Association between the natriuretic action of angiotensin-(1-7) and selective stimulation of renal prostaglandin I2 release.

We previously reported that angiotensin-(1-7) [Ang-(1-7)], a heptapeptide derived from the metabolism of either Ang I or Ang II, was biologically active in the rat isolated kidney, producing a marked diuresis and natriuresis that could be dissociated from the modest increase in glomerular filtration rate. The natriuretic response was accompanied by an increase in sodium concentration and concomitant decrease in urinary potassium concentration. Ang-(1-7) has also been shown to stimulate arachidonic acid release from isolated proximal tubules and elicit prostaglandin release from a number of tissues. Therefore, in the present study we tested the hypothesis that prostaglandins participate in the renal actions of Ang-(1-7). Rat isolated kidneys were perfused at 37 degrees C with gassed (95% O2/5% CO2) Krebs-Henseleit buffer containing oncotic agents and amino acids for six 10-minute clearance periods at a constant pressure of 90 mm Hg. Ang-(1-7) was infused at a rate that achieved a final concentration of 3 pmol/mL in the presence and absence of 10 mumol/L indomethacin. Prostaglandin E2 (PGE2) and PGI2 released into ureteral and venous effluents were measured by enzyme-linked immunoassay. During Ang-(1-7) infusion there was a selective increase in 6-keto-PGF1 alpha, an index of PGI2, appearing in both urine and perfusate; PGE2 levels were unchanged. Inhibition of stimulated 6-keto-PGF1 alpha release with indomethacin halved the fourfold increase in urine flow and sevenfold increase in sodium excretion rate without altering the increase in urinary sodium concentration produced by Ang-(1-7).(ABSTRACT TRUNCATED AT 250 WORDS)

Natriuretic action of angiotensin(1-7).

Evidence that angiotensin(1-7) (Ang(1-7)) is biologically active and can be synthesized by the kidney prompted us to examine its actions in the rat, isolated kidney. Ang(1-7) had three major effects producing, (1) a substantial natriuresis and diuresis, (2) an increase in urinary sodium concentration associated with a fall in potassium concentration and (3) an increase in glomerular filtration rate without affecting renal vascular resistance. Thus, Ang(1-7) may participate in the renal effects of the renin-angiotensin system.

Renovascular actions of angiotensin II in the isolated kidney of the rat: relationship to lipoxygenases.

Several actions of angiotensin II have been linked to metabolism of arachidonic acid by lipoxygenases. To evaluate the importance of this interaction intrarenally we tested the effect of three different lipoxygenase inhibitors, BW755c (50 microM), a dual lipoxygenase-cyclooxygenase inhibitor, MK447 (200 microM), a nonselective lipoxygenase inhibitor which can stimulate cyclooxygenase, and baicalein (1 microM), a highly selective 12-lipoxygenase inhibitor, on angiotensin II-evoked hemodynamic changes in the rat isolated kidney, perfused with oncotic agents. Kidneys were pretreated with indomethacin (10 microM) to exclude participation of cyclooxygenase-dependent arachidonate products. Renal perfusion pressure was kept constant at 90 mm Hg by continuous adjustments in perfusate flow rate. Inhibition of cyclooxygenase alone produced a transient potentiation of the vasoconstrictor response to angiotensin II without altering GFR. On the other hand, the lipoxygenase inhibitors attenuated the angiotensin II-induced increase in renal vascular resistance by approximately 50% and promoted an increase in GFR above that of kidneys infused with angiotensin II in the presence of only indomethacin. Base-line values were essentially unchanged by lipoxygenase inhibition. Furthermore, the vasoconstrictor response to the thromboxane/endoperoxide agonist U46619 was unaffected. We conclude that products of the lipoxygenase pathway, arising within the kidney, contribute to the renal hemodynamic effects of angiotensin II.

Urinary epidermal growth factor is excreted from the rat isolated perfused kidney in the absence of plasma.

Large amounts of epidermal growth factor (EGF) are excreted in urine and the majority of this urinary EGF appears to be of renal origin. EGF is synthesized in the kidneys as a membrane-bound 160 kDa precursor, in the thick ascending limb of Henle and in the early part of the distal convoluted tubule. Very little is known about how EGF is released from cell membranes into urine but proteolytic cleavage of the membrane-bound EGF precursor seems likely. The purpose of this study was to examine whether plasma constituents are necessary for urinary excretion of EGF. In the rat isolated kidney perfused at a pressure of 90 mmHg with a modified Krebs-Henseleit buffer containing oncotic agents, the quantity of EGF excreted into the ureteral effluent was 67% of the amount excreted by the rat kidney in vivo. The EGF excreted by the isolated kidney behaved like urinary EGF upon gel filtration. Administration of the proteinase inhibitor aprotinin reduced urinary EGF excretion from the rat isolated perfused kidney by approximately 50%. In conclusion, the rat isolated perfused kidney excreted significant amounts of urinary EGF without having access to plasma, and EGF excretion was reduced by aprotinin. This is further evidence suggesting an intrarenal source of urinary EGF and suggests that the EGF precursor in the rat kidney is processed by enzyme(s) of renal origin.