Marilyn E. Hess

The effect of tri-iodothyronine in combination with imipramine on [3H]-cyclic AMP production in slices of rat cerebral cortex

Abstract Tri-iodothyronine (T3; 15 μg) was administered to rats, alone or in combination with imipramine (20 mg/kg), for 5 days. The net synthesis of [3H]-cyclic AMP in cerebral cortex slices of animals so treated and control rats was then measured. The dose-dependent stimulation of [3H]-cyclic AMP by norepinephrine (NE) was significantly reduced in imipramine-treated rats. Tri-iodothyronine treatment had no effect on the enhanced net synthesis of [3H]-cyclic AMP produced by NE. In cortex slices of rats given both T3 and imipramine, NE produced less stimulation of [3H]-cyclic AMP than in control rats. The magnitude of this inhibitory effect was less than that observed in animals treated with imipramine alone. In vitro addition of imipramine to the cortex slice preparation reduced the stimulation of [3H]-cyclic AMP caused by NE; treatment of rats with T3 did not modify this inhibitory effect of imipramine in vitro. Isoproterenol produced significantly less stimulation of [3H]-cyclic AMP net synthesis than did NE; imipramine added in vitro had no effect on the stimulation produced by isoproterenol. It is concluded that the reason for the enhanced clinical effect of imipramine when given together with T3 is not due to the hormone exaggerating the effect of the antidepressant on NE stimulated adenylate cyclase. Furthermore, for NE to produce maximal stimulation of [3H]-cyclic AMP, uptake of the catecholamine is necessary.

Effect of 6-hydroxydopamine and thyroxine on chronotropic response to norepinephrine.

Abstract Rats were pretreated with 6-hydroxydopamine (6-OH-DA), thyroxine (T 4 or a combination of 6-OH-DA and T 4 . At the end of the treatment period, the hearts were removed and perfused by the Langendorff technique; heart rate was recorded and the chronotropic response to various doses of norepinephrine was measured. Histochemical examination for catecholamine-containing nerves was performed on hearts from each group of animals. It was found that 6-OH-DA, but not T 4 , produced an increase in sensitivity of the heart to norepinephrine. Hearts from rats treated with 6-OH-DA, but not T 4 , were markedly depleted of adrenergic nerve terminals. It was concluded that chemical sympathectomy induced by 6-OH-DA caused the heart to be hypersensitive to norepinephrine and that 6-OH-DA was capable of producing marked depletion of sympathetic fibers in the myocardium.

Interaction Between Thyroxine and Tricyclic Antidepressant Drugs on Cardiac Neurotransmitter Receptors

Summary The effect of chronic administration of desmethylimipramine (DMI) and iprindole on cardiac neurotransmitter receptors was studied. In addition, the influence of these drugs on the action of thyroxine (T4) on myocardial receptors was investigated. Administration of iprindole (10 mg/kg i.p.. twice daily for 11 days) markedly increased the number of β- adrenergic receptors in the heart and significantly reduced the affinity of these receptors for (-) [3H]dihydroalprenolol ([3H]DHA). Injection of T4 (500 mg/rat i.m.. for 5 days) concomitantly with iprindole resulted in a lower β-adrenergic receptor density than with iprindole treatment alone, but significantly higher than that measured in control rats. Affinity of the receptors for (-)[3H]quinuclidinyl benzilate ([3H]QNB) in heart membrane preparations of animals pretreated with T4 alone or with T4 plus iprindole was not different from control. Neither pretreatment with DMI nor with iprindole affected the density of cholinergic muscarinic receptors in the heart or their affinity for [3H]QNB. The decrease in cardiac cholinergic receptors induced by administration of T4 was not prevented by simultaneous injections of DMI. Combined administration of iprindole and T4 caused a reduction in the affinity of myocardial cholinergic muscarinic receptors, but restored the number of these receptors to normal. The results demonstrate distinct differences between DMI and iprindole in their effects on cardiac neurotransmitter receptors and in the influence of these drugs on the actions of T4 on receptors in the heart.

Cardiovascular Effects of Chloroquine with Special Reference to Its Antifibrillatory Action

Intravenous injections of chloroquine terminated experimental atrial fibrillation in open chest dog preparations. Chloroquine and quinidine possess equal vasodilating properties when injected intra-arterially in the same dosage. Chloroquine and quinidine were equally effective in decreasing resting excitability of isolated cat papillary muscle; conduction velocity was markedly slowed by quinidine, but only slightly decreased by chloroquine.

The effect of epinephrine on isometric tension and phosphorylase activity of the isolated rat heart

Abstract The effect of small doses of epinephrine on isometric tension and phosphorylase activity of the isolated perfused rat heart was studied. The results of the experiments support our previous conclusion that the positive inotropic action of epinephrine on the heart is associated with a simultaneous increase in phosphorylase a activity.

The effect of metabolic inhibitors on the response of the perfused rat heart to epinephrine

Abstract The effects of epinephrine on contractility and metabolism were measured in the isolated, perfused rat heart. Epinephrine produced an initial increase in force of contraction followed by a lowering of tension and finally a sustained increase in contractility. When fluoroacetate or iodoacetate was present in the perfusion fluid, the mechanical response to epinephrine was markedly altered. The initial response to epinephrine was depressed in the presence of either inhibitor and the final increase in force of contraction was poorly maintained during metabolic blockade. When the perfusion fluid contained both pyruvate and iodoacetate, the mechanical response of the heart to epinephrine was restored. Results of determinations of metabolites in the myocardium demonstrated that stimulation of glycogenolysis is not essential for the contractile response to epinephrine when adequate substrate is provided for the reactions of the tricarboxylic acid cycle.

Opposing actions of calcium and magnesium ions on the metabolic effects of epinephrine in rat heart.

Abstract The actions of magnesium and calcium ions on the metabolic and contractile effects of epinephrine were studied in the isolated, perfused rat heart. The breakdown of high energy phosphate and increase in glycogenolysis produced by epinephrine were markedly inhibited in the presence of 20 mM magnesium ions in the perfusion fluid. This depressant effect of magnesium was overcome by raising the extracellular concentrations of calcium. Epinephrine caused a large increase in phosphorylase a activity in hearts perfused with control or a high magnesium medium, although glycogenolysis was severely depressed by excess magnesium. Epinephrine-induced glycogenolysis. as measured by lactate efflux, responded rapidly to alterations in the magnesium concentration in the perfusion fluid in the absence of corresponding changes in force of contraction. It is apparent that, in the heart stimulated by a catecholamine, carbohydrate metabolism is more readily affected by divalent cations than is myocardial contraction.

Metabolic effects of bretylium and phentolamine in euthyroid and thyrotoxic rats

Abstract In rats chronic administration of thyroid hormone produced an increase in cardiac phosphorylase a activity. Intravenous injection of bretylium or phentolamine into normal and thyrotoxic rats caused an acute elevation of heart phosphorylase a ; the increase in enzyme activity greater when bretylium was administered to thyrotoxic animals. When propranolol was given prior to bretylium, the increase in phosphorylase a was completely prevented. Reserpine alone did not alter cardiac phosphorylase a but prevented the rise in enzyme activity observed after injection of bretylium or phentolamine. In adrenal demedullated rats hearts phosphorylase a was below control levels but the metabolic response to bretylium and phentolamine could still be elicited. Stimulation of cardiac phosphorylase a activity by thyroxine was diminished in adrenal demedullated rats and was completely absent in demedullated rats with adrenergic blockade.

Studies of the Effect of Antiarrhythmic Drugs on Carbohydrate Metabolism of Rat Heart Muscle in Vitro

The effect of antiarrhythmic drugs on the oxidation of glucose by heart tissue was studied. Quinine and quinidine inhibited oxygen consumption and glucose utilization by rat heart slices and homogenates, while chloroquine and procaine amide had little effect.

Metabolic effects of acarbose administration in normal and diabetic rats.

The effect of acarbose on cardiac and hepatic metabolism was investigated in normal and diabetic rats. Groups of rats were fed one of the three following diets for 7 days: (1) ground Purina chow, (2) ground Purina chow fortified with raw corn starch and sucrose, and (3) the above high carbohydrate diet, with added acarbose (40 mg/100 g food). At the end of the dietary period the rats were decapitated, and a sample of liver tissue was removed and frozen in liquid nitrogen. The heart was extirpated for subsequent perfusion by the Langendorff technique. Increases in liver and heart glycogen produced by the high carbohydrate diet in the normal rats were prevented completely when acarbose was incorporated into the food. In diabetic animals, liver glycogen was uniformly lower than normal, irrespective of the diet or the presence of acarbose. With animals fed the control diet, cardiac glycogen was higher in diabetic than in normal rats. The high carbohydrate diet caused a lowering of heart glycogen in diabetic rats and this reduction in glycogen content was reversed by including acarbose in the diet. Effects of isoproterenol on myocardial phosphorylase a activity were determined in hearts from normal and diabetic rats given one of the three diets. The high carbohydrate diet decreased the enzymatic response to the catecholamine in hearts from both normal and diabetic animals, and this phenomenon was prevented by the presence of acarbose in the diet. In diabetic rats fed any of the three diets, the activation of cardiac phosphorylase by isoproterenol was greatly accentuated. Measurements of heart uridine kinase showed that the activity of this enzyme was lower than normal in hearts from diabetic rats given either the control or the high carbohydrate diet. The presence of acarbose in the latter diet resulted in a significant decrease in cardiac uridine kinase activity in hearts from normal rats. The results of this study demonstrate the effectiveness of acarbose in modulating tissue metabolism in normal and diabetic animals.