Cinda J. Helke

Evidence for a role of central serotonergic neurones in digitalis-induced cardiac arrhythmias.

EVIDENCE indicates that digitalis drugs administered intravenously increase central sympathetic outflow and that this in turn results in cardiac arrhythmias1–6. The central nervous system transmitter(s) that mediates this effect is not known. According to Saito et al., noradrenaline, the primary transmitter studied so far, is not involved in the case of guinea pigs7. 5-Hydroxytryptamine (5-HT) however, may be an important chemical mediator regulating central sympathetic outflow8,9, and it is involved in the respiratory arrest induced in rats by intravenous administration of digitoxigenin10. We now report evidence that suggests that brain 5-HT is involved in digitalis-induced cardiac arrhythmias.

Effects of serotonin antagonists on digitalis-induced ventricular arrhythmias.

The present study was performed to determine whether pharmacological blockade of serotonin receptors would counteract digitalis-induced ventricular arrhythmias. The effect of the serotonin receptor blocking drugs, methysergide, cinansersin, and cyproheptadine on ventricular arrhythmias produced by ouabain was studied in anesthetized dogs. Each of the three serotonin receptor blocking drugs given as a bolus i.v. injection of 1.5--3.0 mg/kg produced an antiarrhythmic effect. In addition, methysergide administered in the above doses to cats intoxicated with deslanoside, restored an abnormal ventricular arrhythmia to either sinus or junctional rhythm. Methysergide, administered to cats intoxicated with deslanoside but pretreated with p-chlorophenylalanine, exerted an antiarrhythmic effect in less than half of the animals tested. These data indicate that serotonin antagonists are effective in counteracting digitalis-induced ventricular arrhythmias and support the notion that a serotonergic mechanism may be mediating the arrhythmogenic effect of digitalis.

Blockade of the Tonic Hindlimb Extensor Component of Maximal Electroshock and Pentylenetetrazol‐Induced Seizures by Drugs Acting on Muscle and Muscle Spindle Systems: A Perspective on Method

Blockade of tonic hindlimb extension (THE) in the maximal electroshock seizure test was demonstrated for C‐28 ‘882‐Ba, a muscle spindle suppressant, chlorpromazine, a depressant of fusimotor drive, and gallamine, a neuromuscular blocking drug. These agents also blocked THE produced by very large doses of pentylenetetrazol. Dantrolene, a muscle contraction antagonist, and MI‐65‐S, a muscle spindle suppressant, significantly delayed THE. The data indicate that blockade of THE may be effected at a multiplicity of loci and may not be an expression of an “anticonvulsant” effect.

Effect of arrhythmogenic doses of deslanoside on the uptake of monoamines in brain tissue and in cardiac tissue

The purpose of our study was to determine whether a toxic arrhythmogenic dose of digitalis administered to an in vivo preparation would affect the neuronal uptake of norepinephrine, serotonin and dopamine in brain tissue and norepinephrine in cardiac tissue. This was investigated by intoxicating anesthetized cats with deslanoside, removing cardiac and brain tissue at the onset of ventricular fibrillation, and examining the ability of brain tissue to accumulate [3H]-NE, [3H]-T-HT and [3H]-DA and cardiac tissue to accumulate [3H]-NE. It was found that deslanoside inhibited uptake of [3H]-NE into the left ventricle and [3H]5-HT into the area postrema. These selective effects may reflect greater blood flow to these regions or different sensitivities of the transport mechanisms for these amines. This inhibition of uptake into both left ventricular tissue and area postrema may contribute to some of the cardiovascular and emetic effects seen with digitalis drugs.

Interaction of serotonin and deslanoside on cardiac rhythm in the cat.

The present study was performed to determine whether increases in the tissue content of serotonin creatinine SO4 in the periphery would influence the arrhythmogenic effect of deslanoside. This was accomplished by infusing serotonin into anesthetized cats exposed to a subarrhythmic dose of deslanoside, determining doses of deslanoside required to produce ventricular tachycardia and ventricular fibrillation, and determining ventricular pacemaker rate (obtained during vagal-induced sinus node suppression). It was found that animals receiving serotonin creatinine SO4 plus deslanoside exhibited a greater increase in ventricular rate during sinus node suppression than with 5-HT infusion alone. No corresponding increase in ventricular pacemaker rate during sinus node suppression was observed with creatinine SO4 plus deslanoside. In addition, the dose of deslanoside to produce ventricular fibrillation in these animals was significantly correlated with the increase in ventricular pacemaker rate seen during th 5-HT infusion in the presence of deslanoside. Studies were also performed to determine whether the arrhythmogenic interaction of serotonin with deslanoside was associated with alterations in either cardiac tissue, blood or plasma levels of serotonin and 5-hydroxyindoleacetic acid. The data revealed a significant correlation between serotonin content in the left ventricle and the dose of deslanoside required to produce ventricular fibrillation. These results suggest that exogenous serotonin interacts with deslanoside to enhance the arrhythmogenic action of deslanoside.

Antiextensor effects of 3,3-diphenyl-n-propylamine in the mouse☆

Diphenylpropylamine has antiextensor activity in the MES test and worsens clonic seizures produced by pentylenetetrazol. The drug also prevents tonic hindlimb extension produced by large doses of pentylenetetrazol. Diphenylpropylamine appears, therefore, to be a phenytoin-like compound. However, unlike most antiextensor agents, diphenylpropylamine has neuroexcitatory effects and antagonizes barbital-induced loss of the righting reflex.