A wide variety of tissues undergo a change of functional state on exposure to noradrenaline or adrenaline. Those molecular constituents of the effector cells of a tissue with which molecules of these catecholamines must first interact in order to produce a change of state — or response — of the tissue, are the so-called adrenoceptors (also commonly called adrenergic receptors). For convenience, we refer to noradrenaline, adrenaline and other agents which produce responses in tissues by interacting with adrenoceptors, as adrenergic agonists. An agent which specifically inhibits a response produced by an adrenergic agonist is referred to as adrenergic blocking agent or adrenergic antagonist.

The Classification of Adrenoceptors (Adrenergic Receptors). An Evaluation from the Standpoint of Receptor Theory

1. A group of rabbits was made hypothyroid by thyroidectomy, and another group was injected daily with L-thyroxine. After an appropriate interval respective alterations in thyroid state were confirmed by measurement of heart weight and of plasma iodine, and the animals' atria were isolated for recording.

2. Measurements were made of atrial contractions, conduction velocity, spontaneous heart rate and maximum driven frequency, and action potentials were recorded with intracellular micro-electrodes.

3. The resting potential and action potential heights were not affected by differences of thyroid state.

4. Atrial arrhythmias are common in hyperthyroidism, rare in myxoedema. The possibility that hypothyroidism might reduce the rate of rise of the action potential, as do anti-arrhythmic drugs, and hyperthyroidism increase it, was investigated. Although the rate of rise was slower in hypothyroid atria at some driving frequencies, this could not alone account for an anti-arrhythmic effect, because at frequencies near the spontaneous heart rate the rate of rise of the action potential was not reduced.

5. The duration of the repolarization phase of the action potential was greatly prolonged in atria from thyroidectomized rabbits, and was shortened in hyperthyroid atria. These changes could account for a reduced probability of arrhythmias in hypothyroidism, and the converse in hyperthyroidism.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1970.sp009066

The effect of altered thyroid state on atrial intracellular potentials

Papillary muscle-false tendon tissue preparations isolated from dog hearts were perfused with Tyrode's solution containing propranolol in concentrations ranging from 0.1 to 20.0 mg/liter. Transmembrane action potentials of both ventricular muscle fibers and Purkinje fibers were recorded. With sufficient concentration of drug, the velocity of the upstroke and the overshoot of both fiber types decreased. The curve relating upstroke velocity to level of membrane potential for Purkinje fibers was displaced to the right and down. The ability of both ventricular muscle fibers and Purkinje fibers to respond to rapid frequencies of stimulation was decreased. Repolarization of Purkinje fibers was accelerated by propranolol, but repolarization of ventricular muscle fibers was unaffected. Duration of the effective refractory period of Purkinje fibers decreased; that of ventricular muscle fibers was unchanged. Graded responses and decremental impulse conduction in Purkinje fibers were abolished in the presence of propranolol. Low doses of propranolol which caused no change in the transmembrane potential completely blocked the increase in Purkinje diastolic depolarization normally induced by epinephrine. The possible mechanisms by which propranolol might exert its antiarrhythmic actions on ventricular arrhythmias were discussed.

Effects of Propranolol on the Transmembrane Potentials of Ventricular Muscle and Purkinje Fibers of the Dog

All previously studied antiarrhythmic drugs which also have local anaesthetic properties reduce the maximum rate of depolarization (MRD) of cardiac muscle. Recent evidence suggested that lidocaine and diphenylhydantoin (DPH) might have a different mode of action, because they did not reduce MRD except at high concentration. The latter evidence, however, was obtained from tissues nourished by solutions containing 2.7-3 mM potassium. In the present experiments, the effects of lidocaine and DPH were studied in solutions with 5.6 and 3 mM KCl. In the former, both drugs reduced MRD at concentrations similar to those found in the blood of treated patients, but in low [KCl] higher concentrations were necessary. It was concluded that there was no reason to suppose that the mode of action of lidocaine and DPH on the cardiac membrane is fundamentally different from that of quinidine, procaine, procainamide and other compounds which interfere directly with depolarization.

Effect of Altering Potassium Concentration on the Action of Lidocaine and Diphenylhydantoin on Rabbit Atrial and Ventricular Muscle

The use of beta-adrenergic receptor blocking drugs in dysrhythmias.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1967.tb02166.x

Interactions of sympathomimetic drugs, propranolol and phentolamine, on atrial refractory period and contractility

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1966.tb01804.x

Antisympathomimetic and antifibrillatory effects of pronethalol and propranolol.

In spinal cats treated with tri-iodothyronine, the effects of sympathomimetic drugs on cardiac contraction were diminished. Ouabain failed to restore the effects on the contractile force of the heart. The effects of sympathomimetic drugs on the force of contraction of papillary muscle were not reduced by tri-iodothyronine, but the threshold for induction of automaticity was lowered. There was no evidence that in cats treated with reserpine the sensitivity of peripheral vessels to sympathomimetic agents is decreased and that blood pressure changes are merely secondary to changes in cardiac contraction.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1963.tb01513.x

Cardiac and vascular effects of sympathomimetic drugs after administration of triiodothyronine and reserpine

The adrenaline β-receptor blocking drug, pronethalol, and the sympathomimetic amines, (—)-ephedrine, (—)-amphetamine, dexamphetamine, (—)-Ψ-ephedrine and tyramine, inhibited the sympathomimetic effects of butyrylcholine and tyramine on the guinea-pig isolated atrium. Being reversible and noncompetitive, this antagonism was unspecific and not due to blockade of adrenaline receptors, although pronethalol inhibited the effect of noradrenaline competitively.

Inhibition of sympathomimetic effects on the heart.

Synthetic oxytocin (Syntocinon) can be shown to reduce or abolish ST-T changes induced experimentally by hypoxaemia alone, by hypoxaemia and ergometrine, by vasopressin, and by a new procedure involving injection of small doses of picrotoxin into the lateral cerebral ventricle. Ventricular fibrillation induced by picrotoxin can also be reversed by oxytocin. These effects suggest a probable metabolic action of oxytocin against cardiac anoxic changes, and its possible therapeutic usefulness as an antagonist of myocardial ischaemia. It is speculated that this might be a physiological action of the hormone.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1961.tb01281.x

D. R. Varma

Papers

Interactions of sympathomimetic drugs, propranolol and phentolamine, on atrial refractory period and contractility

Antisympathomimetic and antifibrillatory effects of pronethalol and propranolol.

Cardiac and vascular effects of sympathomimetic drugs after administration of triiodothyronine and reserpine

Inhibition of sympathomimetic effects on the heart.

Synthetic oxytocin as an antagonist of experimental cardiac anoxic changes in rabbits.