Salt-dependent inhibition of epithelial Na+ channel-mediated sodium reabsorption in the aldosterone-sensitive distal nephron by bradykinin

Mykola Mamenko, Oleg Zaika, Peter A. Doris, Oleh Pochynyuk

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

We have documented recently that bradykinin (BK) directly inhibits activity of the epithelial Na+ channel (ENaC) via the bradykinin B2 receptor (B2R)-Gq/11-phospholipase C pathway. In this study, we took advantage of mice genetically engineered to lack bradykinin receptors (B1R, B2R -/-) to probe a physiological role of BK cascade in regulation of ENaC in native tissue, aldosterone-sensitive distal nephron. Under normal sodium intake (0.32% Na), ENaC open probability (Po) was modestly elevated in B1R, B2R-/- mice compared with wild-type mice. This difference is augmented during elevated Na+ intake (2.00% Na+) and negated during Na restriction (<0.01% Na). Saturation of systemic mineralocorticoid status with deoxycorticosterone acetate similarly increased ENaC activity in both mouse strains, suggesting that the effect of BK on ENaC is independent of aldosterone. It is accepted that angiotensin-converting enzyme represents the major pathway of BK degradation. Systemic inhibition of angiotensin-converting enzyme with captopril (30 mg/kg of body weight for 7 days) significantly decreases ENaC activity and Po in wild-type mice, but this effect is diminished in B1R, B2R-/- mice. At the cellular level, acute captopril (100 μmol/L) treatment sensitized BK signaling cascade and greatly potentiated the inhibitory effect of 100 nmol/L of BK on ENaC. We concluded that BK cascade has its own specific role in blunting ENaC activity, particularly under conditions of elevated sodium intake. Augmentation of BK signaling in the aldosterone-sensitive distal nephron inhibits ENaC-mediated Na reabsorption, contributing to the natriuretic and antihypertensive effects of angiotensin-converting enzyme inhibition.

Original languageEnglish (US)
Pages (from-to)1234-1241
Number of pages8
JournalHypertension
Volume60
Issue number5
DOIs
StatePublished - Nov 2012

Keywords

  • angiotensin-converting enzyme inhibition
  • collecting duct
  • connecting tubule
  • kallikrein-kinin system
  • natriuresis

ASJC Scopus subject areas

  • Internal Medicine

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