Intestines—The influence of lipids upon intestinal function is marked by the same antagonism between the two groups of agents. Oral administration of large amounts of fatty acids, especially higher unsaturated such as obtained from cod liver oil, was usually followed by diarrhea. Diarrhea also occurred after parenteral administration of these substances in large amounts. It was interesting to note that parenteral administration of the acid lipidic fraction of placenta, blood or even organs had a marked influence upon the colon and rectum in particular. High doses produced tenesmus with a mucous or even sanguinolent secretion. This localization of the effects of the lipidic fraction appeared to be especially interesting from a therapeutic point of view, as will be seen later. The oral or parenteral administration of the opposite group of lipids, sterols and insaponifiable fractions, has an opposite effect, a constipating one, which we will discuss later together with its therapeutic aspects.

Kidney—The manifest opposite effects exerted by the two groups of antagonistic lipids upon diuresis raise the question of where these effects take place. While a systemic effect can be recognized, a more direct intervention upon the kidney also must be considered. The addition of the acid lipidic fraction of organs, and especially those obtained from pork kidney, to the perfusion fluid in a dog kidney preparation produces a manifest decrease of excreted urine. The administration of insaponifiable fraction has a marked diuretic effect which we will discuss below with its therapeutic aspect.

Nervous System—Interesting effects by the two groups of antagonistic lipids upon many manifestations of the central nervous system have been noted.

Convulsions—Administration of sterols and insaponifiable fractions of many organs such as placenta, liver, butter, eggs, etc., in large amounts induces convulsions in rats. Convulsions also were noted in humans when huge doses of these agents were administered. But even in relatively small amounts, these lipid agents sensitized animals to the administration of other convulsant agents. In rats or mice receiving such lipids, thiamine chloride induced convulsions in doses without effect in controls. (Note 39)

An opposite effect was observed for lipids with negative character. Saturated fatty acids showed no influence on thiamine induced convulsions. Such convulsions were prevented by the administration of nonsaturated members. The effect was related to the degree of desaturation of the fatty acids. With increases of the iodine number, the necessary effective doses of these fatty acids became progressively smaller. While hundreds of milligrams of mono- and diethenic acids were necessary for each 100 gram of body weight, the anti convulsant effect was obtained with only a few milligrams of clupanodonic acids, and with still less of the nonenic acid, bixine.

The study of the pathogenesis of convulsions also covered the influence exerted by these lipids of the adrenal corticoids. The administration of mineralocorticoids, especially desoxycorticosterol, even in small doses, to subjects who had received any one of the lipids with a positive polar group, such as cholesterol or insaponifiable fraction of placenta, liver or kidney, was followed almost invariably by convulsions. We will present more details on this effect later in the discussion of synthetic substances. For the moment we want only to note the relationship between mineralocorticoids and lipids with positive character in the pathogenesis of convulsions. The concomitant intervention of the two factors—an offbalance induced by lipids with positive character, and action of mineralcorticoids—seems to provide new light on the pathogenic problem of epilepsy and convulsions in general.

Coma—The role of cortical hormones in the pathogenesis of convulsions was confirmed by the opposite effect produced by neoglucogenic corticoids. We will see later that the administration of cortisone to subjects receiving higher alcohols such as heptanol, octanol or octandiol in large doses, induced a subcomatose condition at first which progressively changed into coma. (Note 40) Opposite properties of the mineral and neoglucogenic corticoids, which made Seyle separate them according to their "phlogistic" and "antiphlogistic" activity, would explain the two opposite manifestations inducing convulsions and coma, produced in individuals previously treated with the same anti fatty acid agents.

On Cardiac Rhythm—The influence exerted by the two groups of lipoids upon the cardiac rhythm was studied under the same dualistic aspect. The effects observed can easily be interpreted considering the role of the differentiation of the cardiac cells for their part in the cardiac physiology. The role of a cell in cardiac physiology is a direct function of its own automatism which can ultimately be related to its degree of differentiation. The fact that the two groups of lipids act antagonistically upon this cellular differentiation, the acid lipids exaggerating it and the insaponifiable fraction of sterols reducing it, has explained some of the effects induced by these agents upon normal and abnormal cardiac rhythm. (Note 41)

On Oestral Cycles—The action of the two groups of lipids at the organic level was also studied in the rat ovarian cycle. Daily, and even twice a day, vaginal smears were made in animals treated with these agents. When large amounts were administered, both groups suppressed the cycle. With smaller doses, only the lipids with positive polar groups, especially sterols, produced this effect.

Systemic Level—Blood has appeared especially suitable for in vitro and in vivo studies of the effects of the two groups of lipids at the systemic level. The effects on different blood constituents were analyzed and led to very conclusive results. We will outline here the principal points of this study.

Under the influence of anti fatty acids, the erythrocytes become more turgescent, increase in volume, show a strong refringency of their crown in dark field examination, and remain isolated from one another. The sedimentation rate, if previously high, is reduced by treating blood in vitro with insaponifiable fractions of organs. Oxygen appears to be retained longer in treated red cells than in controls.

The fatty acids have an opposite effect. Under their influence, the red cells become crenelated and develop a tendency to form sludges. The sedimentation rate is increased. The color of the treated blood is dark and, even after oxidation, rapidly darkens again. In vivo, lipids with a positive character induce leucocytosis, those with a negative character leucopenia. This last effect is seen even in vitro. In Note 42, the influence exerted by lipids upon the blood is presented with more details. (36)

On Temperature—The administration of sufficient amounts of positive lipids induces a frank elevation of temperature, while hypothermia follows the administration of negative lipids. The relationship between temperature and lipids, however, is not so simple since changes in external temperature influence the balance between the antagonistic lipids. For example, animals kept in incubators at a temperature of 35°C show an increase in lipids with a positive character. Animals kept in a cool place, such as a refrigerator, show an increase in lipids with a negative polar group. The organisms are able to combat the increase of lipids with negative character by means of the normal defense mechanism, but are less capable of dealing with an increase of lipids of positive character. Therefore, while a high proportion of animals kept in refrigerators adapt themselves to the new conditions, those in incubators die in a few days.

On Systemic Patterns—The influence exerted by lipids upon various other systemic manifestations which are reflected in abnormal patterns in urine analyses has been studied. In general, the fatty acids induce patterns corresponding to the offbalance of type D, while the sterols induce patterns of the type A offbalance. Here again we must emphasize that any lipid, if administered in large quantity, influences all analytical values. A certain specificity, however, is noted since, in relatively small doses, lipids induce changes only in certain values. Because of the inherent technical problems concerning the patterns, only a few analyses could be followed accurately over the period of time necessary for a clear recognition of changes in small laboratory animals. It is for this reason that most of our studies in this area were made on humans where pattern changes could be easily identified and followed over long periods.

It is to be emphasized that, under these conditions, the influence of lipids is exerted especially upon already existing abnormal patterns, increasing or decreasing their deviations from the normal, or changing the patterns entirely. Abnormal patterns were induced through huge amounts of lipids, which very seldom were administered to patients. Table X shows schematically the analytical changes induced by the two groups of lipids upon various urine and blood analyses, expressed as patterns corresponding to abnormal conditions, as well as upon the manifestations present at other levels.

We will discuss these effects in more detail when describing the pharmacodynamic properties of lipids and lipoids.