Aldosterone regulates blood pressure (BP) through water and sodium balance. In our study, we studied if continuous treatment with a mineralocorticoid receptor antagonist, spironolactone (30 mg/kg/day) for 20 days can: 1) attenuate hypertension development and restore inverted 24-h BP rhythm in hypertensive transgenic (mRen-2)27 rats (TGR) measured by telemetry; 2) improve function of the kidneys and heart; 3) be protective against high salt load (1% in water) by mitigating oxidative injury and improving kidney function. Spironolactone decreased albuminuria and 8-isoprostane in normal and salt load conditions in BP-independent effects. Salt load increased BP, impaired autonomic balance, suppressed plasma aldosterone level and increased natriuresis, albuminuria and oxidative injury in TGR. Spironolactone did not restore the inverted 24-h rhythm of BP in TGR, therefore, mineralocorticoids are not crucial in regulation of BP daily profile. Spironolactone improved kidney function, decreased oxidative stress and was protective against high salt load in the BP-independent manner.

• MeSH
• albuminurie MeSH
• aldosteron * farmakologie   MeSH
• antagonisté mineralokortikoidních receptorů farmakologie   MeSH
• geneticky modifikovaná zvířata MeSH
• hypertenze * MeSH
• krevní tlak MeSH
• krysa rodu rattus MeSH
• ledviny MeSH
• receptory mineralokortikoidů genetika   MeSH
• spironolakton farmakologie   MeSH
• voda farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

In this work, we investigate the mode of binding of several steroid hormones, namely aldosterone, deoxycorticosterone, and progesterone to the wild-type and S810L mutated mineralocorticoid (MR) receptor using the newly formulated density functional theory with an empirical dispersion term (DFT-D) molecular electronic structure method. It is found that the MR agonists, aldosterone and deoxycorticosterone, form tight hydrogen bonds with residues Thr945 and Asn770, which leads to the formation of hydrogen bond networks near the steroid D-ring, allowing for activation of this transcription factor. Progesterone, an MR antagonist, fails to form the necessary hydrogen bonds near the steroid D-ring. Progesterone is known to be an agonist of the mutated S810L MR receptor. Our studies indicate that this is possible because of a strong hydrogen bond between progesterone and Thr945 and a relatively strong hydrophobic interaction between progesterone and Asn770.

• MeSH
• financování organizované MeSH
• hormony chemie   metabolismus   MeSH
• leucin genetika   metabolismus   MeSH
• ligandy MeSH
• molekulární modely MeSH
• mutace genetika   MeSH
• receptory mineralokortikoidů genetika   chemie   metabolismus   MeSH
• serin genetika   metabolismus   MeSH
• steroidy chemie   MeSH
• terciární struktura proteinů MeSH
• vodíková vazba MeSH

• MeSH
• aldosteron fyziologie   MeSH
• lidé MeSH
• receptory mineralokortikoidů genetika   MeSH
• Check Tag
• lidé MeSH