No abstract

There is considerable evidence which can be interpreted to indicate a familial trend in human essential hypertension (1-5). A familial disease could be due exclusively to common environmental factors, exclusively to common genetic patterns, or to an interaction of the two.For some years we have been exploring the effects of chronic excess salt ingestion in both man and animals and have brought forward evidence to support the thesis that dietary salt plays an etiologic role in human essential hypertension (6-12). However, it was observed repeatedly that some individuals, and some rats, remained normotensive despite the fact that they were chronically consuming large amounts of salt.In our nutritional experiments with rats (13-15) the control of environmental factors was rigid. In spite of this, in a given group, some salt-fed animals never developed hypertension whereas a few became hypertensive after 1 month on the diet and rapidly developed fulminating hypertension. It was thought that such wide variations in response to excess salt consumption represented either the statistical limits of a homogeneous populatoin or the extreme consequences of genetic heterogeneity. If the population were homogeneous, it would not lend itself to fractionation by genetic techniques. By contrast, if sensitivity to salt were genetically controlled, it should be possible to separate two strains that differ demonstrably in the incidence and gravity of hypertension developing from excess salt consumption.The present paper is a report of experiments that resulted in the separation of two strains of rats differing markedly from one another in their susceptibility to the development of experimental hypertension from excess salt ingestion. Experiment 1We were aware that thyroid hormone enhanced the development of experimental hypertension produced by salt and desoxycorticosterone acetate (16)(17)(18)(19)(20).

In an earlier study (1, 2) we reported that by using the technique of selective inbreeding~ two strains of rats were evolved which differed markedly in their tendency to develop hypertension from chronic excess salt ingestion: one population was predisposed to develop hypertension (the sensitive or S strain) from the same high salt intake that proved ineffective in producing hypertension in the other population (the resistant or R strain). It was concluded that generic factors played an important role in determining susceptibility to that form of experimental hypertension.Prior to working with these two strains of selectively inbred rats, over a period of about 15 years we had observed the response of hundreds of stock animals to a chronically high sodium intake and had found that only about three-fourths of such animals would develop varying degrees of hypertension. Our experience with a combination of desoxycorticosterone acetate and a high sodium chloride intake (DOCA-salt) was similar. We were intrigued to learn that other investigators had found unilateral renal artery compression in the rat gave roughly similar results, namely ~only about half to two-thirds of animals so treated developed hypertension (3, 4). These several experiences suggested that variations in genetic susceptibility were operating in experimental hypeffension induced by either renal artery compression or DOCA-salt, just as we had observed in that from salt alone.The present paper is a report of experiments which demonstrate that this is true. Depending upon whether animals were derived from the sensitive or resistant strain of rats, susceptibility to experimental hypertension induced by either unilateral renal artery compression or DOCA-salt was found to be significantly different. Thus, variations in genetic substrate clearly influence the development of at least 3 "varieties" of experimental hypertension. It is postulated that this may hold true for other, and conceivably all, means of producing experimental hypertension. If so, it may be possible to develop a general hypothesis that will unify these presently disparate entities.

Rats with a genetic susceptibility to salt hypertension were given repeated neonatal injections of guanethidine. Vascular reactivity and tissue catecholamine concentrations indicated that a peripheral sympathectomy had been produced. Chemically sympathectomized rats had lower blood pressure than controls while fed a diet containing 0.4% NaCl. Furthermore, the dramatic rise in blood pressure exhibited by control rats fed a diet containing 8.0% NaCl was completely absent in sympathectomized rats similarly fed. The absence of salt-induced hypertension was observed regardless of whether the animals were anesthetized with ether or pentobarbital or had the blood pressures determined in an unanesthetized state. Finally, two-kidney Goldblatt hypertension did develop in sympathectomized rats, but to a level below intact rats similarly treated.

Despite the relatively large amounts of magnesium present in the cells of most mammals, its in vivo functions in man remain poorly defined, a point which is emphasized in a recent review by Wacker and Vallee (1). There is evidence, which is still equivocal, that abnormalities of magnesium metabolism may be involved in several disease states including atherosclerosis (2), myxedema (3), hyperthyroidism (4), acute alcoholism (5), and possibly other conditions (6). Although Wacker and Vallee emphasized that, in view of its established capacity to function as an activator for many in vitro enzyme systems magnesium must play a significant role in intracellular metabolic activity, one of the intriguing aspects of magnesium has been its apparently relative inertness-particularly striking when compared with the other major ions in the body. Study of magnesium has been aided by the advent of the isotope Mg28 (7), although some caution has been necessary in using this isotope as well as in interpreting results obtained with it because of the relatively low specific activity which has been attained. With these limitations in mind we have made studies that tend to confirm earlier data arrived at by nonisotopic techniques, namely, that there are several relatively small, rapidly equilibrating compartments and one or more in which turnover is very slow. These data on man suggest that there are at least three compartments in the body pool of magnesium turning over with half-times of 1, 3, and 14 to 35 hours, respectively, but that probably 25 to 50 per cent of the magnesium has a turnover rate of less than 2 per cent per day. MATERIALS AND METHODSClinical data. The 10 white adults-3 males of 45, 55 and 62 years of age, and 7 females aged 38, 46, 52, 53, 55, 64 and 72 years-were studied on the metabolic wards of the Hospital of the Brookhaven Medical Research * This investigation was supported by the United States Atomic Energy Commission.Center for several months or more during the period of these investigations. All but the male aged 55 suffered from hypertension. Since the present observations are not clearly relevant to hypertension, only clinical data which might be pertinent to the present study are mentioned. The male of 55 had had classical rheumatoid arthritis of 3 years' duration but no other disease. The male of 62, who had a history of syphilis, was found to have positive serological tests for syphilis; the root of the ascending aorta was somewhat dilated by X-ray and a