Lewis K. Dahl

Primary Role of Renal Homografts in Setting Chronic Blood Pressure Levels in Rats

The genotype of homograft kidneys plays the primary role in determining chronic blood pressure levels in two strains of rats with opposite genetically controlled propensities for hypertension. In hypertensive rats from the hypertension-prone (S) strain, a renal homograft from the same strain resulted in a slight rise in blood pressure to a level that was equivalent to that in appropriate uninephrectomized S controls. In contrast, a renal homograft from the hypertension-resistant (R) strain led to a sharp fall in blood pressure in hypertensive S recipients. Opposite results were found when the host came from the R strain: R homografts maintained the same low pressure as that seen in controls, whereas S homografts resulted in hypertension. We concluded that genetically controlled factors operating through the kidney can chronically modify the blood pressure up or down. The central role of the kidney in hypertension is thus further documented.

Genetic influence of the kidneys on blood pressure. Evidence from chronic renal homografts in rats with opposite predispositions to hypertension

In two strains of rats with opposite genetic propensities for hypertension, interstrain renal transplants chronically modified the blood pressure of the recipients. The blood pressure of rats with these renal homografts was largely determined by the genotype of the donor kidney rather than by the genotype of the recipient. Kidneys from the hypertension-resistant (R) rats generally had an antihypertensive effect, and kidneys from the hypertension-prone (S) rats had a prohypertensive effect. These effects on blood pressure were most clear-cut in rats maintained on a low-sodium diet, but they were still evident in a modified form in rats on a high-sodium diet. Results from this study and from earlier studies suggest that kidneys from S rats have a greater hypertensinogenic and a smaller antihypertensive capacity than do kidneys from R rats. Therefore the influence of the kidney on blood pressure appears to have genetic determinants. If this finding is applicable to man, it would help to explain the well-established but anomalous observation that one of two individuals who apparently have similar renal disorders can have hypertension when the other does not.

Effects of Chronic Excess Salt Ingestion: Modification Of Experimental Hypertension In The Rat By Variations In The Diet

A strain of rats that will predictably develop experimental hypertension by means of different techniques was used to study NaCl-induced hypertension. Observations were continued for 1 year after weaning unless death intervened. Among groups of rats on 0.4, 1, 2, 4, and 8% NaCl chow, respectively, blood pressures generally rose as dietary NaCl increased. Average blood pressures ranged from 146.8 mm Hg in the group on the lowest, to 210.2 mm Hg in the group with the highest NaCl intakes. Morbidity and mortality also increased. Even transient high NaCl diets were capable of inducing permanent hypertension; 4 of 34 rats on 8% NaCl chow for only 2 weeks after weaning had pressures of 180 to 206 mm Hg, although most rats did not become significantly more hypertensive than those on the low (0.4%) NaCl diet. When this same diet was continued for a total of 6 weeks in a group of 29 animals, the blood pressure averaged 198.6 mm Hg. The age at which the high NaCl intake began also influenced the course of the hypertension. Weanling rats rapidly developed fulminating hypertension on the high NaCl diet. After 3 months on this regimen, the average pressure of 40 rats exceeded 200 mm Hg, and 35 animals were dead or terminally ill. In rats that were older when high NaCl diets were started, hypertension developed more slowly and was less fulminant. Among 38 rats in which NaCl was not begun until 3 or 6 months past weaning, blood pressures averaged 175 to 180 mm Hg after 3 months on NaCl; 31 appeared in good health but none survived 8 months.

Genetic Influence of the Kidneys on Blood Pressure

In two strains of rats with opposite genetic propensities for hypertension, interstrain renal transplants chronically modified the blood pressure of the recipients. The blood pressure of rats with these renal homografts was largely determined by the genotype of the donor kidney rather than by the genotype of the recipient. Kidneys from the hypertension-resistant (R) rats generally had an antihypertensive effect, and kidneys from the hypertension-prone (S) rats had a prohypertensive effect. These effects on blood pressure were most clear-cut in rats maintained on a low-sodium diet, but they were still evident in a modified form in rats on a high-sodium diet. Results from this study and from earlier studies suggest that kidneys from S rats have a greater hypertensinogenic and a smaller antihypertensive capacity than do kidneys from R rats. Therefore the influence of the kidney on blood pressure appears to have genetic determinants. If this finding is applicable to man, it would help to explain the well-esta...

Possible role of chronic excess salt consumption in the pathogenesis of essential hypertension

Abstract There is evidence which suggests that among groups habitually eating salt in amounts well in excess of requirements, hypertension will be common. Furthermore, it seems likely that as the salt excess increases, so will the prevalence of hypertension. It is proposed that this chronic excess consumption of salt may play a primary role in the pathogenesis of hypertension in man. Variations in biological responsiveness will determine which subjects in a group have the disease.

Genetic influence on the renin-angiotensin system: low renin activities in hypertension-prone rats.

Two strains of rats with opposite, genetically determined predispositions to hypertension were compared. Rats from the hypertension-prone strain had significantly lower plasma and kidney renin activities than did rats from the hypertension-resistant strain. Although renin activities were modified by NaCl intake and blood pressure, significant differences between the two strains were present with all four experimental regimens used: low-NaCl diet, high-NaCl diet, unilateral renal artery constriction, and unilateral renal artery constriction plus contralateral nephrectomy. Therefore, we concluded that renin activities along with blood pressure were modified by genetic influences in these two strains of rats.

Genetic Influence of Renal Homografts on the Blood Pressure of Rats from Different Strains

Summary In two strains of rats with opposite genetic propensities to hypertension, the effect of renal transplants on the chronic blood pressure response has been studied. 113 rats survived an average of 4 months (range 1-14) after this procedure. Among animals maintained on a low NaCl diet, blood pressure, as compared with appropriate controls, was not significantly affected when the recipient animal and its renal homograft came from the same strain; however, animals from the hypertension-resistant strain with a renal homograft from the hypertension-prone strain had higher pressures whereas hypertension-prone rats with a homograft from the hypertension-resistant strain had lower pressures than their respective controls. Thus, the phenotypic response—blood pressure—was more influenced by the genotype of the renal homograft than by the genotype of the recipient.

Role of Hyperplasia in Vascular Lesions of Cholesterol-fed Rabbits Studied with Thymidine-H3 Autoradiography

Rabbit aorta and coronary vessels were studied with thymidine-H3 and autoradiography. They were found to comprise an extremely stable population of cells, the latter probably even more stable than the former. Compensatory repair by means of regeneration at sites of bifurcation seems inadequate. This in part may explain the susceptibility of these areas to the development of atherosclerotic lesions. Proliferation, although sequentially secondary to fatty infiltration, plays an active role in the pathogenesis of cellular atherosclerotic lesions as seen in the rabbit. Foam cells possess the ability to synthesize DNA even when incorporated within the atherosclerotic lesion. Arguments in support of and opposed to some of the current hypotheses for the pathogenesis of atherosclerosis have been presented.

Evidence for an increased intake of sodium in hypertension based on urinary excretion of sodium.

Conclusion Among 28 subjects with and without hypertension, the group with high blood pressure had significantly greater (p<.01) sodium intakes (as measured by urinary outputs) than did the group of non-hypertensives. This finding was in agreement with a hypothesis previously proposed, namely, that the level of sodium intake was of primary etiologic importance in the development of essential hypertension.

18-Hydroxy-Deoxycorticosterone Secretion in Experimental Hypertension in Rats

Adrenal steroidogenesis was studied in vitro and in vivo in rats which have been specifically bred for susceptibility (S strain) or resistance (R strain) to the hypertensive effects of salt. A marked quantitative difference was found between S and R rats in the adrenal biosynthetic pathways which are subsequent to deoxycorticosterone (DOC). There was a twofold difference in the ability to 18-hydroxylate DOC to form 18-hydroxy-deoxycorticosterone (18OH-DOC) with the greater activity in the S rats. This increment in 18-hydroxylation of DOC in S over R rats was offset by an equal decrement in 11β-hydroxylation of DOC to form corticosterone (B) in S compared with R rats. These alterations in metabolic pathways gave rise to characteristic 18OH-DOC/B ratios for S and R animals that were obvious both in vitro and in vivo. The data suggest, therefore, that in selectively breeding rats on the basis of blood pressure response to salt, a gene (or genes) which affects the 18OH-DOC/B ratio has been segregated in the S and R strains. Although this segregation is in itself good evidence for an effect of 18OH-DOC (or 18OH-DOC/B ratio) on blood pressure in rats, it was also emphasized that there is evidence for more than one gene affecting blood pressure in rats. Thus, the steroid difference described is likely to be controlled by only one of several genes affecting the quantitative character of blood pressure. Comparison of 18OH-DOC/B ratios in S and R strains with other strains of rats showed that the high ratio in S rats was quite common, but that the low ratio in R rats was rather unique. Thus, it seems that the low 18OH-DOC/B ratio of R animals connotes resistance to salt, while the higher ratio in S and unselected strains probably only connotes normal susceptibility to salt. The extreme sensitivity of S rats to salt must therefore be accounted for by other genes.