LY-3971297

Atrial natriuretic peptide (ANP(1-28)) protects the kidneys against acute renal failure in animals; however, its use in humans has been disappointing. Long-acting natriuretic peptide (LANP(1-30)) has natriuretic and diuretic actions similar to ANP(1-28), but it has a longer half-life and a different receptor site. Therefore, this study's aim was to determine if LANP(1-30) has better renal protection than ANP(1-28), which may make it useful in the treatment of acute renal failure.

Three groups of male Sprague-Dawley rats were used, each with a body weight between 250-300 gm. Group 1 (ischemia only, n = 6) had a right nephrectomy followed by 30 minutes of left renal pedicle clamping. Group 2 (LANP Peptide treated, n = 7) had renal ischemia similar to Group 1, followed by an intraperitoneal bolus of 10 microg of LANP(1-30) and the placement of mini-osmotic pumps delivering LANP(1-30) at a rate of 1 microg/hr for 72 hours. Group 3 (controls, n = 6) was used to measure the baseline creatinine level and had no renal ischemia or surgery.

Seventy-two hours post-renal ischemia, the weight loss in the ischemia group was similar to the peptide treated group (7.65 +/- 1.14% and 10.03 +/- 0.9% body weight loss, respectively, p = 0.126). The ischemia group had significantly higher creatinine levels compared to the controls (66.3 +/- 5.3 versus 30.1 +/- 0.9 micromol/L, p = 0.002). The peptide-treated group had higher creatinine (174.1 +/- 77.8 versus 66.3 +/- 5.3 micromol/L, p = 0.035) and LANP(1-30) levels (673.14 +/- 69.64 versus 45.83 +/- 8.45 pg/mL, p = 0.001) than the ischemia group.

Prolonged use of LANP(1-30) has no renal protective effect.

The present investigation was designed to determine whether atrial natriuretic peptides consisting of amino acids 1-30 (i.e. long-acting natriuretic peptide), 31-67 (vessel dilator), 79-98 (kaliuretic peptide), and 99-126 [atrial natriuretic factor (ANF)] of the 126 amino acid ANF prohormone inhibit sodium-potassium-ATPase as part of their mechanism(s) of action for producing a natriuresis and/or kaliuresis. Kaliuretic peptide, long-acting natriuretic peptide, vessel dilator and ANF at their 10(-11) M concentrations inhibited Na(+)-K(+)-ATPase 39.5%, 27.8%, 19.2%, and 4% respectively, in bovine renal medulla, whereas their inhibition in renal cortical membranes was 37.5%, 27.5%, 20%, and 0%, respectively. Ouabain (0.5 mM) inhibited kidney medullary Na(+)-K(+)-ATPase 45% and in the cortex, 38%. There was no additive effect of any of these peptides with ouabain suggesting that they are interacting with the same site on the Na(+)-K(+)-ATPase as ouabain. To help elucidate the mechanism of these peptides' interaction with Na(+)-K(+)-ATPase, naproxen (0.5 mM), an inhibitor of prostaglandin synthesis, and direct measurement of prostaglandin E2 by RIA were used. Naproxen completely blocked the inhibition of Na(+)-K(+)-ATPase by kaliuretic peptide, long-acting natriuretic peptide, and vessel dilator suggesting that their inhibition of Na(+)-K(+)-ATPase in both the kidney medulla and cortex are mediated by prostaglandins. Direct measurement of prostaglandin E2 revealed that kaliuretic peptide > long-acting natriuretic peptide > vessel dilator increased prostaglandin E2 synthesis, whereas ANF did not have any effect. Of interest, angiotensin II and ouabain inhibition of Na(+)-K(+)-ATPase were also completely blocked by naproxen.