transmembrane potential, suggestive of the presence of a junction potential between two cardiac cells, was observed in the guinea-pig's ventricular muscle.

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Durch die dankenswerte Unterstützung derPharmacological Research Foundation (Yakurikenkyu-kai, Tokyo) wurde diese Arbeit ermöglicht.     

The site of gating in the ventricular conducting system of rabbit,dog and monkey hearts

Summary The longest action potential durations of the ventricular conducting system were found at about two thirds of the distance along each false tendon in dog and monkey hearts. In the rabbit heart, this area—which corresponds to the gating mechanism—was found in the middle part of the bundle branches; therefore the number of gates is much smaller in the rabbit than in the other 2 species.Acknowledgements. We wish to thank F. Pezziardi and P. Guiraudou for their technical assistance.     

Relationship between steady-state activation and availability of cardiac sodium channel: evidence of uncoupling

The coupling between steady-state activation and availability from inactivation was characterized for the cardiac Na⁺ channel. To evaluate this coupling, we plotted the relationship between the conductance and availability curve midpoint potentials measured in 92 rat ventricular cardiomyocytes and applied a correlation analysis. We found a high correlation between the midpoints (correlation coefficient = 0.86, slope = 0.95) within the availability midpoint potential range positive to -100 mV. In contrast, the midpoints were not correlated in the myocytes (37 of 92 cells) having mid point potential negative to -100 mV, indicating an uncoupling between activation and availability. Received 1 October 1997; received after revision 28 October 1997; accepted 13 November 1997     

An electrophysiological study on the myocardium of dystrophic mice

Summary Decreased resting potential and prolonged duration of the action potential were observed in left ventricular muscles of dystrophic mice, while there was no change in myocardial potassium content.This study was supported in part by a Research Grant for Cardiomyopathy from the Ministry of Health and Welfare, Japan.     

Electrophysiological actions of chlorimipramine on guinea-pig ventricular fibres

Summary Chlorimipramine (CMI, 1×10^–5M to 7×10^–5M) decreased the amplitude, overshoot and rate of rise of ventricular action potentials and abolished the Ca-mediated action potentials elicited in guinea-pig papillary muscles. These results indicates that CMI inhibits the rise in sodium and calcium conductances during the cardiac action potential.     

Failure of opioids to affect excitation and contraction in isolated ventricular heart muscle

The opioid agonists morphine (selective for mu-receptors) and ethylketocyclazocine (selective for kappa-receptors), at concentrations evoking strong effects in neuronal structures, did not significantly affect the configuration of the intracellularly recorded action potential and the force of contraction in ventricular heart muscle isolated from guinea pigs, rabbits and man. These results suggest that any changes of heart functions in vivo in response to opioid-like drugs are probably not mediated postsynaptically at the myocardial cell membrane but rather presynaptically, influencing the release of noradrenaline and/or acetylcholine from the nerve terminals.     

Tetrodotoxin slightly shortens action potential duration in ventricular but not in atrial heart muscle

Summary Tetrodotoxin (TTX), at concentrations significantly decreasing maximal upstroke velocity (dV/dt_max) of the action potential, exerted variable effects on action potential duration (APD) in different myocardial preparations. APD was virtually unchanged by tetrodotoxin in the guinea pig atrium, but slightly shortened in the guinea pig ventricle at maximally effective concentrations. In the human ventricle, both dV/dt_max and APD were reduced in the same concentration range of TTX. These results suggest that a TTX-sensitive sodium current significantly contributes to the repolarization phase of the action potential in ventricular but not in atrial heart muscle.Supported by the Deutsche Forschungsgemeinschaft (Na 105/5-5) and by the Fonds der Chemischen Industrie. Author to whom reprint requests should be addressed. We thank Mrs. Johanna Rupp for expert technical help. We also thank one referee for suggesting the experiments depicted in figure 4.     

Conduction of the impulse in the ischemic myocardium--implications for malignant ventricular arrhythmias

Ventricular arrhythmias occurring consequent to regional disturbances of myocardial perfusion are the most frequent cause of sudden cardiac death. They are related to marked changes of impulse propagation in the ischemic region, which consist of circulating excitation with re-entry. Mapping of the impulse during ventricular tachycardias and ventricular fibrillation shows that the circus movements change their shape and localization from beat to beat. Zones of tissue which block the impulse during one beat may conduct the impulse at a fast rate during the next beat. The main cause underlying this behavior is the depression of the ischemic action potential. This depression is caused by the partial inactivation and the prolonged recovery of the rapid sodium inward current. In addition to the decrease in resting potential, other factors, such as acidosis, contribute to the inactivation of the inward currents generating the upstroke of the action potential. An increase of coupling resistance between myocardial cells and/or an increase of extracellular resistance appear to be less important for explaining conduction disturbances in acute ischemia.     

Conduction of the impulse in the ischemic myocardium — implications for malignant ventricular arrhythmias

Summary Ventricular arrhythmias occurring consequent to regional disturbances of myocardial perfusion are the most frequent cause of sudden cardiac death. They are related to marked changes of impulse propagation in the ischemic region, which consist of circulating excitation with re-entry. Mapping of the impulse during ventricular tachycardias and ventricular fibrillation shows that the circus movements change their shape and localization from beat to beat. Zones of tissue which block the impulse during one beat may conduct the impulse at a fast rate during the next beat. The main cause underlying this behavior is the depression of the ischemic action potential. This depression is caused by the partial inactivation and the prolonged recovery of the rapid sodium inward current. In addition to the decrease in resting potential, other factors, such as acidosis, contribute to the inactivation of the inward currents generating the upstroke of the action potential. An increase of coupling resistance between myocardial cells and/or an increase of extracellular resistance appear to be less important for explaining conduction disturbances in acute ischemia.     

The potential independent series resistance in rat ventricular fibres

Summary Current clamp experiments performed in rat ventricular fibres revealed the presence of a resistance Rs (between 14.5 and 15.5 K) in series with the membrane capacity. Rs behaved as a lumped resistance and its value remained constant throught the action potential repolarization phase.This work was supported in part by grants from D. G. R. S. T. and C. N. R. S.     

Failure of opioids to affect excitation and contraction in isolated ventricular heart muscle

Summary The opioid agonists morphine (selective for -receptors) and ethylketocyclazocine (selective for kappa-receptors), at concentrations evoking strong effects in neuronal structures, did not significantly affect the configuration of the intracellularly recorded action potential and the force of contraction in ventricular heart muscle isolated from guinea pigs, rabbits and man. These results suggest that any changes of heart functions in vivo in response to opioid-like drugs are probably not mediated postsynaptically at the myocardial cell membrane but rather presynaptically, influencing the release of noradrenaline and/or acetylcholine from the nerve terminals.     

Antiarrhythmic properties of 3-(2-hydroxy-3 isopropylamino-propoxy)-3 phenyl-2 isoindolinone-1, (RS, SR) in the dog]

In the Dog, 3-(2-hydroxy-3 isopropylamino-proxy)-2-phenyl-1-isoindolinone (RS, SR) possesses an anti-arrhythmic activity similar to that of quinidine but at dose levels 2 to 6 times lower than in the case of the latter compound. Furthermore, in contrast to quinidine, at the dose levels where the antiarrhythmic activity is well observed, the compound is devoid of hypotensive activity and of depressive action on cardiac contractility. The first clinical studies of this compound have shown its usefulness in the treatment of ventricular and supraventricular arrhythmias.