Effects of Chronic Excess Salt Ingestion

Abstract

In man, hereditary factors are recognized as essential in the etiology of hypertension. The genetic expression is, however, difficult to assess because it is not known how many genes are involved, how they interact with one another and with environmental factors, or by what mechanisms they exert their influence.In rats, the genetic influence on blood pressure regulation is definitely established. If similar factors operate in humans, rat colonies may provide prototypes of heredity and blood pressure regulation for the study of human health and disease. Work at this laboratory demonstrated in 1962 that the development of salt-induced hypertension strongly depended upon the genetic backgroand of the rats used (1, 2). By selective breeding, two colonies were derived from a single Sprague-Dawley strain. In one colony the rats rapidly developed hypertension on the same salt (NaC1) intake to which members of the other colony were resistant. Later we confirmed these differences with other techniques generally used to induce experimental hypertension. These techniques included: DOCA plus NaC1, unilateral renal artery compression without NaC1, cortisone, adrenal regeneration, and uninephrectomy without NaC1 (3-5). If these experimental models have relevance to man, then several forms of human hypertension would also require for their emergence an appropriate genetic substratum which depends upon environmental determinants for its expression (4).In the present work, which extended over a six year period, we have explored the mode of inheritance of hypertension in these two strains of rats. Approximately 2000 animals were studied in an effort to determine the number of genes involved. The data indicated that regulation of blood pressure is multigenic; the probable number of genes was calculated to be from two to four. The simplest model compatible with our data consists of two nonlinked, autosomal, diallelic loci with a sex-modified expression of the genes at one locus. Materials and MethodsRats were housed three to a cage in air-conditioned rooms, lighted for 10 hr each day. The food pellets were made to order and contained a total of 8% NaC1 (w/w). Pellets and

Dahl salt-susceptible and salt-resistant rats. A review.

“…It was concluded from the genetic experiments that the Hyp-1 locus accounted for a blood pressure difference of about 16 mm Hg between S and R rats in the environment of a high salt diet." Since blood pressure in the S and R model is known to be under polygenic control, 9 the remaining difference in blood pressure between the strains is obviously due to the other (unidentified) genetic loci.…”

“…81 Although blood pressure responses to exogenous mineralocorticoid are greater in S than R, 1 7~ this is probably not due to an increased effect of the mineralocorticoid on S rats at the level of the kidney because distal tubular hypertrophy and skeletal muscle potassium depletion were equivalent in S and R rats. 17 There is no evidence for sex linkage of the genetic effects on blood pressure, 9 meaning that none of the genetic loci controlling blood pressure is located on the X chromosome. Sex steroids do, however, exert effects.…”

“…With similarly treated R rats, blood pressure remained in the normotensive range, and 80% of the animals survived to the 48th week on high salt. 9 The age at which high salt diet was started partly determined the magnitude of the blood pressure response in S rats. When given high salt at weaning, S rats developed fulminating hypertension (above 200 mm Hg) within 6 weeks.…”

“…9 The theoretical formulas from which such estimates were calculated were based on genetic assumptions that in practice are less than perfectly met. 10 Thus, the result of 2-A loci influencing salt susceptibility in S and R rats is approximate.…”

“…There is no evidence for sex-linked genes. 9 In the original selective breeding experiments to produce S and R rats, brother-sister matings (i.e., inbreeding) were made for the first few generations.…”