Epidemiological, migration, intervention, and genetic studies in humans and animals provide very strong evidence of a causal link between high salt intake and high blood pressure. The mechanisms by which dietary salt increases arterial pressure are not fully understood, but they seem related to the inability of the kidneys to excrete large amounts of salt. From an evolutionary viewpoint, the human species is adapted to ingest and excrete <1 g of salt per day, at least 10 times less than the average values currently observed in industrialized and urbanized countries. Independent of the rise in blood pressure, dietary salt also increases cardiac left ventricular mass, arterial thickness and stiffness, the incidence of strokes, and the severity of cardiac failure. Thus chronic exposure to a high-salt diet appears to be a major factor involved in the frequent occurrence of hypertension and cardiovascular diseases in human populations.

Links between dietary salt intake, renal salt handling, blood pressure, and cardiovascular diseases.

Although laboratory experiments document cooperative behavior in humans, little is known about the extent to which individual differences in cooperativeness result from genetic and environmental variation. In this article, we report the results of two independently conceived and executed studies of monozygotic and dizygotic twins, one in Sweden and one in the United States. The results from these studies suggest that humans are endowed with genetic variation that influences the decision to invest, and to reciprocate investment, in the classic trust game. Based on these findings, we urge social scientists to take seriously the idea that differences in peer and parental socialization are not the only forces that influence variation in cooperative behavior.

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Heritability of cooperative behavior in the trust game

Classically, aldosterone is synthesised in the adrenal zona glomerulosa and binds to specific mineralocorticoid receptors located in the cytosol of target epithelial cells. Translocation of the resulting steroid receptor complex to the cell nucleus modulates gene expression and translation of specific 'aldosterone-induced' proteins that regulate electrolyte and fluid balance. However, non-epithelial and rapid non-genomic actions of aldosterone have also been described that account for a variety of actions of aldosterone that contribute to blood pressure homeostasis. These include key actions on endothelial cells and on cardiac tissue. There is also evidence that aldosterone can be synthesised in other tissues; the most convincing evidence relates to the central nervous system. However, suggestions that aldosterone is produced in the heart remain controversial, and adrenal derived aldosterone is the principal source of circulating and locally available hormone. Recent studies have shown major therapeutic benefits of mineralocorticoid receptor antagonism in cardiac failure, which emphasise the importance of aldosterone in causing adverse cardiovascular pathophysiological effects. Additional evidence demonstrates that aldosterone levels predict development of high blood pressure in normotensive subjects, while it is now clear that increased aldosterone action contributes to hypertension and cardiovascular damage in approximately 10% of patients with established hypertension. These new findings highlight the role of aldosterone as a key cardiovascular hormone and extend our understanding of its role in determining adverse cardiovascular outcomes.

/pdf/the-new-biology-of-aldosterone-3hat25hw3x.pdf

The new biology of aldosterone

—The renin-angiotensin-aldosterone system plays an important role in blood pressure regulation by influencing salt-water homeostasis and vascular tone. The purpose of the present study was to search for associations of single nucleotide polymorphisms on 3 major candidate genes of this system with the plasma concentrations of the corresponding renin-angiotensin-aldosterone system components considered as quantitative phenotypes. Genotyping was performed in 114 normotensive subjects for different variants of the angiotensinogen ( AGT ) gene (C-532T, G-6A, M235T), the angiotensin I–converting enzyme ( ACE ) gene [4656(CT) 2/3 ], the aldosterone synthase (CYP11B2), and the type 1 angiotensin II receptor ( AT1R ) gene (A1166C) by hybridization with allele-specific oligonucleotides (ASO) or enzymatic digestion of polymerase chain reaction products. Plasma levels of AGT, ACE, angiotensin II (Ang II), aldosterone, and immunoreactive active renin were measured according to standard techniques. Platelet binding sites for Ang II were analyzed by the binding of radioiodinated Ang II to purified platelets. B max and K D values of the Ang II binding sites on platelets of each individual were calculated to examine a possible relationship between these parameters and the AT1R genotype. A highly significant association of the ACE 4656(CT) 2/3 variant with plasma ACE levels was observed ( P AGT C-532T polymorphism on AGT plasma levels ( P =0.017), but no significant effect was detectable with the other AGT polymorphisms tested, such as the G-6A or the M235T. A significant effect association was also found between the C-344T polymorphism of the CYP11B2 gene and plasma aldosterone levels, with the T allele associated with higher levels ( P =0.02). No genotype effect of the AT1R A1166C polymorphism was detected either on the B max or the K D value of the Ang II receptors on platelets.

/pdf/genotype-phenotype-relationships-for-the-renin-angiotensin-2g43p87zlc.pdf

Genotype-Phenotype Relationships for the Renin-Angiotensin-Aldosterone System in a Normal Population

We analyzed the association between salt sensitivity in essential hypertension and 8 genetic polymorphisms in 6 genes of the renin-angiotensin aldosterone system. Seventy-one patients with essential hypertension were classified as salt sensitive or salt resistant by means of the 24-hour ambulatory blood pressure (BP) change to high salt intake. The polymorphisms evaluated correspond to the following genes: ACE (I/D), angiotensinogen (M235T), angiotensin II type 1 receptor (A1166C), 11beta-Hydroxysteroid dehydrogenase type 2 (11betaHSD2) (G534A), aldosterone synthase (C-344T and Intron 2 conversion), and the mineralocorticoid receptor (G3514C and A4582C); all were determined using standard polymerase chain reaction methods. Thirty-five patients (49%) were classified as salt sensitive. We analyzed the BP response to high salt intake among genotypes and found a significant association for ACE I/D and 11betaHSD2 G534A polymorphisms. Patients homozygous for the insertion allele of the ACE gene (II) had a significantly higher BP increase with high salt intake than did patients homozygous for the deletion allele (DD). Heterozygous patients (ID) exhibited an intermediate response. The prevalence of salt-sensitive hypertension was also significantly higher (P=0.003) in II (68%) and DI patients (59%) compared with DD hypertensives (19%). With respect to 11betaHSD2 G534A, patients with the GG genotype had a significantly higher systolic BP increase with high salt intake than did GA patients. In addition, plasma renin activity suppression in response to high salt was significantly greater in GA patients than in GG patients. The prevalence of salt-sensitive hypertension was 14.3% in GA patients and 50.8% in GG patients (P=0.067). In conclusion, the I allele of ACE I/D polymorphism is significantly associated to salt-sensitive hypertension. The BP response to high salt intake was different among genotypes of ACE I/D and 11betaHSD G534A, suggesting that these polymorphisms may be potentially useful genetic markers of salt sensitivity.

Molecular Basis of Salt Sensitivity in Human Hypertension: Evaluation of Renin-Angiotensin-Aldosterone System Gene Polymorphisms

. Hautanen A, Lankinen L, Kupari M, Janne OA, Adlercreutz H, Nikkila H, White PC (Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland. University of Texas Southwestern Medical Center, Dallas, TX, USA). Associations between aldosterone synthase gene polymorphism and the adrenocortical function in males. J Intern Med 1998; 244: 11–18.



Objectives

Two diallelic polymorphisms, one in the transcriptional regulatory region (promoter) and the other in the second intron, have been identified in the aldosterone synthase (CYP11B2) gene encoding aldosterone synthase, the enzyme catalysing the last steps of aldosterone biosynthesis. We have examined the associations between these genetic variations and adrenocortical function in a cohort of Finnish males.



Design

A cross-sectional study.



Setting

Helsinki University Central Hospital, Finland.



Subjects

Ninety-two males aged 30–55 years.



Main outcome measures

Basal adrenocortical function was assessed by measuring urinary excretion of aldosterone and cortisol. Functional activity was determined by responses of several adrenal steroids to dexamethasone suppression followed by ACTH stimulation. Polymerase chain reactions were used to identify the polymorphisms in the CYP11B2 gene.



Results

The –344TT genotype group in the CYP11B2 promoter had lower systolic blood pressures (P= 0.039), but higher urinary aldosterone excretion (P= 0.016), and 11-deoxycortisol responses to ACTH stimulation (P= 0.021) than the –344CC genotype group. Urinary aldosterone excretion (P= 0.033), 11-deoxycortisol (P= 0.026), and aldosterone (P= 0.013) responses to ACTH were higher in the intron 2 conversion than the nonconversion genotype groups.



Conclusions

Polymorphisms in or near the aldosterone synthase gene are associated with variations in aldosterone and 11-deoxycortisol production in males. This may modulate the activity of the renin–angiotensin system and thereby contribute to blood pressure regulation.

L. Lankinen

Papers

Associations between aldosterone synthase gene polymorphism and the adrenocortical function in males