Renal tubular responsiveness to atrial natriuretic peptide in sodium-retaining chronic caval dogs: A possible role for kinins and luminal actions of the peptide

60% of chronic caval dogs with ascites did not respond to atrial natriuretic peptide (ANP) (75 ng · kg^-1 · min^-1) with a natriuresis (TIVC-NR; ΔU_NaV = 2±0.8 μeq/min) whereas the remaining 40% responded normally (TIVC-R; ΔU_NaV = 216±50 μeq/min). Since proximal tubule neutral endopeptidase 24:11 (NEP) destroys most of intrarenal luminal ANP and kinins, we attempted to convert TIVC-NR into TIVC-R by providing NEP inhibition with SQ 28603 at 30 mg/kg. This potent and specific NEP inhibitor produced a natriuresis when administered alone to nine TIVC-NR dogs (ΔU_NaV = 67±2 μeq/min) and permitted a natriuresis in the presence of ANP (ΔU_NaV = 97±18 μeq/min). A natriuretic response to ANP could also be induced in TIVC-NR dogs by providing renal arterial bradykinin or intravenous captopril, a kininase inhibitor. Urodilatin, a natriuretic peptide not destroyed by intrarenal NEP was without effect in TIVC-NR dogs but increased U_NaV when given to TIVC-R and normal dogs. Providing bradykinin to TIVC-NR now permitted an increment in ΔU_NaV (62 μeq/min) when urodilatin was reinfused. TIVC-R dogs could be converted into TIVC-NR by pretreating with a specific bradykinin antagonist before infusing ANP. We conclude that TIVC-NR dogs are deficient in intrarenal kinins but are converted to responding dogs after NEP inhibition because of increased kinin delivery to the inner medullary collecting duct.