An unsaturated fat diet prevents the increased angiotensin II vascular responses in renal artery stenosis.

OBJECTIVE: The aim was to characterise angiotensin II constrictor responses in two kidney, one clip (2K1C) renal hypertensive rats fed a diet with a high unsaturated fatty acid content. METHODS: Two diets with the same total fat (37% by energy; 17% by weight) but different unsaturated fat contents were fed to rats for a three month period. Thirty four Sprague Dawley rats were used per diet group. After one month on the diets, a group of 19 rats in each diet group was operated upon to induce 2K1C hypertension. A separate group of 15 rats within each diet group received sham operations. Systolic blood pressure was measured weekly from prior to surgery to the end of the three month feeding period. At three months, angiotensin II constrictor responses were evaluated in the isolated kidney vascular preparation and in intact anaesthetised rats fed the different diets. Phenylephrine constrictor responses were also evaluated in intact anaesthetised rats in order to exclude structural vascular changes accounting for differences in angiotensin II constrictor responses. RESULTS: The diet high in unsaturated fats prevented the development of hypertension in 2K1C rats [systolic pressure 134(7) mm Hg at eight weeks] compared to their own preoperative blood pressures [124(3) mm Hg], and to the 2K1C rats fed the control diet [163(7) mm Hg at eight weeks]. The diet high in unsaturated fats did not alter blood pressures in sham operated rats. In isolated perfused kidneys and in anaesthetised 2K1C rats fed the control diet, angiotensin II caused a greater vascular response compared to the sham operated groups. The unsaturated fat diet prevented this effect. No differences were found in blood pressure responses to phenylephrine. CONCLUSIONS: These data suggest that the antihypertensive effect of a high unsaturated fat diet may in part be due to a depressed responsiveness of vascular smooth muscle to endogenous angiotensin II. The effect is likely to be due to modulation of angiotensin II vascular responses by local vascular changes that cannot be accounted for by structural vascular differences.

Dynamic electrocardiography, the electromechanical S wave: the problem of the contradictory converse.

Two basic hypotheses concerning an electromechanical S wave of the electrocardiogram during exercise have been expanded to five to include the effect of recovery which should produce converse changes. Four hypotheses have been supported and the fifth contradicted. An attempt has been made to analyse the ensuing dilemma and a conclusion is reached that either the electromechanical hypothesis is in error or a new hypothesis, which predicts an increase in the cardiac end-diastolic volume after exhaustive exercise, must be proposed. This new hypothesis is commonly accepted by physical educationalists but appears to be rarely discussed in physiological texts.

Cancer: a simple metabolic disease?

Recent studies on the effects of the essential fatty acid metabolic intermediate, gamma-linolenic acid, on the growth of cancer cells in culture and on induced mammary cancer tumours in rats, strongly suggest that the metabolic defect in the cancer cells studied is simply a metabolic block involving the enzyme delta-6-desaturase. The latter enzyme is responsible for the conversion of linoleic acid to gamma-linolenic acid. These observations would suggest that cancer in the cell lines studied could be a relatively simple metabolic disease.

The role of unnatural dietary trans and cis unsaturated fatty acids in the epidemiology of coronary artery disease.

During 1956 the first report on the hypocholesterolemic effect of unsaturated fatty acids of plant and marine origin was published in The Lancet. Consequently it was stated in a Lancet Editorial that hydrogenation of vegetable oils could have contributed to the causation of coronary artery disease and predicted that a decade would probably be required to resolve this question. However, after the lapse of three decades this issue would appear to be no nearer to a clear answer now than it was then. During 1956 hydrogenation was assumed to effect only a reduction in the level of unsaturated fatty acids in the products produced from hydrogenated oils. However, since that time essential fatty acid metabolic pathways to eicosanoids were discovered and described. Also large quantities of unnatural trans and cis unsaturated fatty acids have been shown to form during hydrogenation and these occur in margarines and many other common foods in high concentrations. It has also been shown that these unnatural trans and cis fatty acids block essential fatty acid metabolism by the competitive inhibition of the desaturase enzyme delta-6-desaturase. Therefore some of the possible metabolic mechanisms whereby "hydrogenation plants could have contributed to the causation of a major disease" have become clearer during the last three decades. Despite a recent conclusion by an ad hoc FDA panel that there need be little concern about the effects of trans fatty acids in the American diet on health, it is nevertheless proposed that on the basis of available evidence, unnatural dietary trans and cis unsaturated fatty acid isomers should be regarded as a definite risk factor in the etiology of coronary artery disease.

Dietary fats and cancer.

The mono-unsaturated non-essential fatty acid oleic acid (OA) has been shown to stimulate malignant cell proliferation in culture significantly. In contrast, the essential fatty acids (EFAs) linoleic acid (LA) and alpha-linolenic acid (ALA) and their longer chain metabolic derivatives have been shown to have potent proliferation suppressive effects on malignant cells in culture. OA is normally synthesized in the body and present in most vegetable oils and therefore also in most experimental polyunsaturated fatty acid diets used for assessing the effects of dietary fatty acids on tumorigenesis in rats. Dietary OA could therefore specifically account for the general observation that diets containing polyunsaturated fatty acids (PUFAs) are tumorigenic (1). It has been repeatedly demonstrated that many EFAs and EFA metabolites suppress proliferation of a wide range of malignant cells in culture. These cytotoxic effects of EFAs do not inhibit the proliferation of nonmalignant cultured cells. The EFAs which have proliferation-suppression activities are components of cell membranes and many are also eicosanoid precursors. It is proposed that the membranes of malignant cells are inherently unstable. Thus the EFAs may have effects which either fluidise or stabilise these membranes. This results in either cytolysis or inhibition of proliferation. The relative quantities of the different EFAs may be critical for these effects. Eicosanoid metabolites may further compound these actions. It is suggested that one pathway for these actions could be a metabolic imbalance of EFA metabolites and their eicosanoid products. This would arise due to a combination of inhibited desaturase enzymes and a concomitant free cellular supply of dietary arachidonic acid (AA). This imbalance also could be causally involved in the promotion of malignancy. A simple procedure, which only involves dietary supplementation with gamma-linolenic acid (GLA) and eicosapentaenoic acid (EPA), is proposed as prophylaxis against the possible tumorigenic effect of dietary fats. "By some estimates, as much as 90% of all cancer in humans has been attributed to various environmental factors, including diet. The evidence reviewed by the committee suggests that cancers of most of the major sites are influenced by dietary patterns. The committee concluded that of all the dietary components it studied, the combined epidemiological and experimental evidence is most suggestive for a causal relationship between fat intake and the occurrence of cancer" - (1).

The use of drugs for the inhibition of prostaglandin or leukotriene synthesis from arachidonic acid is theoretically hazardous.

It would appear that it has become almost common practice to regard arachidonic acid (AA) as the sole precursor of eicosanoids. The fact that both dihomogamma-linolenic acid (DGLA) and eicosapentaenoic acid (EPA) give rise to distinct families of eicosanoids is commonly almost completely ignored. Elevated tissue levels of AA eicosanoids have been found in and have been implicated in the etiology of a number of diseases. Drugs which selectively block AA mobilization or its eicosanoid metabolism have therefore been developed for therapeutic use in these conditions. The fact that such drugs will also simultaneously block the eicosanoid metabolism from DGLA as well as from EPA is also commonly ignored. It is suggested that the profoundly adverse side-effects displayed by some of these drugs, resulting in some instances in their withdrawal from use, could be the direct result of their concomitant action of interfering with the eicosanoid metabolism of DGLA and EPA. It is further suggested that, before the interactions between the eicosanoids derived from AA and those derived from DGLA and EPA are understood, the use of drugs for the manipulation of AA eicosanoid metabolism in isolation, could be hazardous. This implies that all such drugs currently in use are to be regarded as experimental and provisionally toxic in terms of their effects on the whole system of eicosanoid metabolism. Thus even drugs which have been passed by the FDA and similar Drug Control Councils require total re-evaluation especially in view of the fact that the non-steroidal anti-inflammatory drugs are often prescribed for chronic conditions which require therapy for several years.(ABSTRACT TRUNCATED AT 250 WORDS)

The Eskimo diet. Prophylactic effects ascribed to the balanced presence of natural cis unsaturated fatty acids and to the absence of unnatural trans and cis isomers of unsaturated fatty acids.

In addition to the well recognised roles of eicosapentaenoic acid and possibly docosahexaenoic acid, there are two other major important, but unrecognised, features of the traditional Eskimo staple diet namely that it contains the unsaturated fatty acids (UFA) cis oleic, cis linoleic and cis alpha-linolenic as well as their respective C20 and C22 metabolites in physiologically optimal concentrations and, it is virtually totally devoid of unnatural and potentially hazardous trans and cis isomers of these fatty acids. Large quantities of unnatural trans and cis isomers of UFA are found in the Western diet as partially hydrogenated UFA in many foods. These isomers are formed during the manufacture of margarines and related compounds, as food contaminants during excessive heating of cooking oils for deep-frying and other excessive heat-requiring mass food preparation procedures and it is suggested, as the result of excessive feeding with an unnatural diet of ruminants and non-ruminants for increased meat and/or milk production and of poultry for increased egg and/or meat production. These isomers have been shown to display potentially hazardous metabolic effects which include the competitive inhibition of UFA metabolism at various steps and have been causally implicated in the etiology of ischemic heart disease and cancer. It is suggested that the myth of the safety of trans fatty acids arises from misinterpretation of the observation that increasing dietary cis linoleic acid reduces the toxic effects of trans UFA. It is suggested that the decrease of 20% in the ischemic heart disease mortality in the USA during the past two decades is directly related to a shift in the dietary ratio of unnatural trans and cis UFA isomers: cis linoleic acid in favour of the latter. It is predicted that this ratio will be found to correlate with ischemic heart disease patterns in other countries. Eskimos consume the bulk of their food frozen, raw or dried, seldom boiled, but never deep-fried or after exposure to excessive heat. Moreover the proportionality of cis UFA and their metabolites in their traditional staple diet would render gross tissue UFA utilization relatively independent of desaturase enzyme activity. In the Eskimo tissues these enzymes would function to make the minute, critical UFA metabolic adjustments required to ensure the presence of structural UFA in membranes in functionally optimal quantities and, ensure the synthesis of eicosanoids from dihomogamma-linolenic acid, arachidonic acid and eicosapentaenoic acid in balanced, optimal physiological concentrations for the genetic make-up of Eskimos.(ABSTRACT TRUNCATED AT 400 WORDS)

Dynamic electrocardiography. III. The "imaginary cardiac vector" hypothesis: theoretical basis.

The "imaginary cardiac vector" hypothesis states that the "cardiac vector" is not a "real" vector entity. The hypothesis arises from the fact that voltage is not a vector but a scalar quantity. Nevertheless, in classical electrocardiographic analysis and teaching, the ECG voltage is treated as a vector. These voltages are used as "vector" components--first, to calculate a "resultant manifest potential difference", represented by the "cardiac vector" arrow in electrocardiography, and second, to draw the "cardiac vector" loop in vectorcardiography. The resultant "cardiac vector" is usually considered to be a "real" vector quantity describing the electrical activity of the heart. It is also widely believed that this "vector" was first described by Einthoven in 1913. To evaluate the hypothesis, we have utilised the actual values and methods presented by Einthoven, and demonstrated that the theoretical basis of the "cardiac vector" is false. It appears that Einthoven followed scalar and not vector procedures and that he did not describe a vector.

Chronic arachidonic acid eicosanoid imbalance: a common feature in coronary artery disease, hypercholesterolemia, cancer and other important diseases. Significance of desaturase enzyme inhibition and of the arachidonic acid desaturase-independent pathway.

A chronic imbalance between the essential fatty acid metabolites arachidonic acid, gamma-linolenic acid and eicosapentaenoic acid and of their respective eicosanoid derivatives appears to be implicated in the etiology of many intractable disease. Most notable among these are coronary artery disease, cancer and chronic inflammation. The factors leading to such an imbalance and their relatively simple prophylactic and therapeutic circumvention are discussed briefly.

Dynamic electrocardiography V. The "imaginary cardiac vector" hypothesis: experimental evaluation.

This paper experimentally evaluates the "imaginary cardiac vector" hypothesis, that the cardiac vector is not a real vector. We have previously shown on theoretical grounds that the basis of the cardiac vector is invalid in that Einthoven used scalar, not vector, procedures. Attempts by subsequent workers to compensate for the theoretical flaws have not succeeded. The concept of the "cardiac vector" which they have invented has the dimensions of an imaginary entity. Experimental measurement of isopotential maps derived from dipoles in a volume conductor demonstrates that these dipoles do not summate vectorially. Isopotential maps of the thoracic surface confirm that this applies to the human ECG. An imaginary "man-frog" cardiac vector loop is demonstrated using a lead from a man and a lead from a frog. This illustrates that the "imaginary cardiac vector" is a tenable concept. Finally, a crucial test of the hypothesis is reported which demonstrates that exercise causes deviations of the so-called cardiac vector in opposite directions, simultaneously, in different VCG lead systems. Since a physical entity can only be in one place and more in one direction at a particular instant, this experiment invalidates the "real cardiac vector" hypothesis. This strongly suggests that the cardiac vector is a brilliant, but imaginary, construction with immense clinical value, especially in the interpretation of the sequence of depolarization. Nevertheless, it obstructs analysis of the real basis of the electricity of the heart.

A psychophysiological hypothesis on the aetiology of duodenal ulceration.

A previously undescribed explanation for the development of duodenal ulcer is advanced. Stressful situations and avoidance-avoidance conflicts in individuals with a dependant compliant personality incapable of appropriate "stimulus-seeking behaviour" lead to an immobilised state. This predicament is denied. Helplessness develops. This state is associated with an autonomic imbalance in which a central monoamine depletion results in uncompensated parasympathetic overactivity which facilitates the development of duodenal ulceration. Denial often invalidates superficial psychological investigations into the aetiology of duodenal ulceration and may explain the contradictory findings in the literature.

Dynamic electrocardiography. II. A crucial test of the electromechanical QRS wave theory.

The dynamic electromechanical electrocardiogram hypothesis, that QRS voltage fluctuations can be used as a simple noninvasive transducer of cardiac mechanical function, has been subjected to a crucial experiment. Under direct vision, transient modifications of the end-diastolic volume of the baboon heart were produced and photographed. Sequential obstructions to filling (by vena caval compression) and to emptying (by aortic compression), and vice versa, significantly distorted the size and shape of the heart. The instantaneous effects of these manipulations on the amplitudes of the R and S waves were evaluated in electrocardiograms recorded from electrodes glued to selected pericardial and epicardial sites. Major QRS voltage deviations occurred in the perircardial leads. Manipulations increasing the left ventricular volume increased the S wave and reduced the R wave, while those decreasing heartsize had the opposite effect. These findings refute the null hypothesis, that the electrocardiogram is not an indicator of mechanical function. No changes of the QRS waves in the epicardial lead were detected, supporting the concept that displacement relative to the recording electrode is the basis of the QRS CHANGEs due to heartsize variation. The results negate the classical concept that the electrocardiogram does not reflect cardiac mechanical function, and strongly corroborate the dynamic electromechanical electrocardiogram hypothesis.

Exercise stress testing and an electromechanical S wave of the electrocardiogram. Does the S-wave voltage change with increasing work rate?

A new view of the electrocardiogram, first proposed by Posel and arising from Craib's travelling dipole concept, predicts an electromechanical relationship between S-wave amplitude changes and cardiac mechanical function changes. In an attempt to determine whether the S-wave voltage changes with increasing work rate, 10 male subjects were tested at rest and at maximum exercise. A statistically significant increase in the S wave occurred with increased mechanical work. The theoretical prediction of an electromechanical S wave is thus validated and a request is extended to other workers to verify or refute its existence.

Electrocardiographic measurement of cardiac function. Are the amplitude changes of the S wave indicative of changes in the size of the heart?

Preliminary tests to determine whether there is an electromechanical link between the electrocardiogram and cardiac function have been done by means of echocardiography. Three different haemodynamic manipulations which alter cardiac function, viz. nitroglycerin, intravenous digoxin and exercise-induced angina, were used. The changes in the S-wave amplitude, in selected leads, appear to be directionally related to the changes in the left ventricular enddiastolic volume. It is thus suggested that the S-wave changes may be indicative of changes in cardiac function.

Antistress hormonal responses of analgesic nitrous oxide.

We briefly describe the hormonal responses associated with stress and provide evidence that endogenous and exogenous opioids have "antistress" hormonal profiles. We present data which indicate that analgesic nitrous oxide produces a typical opioid hormonal response, viz. increased prolactin and decreased cortisol levels. There was no significant change in ACTH levels despite the fall in cortisol. We present evidence which supports the hypothesis that the antistress hormonal effects of opioids and analgesic nitrous oxide are mediated by uncoupling the adrenal gland from hypothalamico-pituitary stimulation. It would appear that the opioid system acts antagonistically to the adrenocortical system in stress. We propose that any method stimulating the opioid system optimally may have the antistress effects.

The reversibility of cancer: evidence that malignancy in melanoma cells is gamma-linolenic acid deficiency-dependent.

Certain metabolic abnormalities are common to all malignant cells, and Horrobin proposed that the underlying cause is the inability of cancer cells to produce prostaglandin E1 (PGE1). This appears to be due to the lack of the enzyme delta-6-desaturase which converts the essential fatty acid, linoleic acid, to gamma-linolenic acid (GLA), from which PGE1 is then synthesized. Our studies strongly support this contention. Addition to GLA to cancer cells, thus bypassing the block in the metabolic pathway, results in very marked, statistically highly significant inhibition of growth, while having no effect at all on normal cells. Our finding of the regression of cancer through such proposed normalization offers preliminary hope for a new effective and harmless approach to the treatment of cancer.

The effect of gamma-linolenic acid on the growth of human osteogenic sarcoma and oesophageal carcinoma cells in culture.

A statistically highly significant growth-suppressive effect of the prostaglandin precursor gamma-linolenic acid (GLA) on MG63 human osteogenic sarcoma and oesophageal carcinoma cells in culture was found. In view of the results reported on the growth-suppressive effect of GLA on cancer cells in culture, on transplanted mammary tumours in rats and in primary liver cancer patients, it would appear that further investigation of the effects of this fatty acid on cancer cell growth both in vitro and in vivo is warranted.