title: Salt-dependent inhibition of epithelial Na+ channel-mediated sodium reabsorption in the aldosterone-sensitive distal nephron by bradykinin.
abstract: We have documented recently that bradykinin (BK) directly inhibits activity of the epithelial Na(+) channel (ENaC) via the bradykinin B2 receptor (B2R)-G(q/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 (P(o)) 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 P(o) 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.
authors.affiliation: Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, 6431 Fannin, Houston, TX 77030, USA.
authors.forename: Mykola
authors.initials: M
authors.lastname: Mamenko
authors.forename: Oleg
authors.initials: O
authors.lastname: Zaika
authors.forename: Peter A
authors.initials: PA
authors.lastname: Doris
authors.forename: Oleh
authors.initials: O
authors.lastname: Pochynyuk
mesh_terms: D000450:Aldosterone / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002216:Captopril / Q000494:pharmacology; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009399:Nephrons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D043783:Receptor, Bradykinin B1 / Q000172:deficiency / Q000235:genetics; D043782:Receptor, Bradykinin B2 / Q000172:deficiency / Q000235:genetics; D012964:Sodium / Q000008:administration & dosage / Q000378:metabolism*; D012965:Sodium Chloride / Q000378:metabolism; D013997:Time Factors
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D053503:Epithelial Sodium Channels; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D012965:Sodium Chloride; D000450:Aldosterone; D002216:Captopril; D012964:Sodium; D007703:Peptidyl-Dipeptidase A; D001920:Bradykinin; D002118:Calcium