Enhanced Erythropoietin and Prostaglandin E Production in the Dog following Renal Artery Constriction

Abstract

The precise mechanism of erythropoietin (ESF) production and release from the kidney still remains obscure although it is well known that many forms of hypoxia, e.g., anemic, hypoxic, ischemic, and histotoxic, are capable of increasing erythropoietin production by the kidney (1). Recent observations (2, 3) indicate that following renal artery constriction in the dog, there is a release of prostaglandins (PG) into the renal venous blood. We have reported recently (4-6) that both hypoxic and ischemic hypoxia are capable of producing a significant increase in prostaglandin E (PGE) release into the renal venous effluent, which was blocked by the potent prostaglandin synthetase inhibitor, indomethacin. We have also demonstrated (7, 8) that indomethacin is capable of blocking erythropoietin production as well.Thus, the present studies were carried out to assess the relationship between PGE release and erythropoietin production by the kidney during a 12-hr ischemic hypoxic stimulus induced by means of renal artery constriction as well as the effects of indomethacin on these changes.Materials and methods. Twelve female mongrel dogs (six control and six indomethacin-treated) weighing 14.5-21 kg were used in this study. The animals were anesthetized with sodium pentobarbital (30 mg/ kg iv), and the left femoral arteries were cannulated for monitoring systemic arterial blood pressure (Statham P23AC pressure transducer) and the collection of arterial blood samples for erythropoietin bioassay. The animals were subjected to retroperitoneal laparotomies permitting extirpation of the right kidney and the exposure of the left kidney through a flank incision. A branch of the left ovarian vein was isolated and a cannula was inserted through this vein into the left renal vein to collect renal venous blood samples for PGE assay. Utilizing a squarewave electromagnetic blood flowmeter (Carolina Medical Electronics, Model 501) and either an 8-or 10-mm circumference flow probe, renal blood flow (RBF) was monitored with the probe placed around the left renal artery. Systemic arterial blood pressure (BP) and RBF were recorded continuously throughout the experimental period on a Grass oscillographic recorder (Model 7PCPA).After the initial zero time parameters (BP, RBF) and blood samples for PGE and erythropoietin were collected, a vascular occluder (Model OC12, IN VIVO Metric Systems) was placed around the left renal artery between the flow probe and the kidney. Renal blood flow was reduced to 30% of normal and sustained throughout the 12-hr experimental period with minor adjustments as needed. Six of the 12 dogs in the experimental group were pretreated with indomethacin (5 mg/kg orally) 18 and 2 hr prior to the application of the vascular occluder. Anesthesia was maintained throughout the experiments by administration of sodium pentobarbital as required via a cannula in the femoral vein.Blood samples for erythropoietin and 498

The regulated expression of erythropoietin by two human hepatoma cell lines.

“…We have demonstrated that Epo production in this system does not appear to be dependent upon cyclooxygenase products, such as PGE2, in contrast to the mechanism previously suggested in other systems (48)(49)(50)(51). PGE2 is not produced by either HepG2 or Hep3B cells, and Epo production is not significantly impaired when hypoxic Hep3B cells are grown in the presence of indomethacin, a potent cyclooxygenase inhibitor.…”

Regulation der Erythropoietin-Bildung

“…Unter denjenigen biochemischen Pa rametern, die eine Hypoxiereaktion vermitteln könnten, werden die Prostaglandine als ernsthafte Kandidaten betrachtet. Dies beruht auf folgenden Erkenntnissen: 1) verschiedene Gewebe, einschliesslich der Nieren, setzen auf Hypoxie hin mehr Prostaglandine frei [47,48]; 2) die Prostaglandine können die Bildung von EPO in der Nie re [49,50] und in Zellkulturen [51] stimulieren, und 3) die Hemmung der Prostaglandinbildung hemmt die durch CL-Mangel induzierte Bildung von EPO in vivo [21,52,53].…”

THE EFFECT OF ANGIOTENSIN I CONVERTING ENZYME INHIBITOR (SQ 20881) ON THE RELEASE OF PROSTAGLANDINS BY RABBIT KIDNEY, in vivo

“…Another stimulus which leads to an increase in renin release from the kidney is renal artery constriction (Johns & Singer, 1974). This stimulus has 37 also been reported to induce an increase in the release of prostaglandin from the kidney in the dog (McGiff, Crowshaw, Terragno, Lonigro, Strand, Williamson, Lee & Ng, 1970;Gross, Mujovic, Jubiz & Fisher, 1976). Although these results suggest that the increased formation of angiotensin II within the kidney leads to the local formation of prostaglandin, other evidence indicates that the relationship between these substances is very complex, and that the kallikrein-kinin system may also be involved.…”