a-68828 and Ischemia

We have recently reported that administration of the ANF analog A68828 improves renal function in an acute model of postischemic acute renal failure. The current investigation examined the question whether a short-term infusion of A68828 can attenuate the long-term decrement in renal function following an ischemic event. Acute renal failure was induced in male Sprague-Dawley rats (200-250 g) by complete occlusion of both renal arteries for 30 min. During the initial 60 min following ischemia, vehicle (0.1% BSA in saline), A68828 (10 micrograms/kg/min); dopamine (10 micrograms/kg/min); A68828 (10 micrograms/kg/min) plus dopamine (10 micrograms/kg/min); or ANF[1-28] (0.5 microgram/kg/min) were infused intravenously. In vehicle-treated animals, a very large increase in plasma creatinine was observed, with peak levels at 2 days postischemia (5.5 +/- 1.2 mg/dL). A68828 alone, A68828 with dopamine, or ANF[1-28] infusion attenuated the rise in plasma creatinine levels by approximately 50% on each day of the study; dopamine alone was no different from vehicle-treated controls. Gross histological examination of kidneys on the fourth day postischemia revealed that significantly less damage occurred only in the group treated with A68828 alone. These results indicate that infusion of a reduced-size analog of ANF for a brief period in the postischemic kidney improves renal function and lessens tissue damage as evaluated several days after the ischemic event. Furthermore, dopamine infusion provides no discernable beneficial effect.

Topics: Acute Kidney Injury; Animals; Atrial Natriuretic Factor; Creatinine; Dopamine; Drug Therapy, Combination; Infusions, Intravenous; Ischemia; Kidney; Male; Organ Size; Rats; Rats, Inbred Strains

Short-term administration of atrial peptides has been reported to improve renal function in several animal models of acute renal failure. We designed experiments that determined the effect of a 13-amino acid analog of atrial natriuretic factor (ANF), A68828, on renal function in the postischemic model of acute renal failure. Experiments were conducted using euvolemic, male Sprague-Dawley rats (200-250 g) under Inactin anesthesia. Acute renal failure was induced by complete occlusion of both renal arteries for 30 min. After release of the clamp, vehicle (0.1% bovine serum albumin in saline), A68828 (3, 10 or 30 micrograms/kg/min), dopamine (10 micrograms/kg/min), A68828 (10 micrograms/kg/min) plus dopamine (10 micrograms/kg/min) or ANF (1-28) (0.5 micrograms/kg/min) were infused i.v. for a 2-h period. A68828 at 10 micrograms/kg/min produced a significant increase in glomerular filtration rate (GFR) compared with vehicle controls (0.39 +/- 0.08 vs. 0.19 +/- 0.04 ml/min/100 g; P less than .05) despite a lower arterial pressure (87 +/- 5 vs. 101 +/- 5 mm Hg; P less than .05). A subpressor dose of dopamine had no effect on GFR during the postischemic period (0.25 +/- 0.11 ml/min/100 g). Dopamine in combination with A68828 prevented the decrease in arterial pressure seen with A68828 alone but did not potentiate the beneficial effects on GFR (0.28 +/- 0.05 ml/min/100 g). ANF (1-28) at 0.5 micrograms/kg/min increased GFR to levels nearly identical to those induced by A68828 (0.40 +/- 0.04 ml/min/100 g). These results indicate that infusion of a reduced-size analog of ANF improves renal function in the immediate postischemic period. Furthermore, prevention of the hypotensive effects of the analog with dopamine provides no additional beneficial effect.

Topics: Acute Kidney Injury; Amino Acid Sequence; Animals; Atrial Natriuretic Factor; Blood Pressure; Dopamine; Drug Therapy, Combination; Glomerular Filtration Rate; Heart Rate; Ischemia; Kidney; Kidney Tubules; Male; Molecular Sequence Data; Rats; Rats, Inbred Strains; Sodium; Time Factors