Atrial natriuretic peptide is negatively regulated by microRNA-425.

Numerous common genetic variants have been linked to blood pressure, but no underlying mechanism has been elucidated. Population studies have revealed that the variant rs5068 (A/G) in the 3' untranslated region of NPPA, the gene encoding atrial natriuretic peptide (ANP), is associated with blood pressure. We selected individuals on the basis of rs5068 genotype (AG vs. AA) and fed them a low- or high-salt diet for 1 week, after which they were challenged with an intravenous saline infusion. On both diets, before and after saline administration, ANP levels were up to 50% higher in AG individuals than in AA individuals, a difference comparable to the changes induced by high-salt diet or saline infusion. In contrast, B-type natriuretic peptide levels did not differ by rs5068 genotype. We identified a microRNA, miR-425, that is expressed in human atria and ventricles and is predicted to bind the sequence spanning rs5068 for the A, but not the G, allele. miR-425 silenced NPPA mRNA in an allele-specific manner, with the G allele conferring resistance to miR-425. This study identifies miR-425 as a regulator of ANP production, raising the possibility that miR-425 antagonists could be used to treat disorders of salt overload, including hypertension and heart failure.

Effects of subacute dietary salt intake and acute volume expansion on diastolic function in young normotensive individuals.

AIMS: Chronic excess salt intake may have blood pressure-independent adverse effects on the heart such as myocardial hypertrophy and fibrosis. Effects of subacute sodium loading with excess dietary salt on diastolic function in normotensive individuals have been conflicting and the mechanisms are poorly understood. METHODS AND RESULTS: Thirteen healthy normotensive subjects (age 24 ± 4 years) entered a 2-week crossover study with 1 week of a low-salt diet <10 mEq/day and 1 week of a high-salt diet >200 mEq/day. At the end of each study week, left ventricular dimensions, systolic, and diastolic function were assessed with echocardiography before and after 2 L of normal saline infusion. One week of high-salt and low-salt diets did not lead to differences in echocardiographic parameters of systolic or diastolic function, even after rapid volume expansion with saline infusion. The peak early diastolic strain rate (SR) increased after volume loading both after completion of low-salt (1.62 ± 0.23/s vs. 1.82 ± 0.14/s, P < 0.05) and high-salt diets (1.67 ± 0.16/s vs. 1.86 ± 0.22/s, P < 0.05). There was a positive correlation between the peak early diastolic SR and the cardiac index (r = 0.52, P = 0.017). CONCLUSION: In healthy normotensive individuals, subacute excess dietary sodium intake does not affect diastolic function. The peak early diastolic SR, similar to other mitral Doppler and tissue Doppler parameters of diastolic function, appears to be strongly dependent on pre-load.

Antiseizure effects of 3alpha-androstanediol and/or 17beta-estradiol may involve actions at estrogen receptor beta.

Testosterone (T), the principal androgen secreted by the testes, can have antiseizure effects. Some of these effects may be mediated by T's metabolites. T is metabolized to 3alpha-androstanediol (3alpha-diol). T, but not 3alpha-diol, binds androgen receptor. We investigated effects of 3alpha-diol (1 mg/kg, SC) and/or an androgen receptor blocker (flutamide 10 mg, SC), 1 hour prior to administration of pentylenetetrazol (85 mg/kg, IP). Juvenile male rats administered 3alpha-diol had less seizure activity than those administered vehicle. Flutamide had no effects. T is aromatized to 17beta-estradiol (E(2)), which, like 3alpha-diol, acts at estrogen receptors (ERs). Selective estrogen receptor modulators that favor ERalpha (propyl pyrazole triol, 17alpha-E(2)) or ERbeta (diarylpropionitrile, coumestrol, 3alpha-diol), or both (17beta-E(2)), were administered (0.1 mg/kg, SC) to juvenile male rats 1 hour before pentylenetetrazol. Estrogens with activity at ERbeta, but not those selective for ERalpha, produced antiseizure effects. Actions at ERbeta may underlie some antiseizure effects of T's metabolites.

Antiseizure effects of 5*-androstane-3*,7beta-diol may be independent of actions at estrogen receptor beta.

Testosterone (T), the principal androgen secreted by the testes, can have antiseizure effects; however, the mechanism(s) underlying this action is not well understood. T is metabolized to dihydrotestosterone (DHT) by the enzyme 5*-reductase. DHT is then converted to 5*-androstane-3*,17beta-diol (3*-diol) by the enzyme 3*-hydroxysteroid dehydrogenase. T and DHT bind with high affinity to intracellular androgen receptors; however, 3*-diol does not. The mnemonic effects of 3*-diol are mediated in part through the beta isoform of estrogen receptors (ERbeta) in the hippocampus. As such, we investigated whether 3*-diol has antiseizure effects in mice that require action at ERbeta. 3*-Diol (2 mg/kg subcutaneously) was administered to wild-type C57/B6 mice and heterozygous and homozygous ERbeta knockout (betaERKO) mice 1 hour prior to administration of pentylenetetrazol (PTZ; 85 mg/kg intraperitoneally). Mice administered 3*-diol had significantly longer latencies to clonic seizure and death and lower seizure scores than did mice administered vehicle. This pattern of effects was observed in wild-type or betaERKO mice. Thus, for these mice, the antiseizure effects of 3*-diol for the chemoconvulsant PTZ occur independent of actions at ERbeta.