Noradrenaline is present in postsynaptic sympathetic neurones, being located both in the adrenergic nerve fibers and in the ganglia from which these fibers originate. More recently noradrenaline was also shown to be present in mammalian brain (Rabb, 1943A, 1943B; von Euler, 1946). That noradrenaline is the chemical transmitter substance liberated by postsynaptic sympathetic neurones is now generally accepted. Whether or not noradrenaline has a functional role at synaptic levels is still unknown.

The literature contains indications that adrenaline antagonists inhibit muscarinic actions of acetylcholine, however, this is generally regarded as a weak and unspecific affect, and a quantitative evaluation has rarely been carried out. Employing the isolated guinea pig atrium and ileum, this study shows that phenoxybenzamine is a patent and specific atropine-like agent. Chlorpromazine is less patent than phenoxybenzamine, and other adrenaline antagonists - phentolamine, prosympal, and yohimbine – are even less patent than chlorpromazine. The work originated from observations that phenoxybenzamine reverses the effect of vagal stimulation on the isolated guinea pig atrium so that stimulation instead of inhibition occurs (Benfey and Greeff, 1961).

The sensitivity of the myocardium to alterations in its electrolyte environment has been extensively studied. Danowski and Elkinton (1951) in a detailed review on the effects of potassium on the functions of various organs and systems of the body conclude that "the heart is the most sensitive of all organs to alterations in its extracellular potassium concentration." It is now well established that the concentration of potassium in the extra cellular fluid is low (4 to 5 mEq. per liter in plasma) while the intracellular concentration is considerably higher--approximately 40 mEq. per 100 grams of cat heart tissue (Robertson and Peyser, 1951).

Histamine, a naturally occurring substance has been identified, located and traced through its metabolism. It is very widely distributed in the body and there is scarcely any organ which does not contain at least some histamine. Abnormal release of this substance or altered reactivity to histamine has been round to occur in many pathological conditions. However, the great amount of information which has accumulated over the years, has contributed very little in understanding the role, that is the physiological function, if any, of this biological amine. In 1960 KAHLSON suggested that histamine has an important role in tissue growth. He based this theory on experiments performed on rats and round that during embryonal development and in regenerative and reparative growth, the histamine-forming capacity of the tissues involved is greatly increased.

In earlier reported studies from this laboratory (Share and Melville, 1961; Varma et al, 1962; and Melville and Share, 1963) it was shown that injection of the convulsant drug, picrotoxin, into the lateral cerebral ventricles of cats and rabbits can lead to a rise in arterial blood pressure associated with various types of electrocardiographic ST-T alterations and cardiac arrhythmias (bradycardia, tachycardia, extrasystoles and even ventricular fibrillation in rabbits). It was suggested that these cardiovascular effects of picrotoxin were mediated through central excitation of adrenergic mechanisms, probably involving "release" of catecholamines (noradrenaline mainly) from the hypothalamus and midbrain.

The primary object of this investigation was to study further the movement of labelled noradrenaline in the isolated perfused rabbit heart, with special reference to its significance in cardiac drug action. Since the movment (uptake and outflow) of noradrenaline might be influenced by changes in heart functions, e.g. coronary flow, heart rate and cardiac contractility, attempts were made to cerrelate movement of noradrenaline with changes in these functions. It is now clearly established that the heart can take up exogenous noradrenaline and that the absorbed noradrenaline appears to be localised at similar sites to those of the physiologically occurring amine. It has also been reported that radioactive labelled noradrenaline is retained by the heart for a long time in some type of inactive bound form [...]

The presence of noradrenaline and other catecholamines in the brain was early demonstrated by Raab (1943A and 1943B) and also by von Euler (1946). Holtz (1950) showed that noradrenaline was the predominant catecholamine in brain tissues. In a study of the distribution of adrenaline and noradrenaline ("sympathin") in brain tissue from different areas, Vogt (1954) showed that these amines are found in all parts of the central nervous system but are unevenly distributed. The highest concentrations of amines were detected in the regions of sympathetic representation (diencephalic, mesencephalic and bulbar). [...]

The search for drugs to relieve angina pectoris has been primarily a search for agents which enhance coronary flow without significantly increasing cardiac oxygen demand. Glyceryltrinitrate (nitroglycerin) has long been used clinically in angina pectoris and remains the standard by which the potency of other agents may be classified. The exact cause of the benefit derived from nitroglycerin in cardiac ischemic disease is far from clear. Usually it is attributed to improved myocardial oxygenation resulting from coronary dilatation and/or reduced peripheral resistance with a reduction in myocardial oxygen requirement. [...]

Antagonists have been used for the quantitative measurement of drug interactions with receptors. Using quantitative measurements based on Gaddum's hypothesis (12) that agonists and antagonists compete for receptors according to the mass law, Arunlakshana and Schild (1) have shown that there are remarkable similarities between the effective concentrations of atropine as an acetylcholine antagonist in such widely differing preparations as the guinea pig ileum, guinea pig lung, and chick amnion. It was concluded the receptor for acetylcholine was similar in all three preparations. [...]

Experimental animal studies on the effects of drugs on the coronary circulation have usually been employed to provide quantitative and qualitative data for clinical trials of this group of agents in humans. Species variations in the responses to these drugs have been largely overlooked. [...]