Stimulation of renin release by PGE2 and PGI2 infusion in the dog: enhancing effect of ureteral occlusion or administration of ethacrynic acid.

This study on 19 anaesthetized dogs had two objectives. The first was to compare the potencies of PGE2 and PGI2 as stimulators of renin release and demonstrate their dependency on activation of intrarenal mechanisms for renin release. The second objective was to demonstrate that ethacrynic acid (ECA) increases renin release not as a stimulator, but by activating intrarenal mechanisms. After inhibiting renal prostaglandin synthesis by indomethacin, PGE2 and PGI2 infused into the aorta proximal to the renal arteries exerted no significant effects on renin release, but increased renin release during ureteral occlusion. At equimolar infusion rates, PGI2 increased renin release twice as much as PGE2, but this difference in potency may reflect differences in degradation since 86% of PGE2 and 29% of PGI2 (measured as 6-keto-PGF1 alpha) were degraded during one passage through the kidney. By infusing PGF2 at 8 nmol min-1 and PGI2 at 2 nmol min-1 renin release increased equally and the prostaglandin outputs increased to the same levels as during ureteral occlusion before indomethacin administration. ECA did not increase renin release after indomethacin administration. However, infusion of PGE2 during continuous ECA administration increased renin release in a dose-dependent manner similar to the experiments performed during ureteral occlusion. We conclude that PGI2 and PGE2 in the amounts synthesized in the kidney seem to be equally important stimulators of renin release but their relative potencies cannot be determined because the site of degradation is uncertain. Renin release is enhanced by intrarenal mechanisms activated by ECA infusion or ureteral occlusion, which both cause autoregulatory vasodilation and reduce NaCl reabsorption at the macula densa.

Renal degradation and distribution between urinary and venous output of prostaglandins E2 and I2.

To examine renal degradation and distribution between urine and renal venous blood, prostaglandins E2 and I2 (PGE2 and PGI2), and a metabolite of PGI2, 6-keto-PGF1 alpha, were infused into the suprarenal aorta of anaesthetized dogs after blocking prostaglandin synthesis by indomethacin, 10 mg kg-1 body wt iv. During one passage through the kidney 80% of PGE2 and only 25% of PGI2 and 6-keto-PGF1 alpha were metabolized. Prostaglandin degradation and arterial input were proportional (r greater than 0.90). To stimulate the intrarenal prostaglandin synthesis in unblocked kidneys, arachidonic acid was infused at rates ranging from 24 to 160 micrograms min-1 kg-1 body wt. During arachidonic acid and PGE2 infusion the urinary excretion of PGE2 was about 20% of the renal venous output over a wide range of infusion rates. During arachidonic acid and PGI2 infusion urinary excretion of 6-keto-PGF1 alpha was about 10% of total renal output, but failed to increase further when total renal output exceeded 70 pmol min-1. Further increase in output occurred only in the renal vein. In contrast, during 6-keto-PGF1 alpha infusion the urinary excretion and the renal venous output of this metabolite were related as 1:2 over a wide range of infusion rates. Thus, PGI2 is much less degraded by renal tissue than PGE2, and the distribution patterns differ. Similar distributions between urine and renal venous blood during aortic infusion and stimulated intrarenal synthesis suggest a pre-glomerular vascular origin of both prostaglandins.

Comparison of PGE2, 6-keto PGF1 alpha and renin release from dog kidneys.

Several renal cell types synthesize prostaglandin E2 (PGE2) and prostacyclin (PGI2). To examine whether the release of these prostaglandins varies in proportion, prostaglandin synthesis was stimulated in anaesthetized dogs by renal arterial constriction, ureteral occlusion, intrarenal angiotensin II infusion and infusion of arachidonic acid, the precursor of PG synthesis. PGI2 was measured as its stable hydrolysed product, 6-keto PGF1 alpha. The two former procedures raised PGE2 release to 13 +/- 2 pmol min-1, 6-keto PGF1 alpha release to 5 +/- 2 pmol min-1 and renin release to 23 +/- 5 micrograms AI min-1. Angiotensin II infusion, reducing the renal blood flow by 30%, increased PGE2 and 6-keto PGF1 alpha release only half as much as ureteral and renal arterial constriction, and exerted no significant effect on renin release. By increasing the infusion rate of angiotensin II up to 10 times, the renal blood flow remained unaltered in four dogs and fell to 50% of control in two dogs, but PGE2 and 6-keto PGF1 alpha release did not increase further in any of the experiments. Arachidonic acid, infused at 40 and 160 micrograms kg-1 min-1, increased prostaglandin release in proportion to the infusion rate. At the highest infusion rate, PGE2 release averaged 166 +/- 37 pmol min-1 and 6-keto PGF1 alpha release 98 +/- 28 pmol min-1. All procedures increased PGE2 and 6-keto PGF1 alpha release in a fixed proportion of about 2.5:1, whereas renin release increased only during autoregulatory vasodilation.

Dissociation between renal prostaglandin E2 and renin release. Effects of glucagon, dopamine and cyclic AMP in dogs.

To examine the relationship between prostaglandin E2 (PGE2) and renin release, glucagon, dopamine and dibutyryl cyclic AMP (DB-cAMP) were infused into dog kidneys during autoregulatory dilation of preglomerular vessels. Autoregulatory vasodilation, which enhances PGE2 and renin release, was induced by renal arterial constriction or ureteral occlusion. Glucagon infusion increased both PGE2 and renin release during autoregulatory vasodilation, and renin release was almost abolished after inhibiting PGE2 release by indomethacin. In contrast, dopamine and DB-cAMP infused during autoregulatory vasodilation increased renin release without significantly changing PGE2 release. Stimulation of renin release was not dependent on vasodilatory effects, which for all drugs were greatly diminished during autoregulatory vasodilation. Hence, glucagon stimulates both PGE2 and renin release. Most of the increase in renin release during glucagon infusion is prostaglandin-dependent since indomethacin greatly reduced the stimulatory effect. In contrast, dopamine and DB-cAMP stimulate renin release without increasing PGE2 release as previously found for beta-adrenergic stimulation.

Autoregulatory vasodilation enhances renal prostaglandin E2 and associated renin release during arachidonic acid infusion in dogs.

To examine whether autoregulatory dilation of preglomerular vessels enhances prostaglandin (PG)E2 and renin release during arachidonic acid infusion, the ureter was occluded or the renal artery constricted in anesthetized dogs. Intrarenal arachidonic acid infusion (40 micrograms X kg-1 X min-1) increased PGE2 release by 41 +/- 17 pmol/min at control pressures and by 149 +/- 60 pmol/min during ureteral occlusion. Arachidonic acid infusion (160 micrograms X kg-1 X min-1) increased PGE2 release by 149 +/- 60 pmol/min at control pressures, by 505 +/- 211 pmol/min during ureteral occlusion and by 581 +/- 201 pmol/min during renal arterial constriction. Thus, PGE2 release during arachidonic acid infusion was trebled by autoregulatory dilation. Arachidonic acid infusion (160 micrograms X kg-1 X min-1) raised renin release by 6 +/- 2 micrograms of angiotensin I per min at control pressures, by 25 +/- 9 micrograms of angiotensin I per min during renal arterial constriction and during ureteral occlusion by 16 +/- 4 micrograms of angiotensin I per min, which was not significantly higher than induced by the lower rate of infusion. Arachidonic acid infusion (160 micrograms X kg-1 X min-1) raised renal blood flow by 54 +/- 5% at control pressures but exerted no vasoactive effect during ureteral occlusion and renal arterial constriction. We conclude that autoregulatory dilation enhances the stimulatory effects of arachidonic acid on renal PG synthesis. Both increased intrarenal PG concentration and autoregulatory dilation may contribute to enhancement of renin release. The stimulatory effects of arachidonic acid on PG synthesis and renin release are independent of the vasoactive effects of arachidonic acid.

Haemodynamic conditions for renal PGE2 and renin release during alpha- and beta-adrenergic stimulation in dogs.

Constriction of the renal artery and infusion of an alpha-adrenergic agonist induce autoregulated vasodilation and increase prostaglandin E2 (PGE2) and renin release. The enhancement of renin release during autoregulated vasodilation might be mediated by prostaglandins. To examine this hypothesis, experiments were performed in three groups of anaesthetized dogs. In six dogs constriction of the renal artery to a perfusion pressure below the range of autoregulation raised renin release from 2 +/- 1 to 27 +/- 6 micrograms AI X min-1 and PGE2 release from 1 +/- 1 to 10 +/- 2 pmol X min-1. After administration of indomethacin (10 mg X kg-1 b.wt), PGE2 release was effectively blocked and constriction of the renal artery raised renin release only from 0.1 +/- 0.1 to 6 +/- 1 micrograms AI X min-1. During subsequent continuous infusion of a beta-adrenergic agonist, isoproterenol (0.2 micrograms X kg-1 X min-1), constriction of the renal artery raised renin release from 0.1 +/- 0.1 to 52 +/- 11 micrograms AI X min-1, although there was no rise in PGE2 release. In six dogs, intrarenal infusion of phenylephrine, an alpha- adrenergic agonist, increased PGE2 and renin release before, but not after, indomethacin administration. In six other dogs, phenylephrine infused during isoproterenol infusion increased renin release equally before and after indomethacin administration. Thus the enhancing effect of constricting the renal artery or infusing an alpha-adrenergic agonist is not dependent upon prostaglandins. We propose that autoregulated dilation enhances renin release whether the stimulatory agent is a prostaglandin or a beta-adrenergic agonist.

Enhancement of renal prostaglandin E2 and renin release by autoregulatory dilation of preglomerular vessels in dogs.

To examine the PGE2 and renin release during autoregulatory dilation of preglomerular vessels, experiments were performed in three groups of anesthetized dogs. By reducing the arterial perfusion pressure from 113 +/- 3 to 78 +/- 3 mm Hg, renin release rose to 20 +/- 50% and PGE2 release to 74 +/- 12% of the maximal values attained at two perfusion pressures below the range of autoregulation. During ureteral occlusion, PGE2 and renin release rose to maximal values already at control blood pressure and remained unaltered as the arterial perfusion pressure was reduced from 124 +/- 7 to 68 +/- 2 mm Hg. Renal blood flow fell in proportion to the perfusion pressure indicating abolished autoregulation. At a perfusion pressure below the range of autoregulation, saline infusion restored sodium excretion and reduced renin release but did not alter PGE2 release. We conclude that PGE2 release is raised by autoregulatory dilation of preglomerular arteries. Prostaglandins enhance renin release when afferent arterioles are dilated. Renin release mediated by a macula densa mechanism is not PGE2 dependent.

Ouabain inhibits renin release by a direct renal haemodynamic effect.

The effect of intrarenal infusion of ouabain (90 micrograms/kg) on renin release was examined in the anaesthetized dog. Ouabain reduced cortical Na-K-ATPase activity to 23% and outer medullary activity to 18% of the control level. During renal arterial constriction to a perfusion pressure below the autoregulatory range, renin release rose from 1.2 +/- 0.4 to 47.4 +/- 6.9 micrograms/min (P less than 0.001). This response was abolished by ouabain. When superimposed on renal arterial constriction, beta-adrenergic stimulation enhanced renin release from 25.6 +/- 10.7 to 56.9 +/- 9.5 micrograms/min (P = 0.02) at a urinary sodium excretion of 2 +/- 1 mumol/min. After ouabain, the corresponding increment substantially decreased since release rose from 5.6 +/- 2.0 to 19.9 +/- 5.3 micrograms/min only (P = 0.02), at a urinary sodium excretion of 140 +/- 67 mumol/min. When glomerular filtration was reduced to zero by ureteral occlusion in one series, renin release increased to 22.6 +/- 5.1 but was reduced (P less than 0.05) by ouabain to 13.5 +/- 5.5 micrograms/min and superimposed isoproterenol had no effect. According to these observations, ouabain inhibits renin release by a direct effect on the afferent arteriole through constriction of the autoregulating renin-secreting segment.

Relationship between PGE2 and renin release in dog kidneys. Effects of afferent arteriolar dilation and adrenergic stimulation.

To study the relationship between PGE2 and renin release from the kidney, examinations were performed on anesthetized dogs during afferent arteriolar dilation. This condition is known to increase renin release and enhance the stimulatory effects on renin release of beta-adrenergic agonists, such as isoproterenol. Afferent arteriolar dilation induced by constricting the renal artery or occluding the ureter increased PGE2 and renin release before, but not after, indomethacin administration. Isoproterenol infusion during afferent arteriolar dilation increased renin release but not PGE2 release both before and after indomethacin administration. Phenylephrine, an alpha-adrenergic agonist, which also induces afferent arteriolar dilation, increased PGE2 and renin release at control blood pressure but not when the afferent arterioles already were dilated by ureteral occlusion. We conclude that afferent arteriolar dilation caused by renal arterial constriction, ureteral occlusion or infusion of phenylephrine increases prostaglandin synthesis which stimulates renin release. The effect of isoproterenol on renin release is independent of prostaglandin synthesis.

Renal venous and urinary PGE2 output during intrarenal arachidonic acid infusion in dogs.

Inferences about total renal (venous and urinary) PGE2 output from determinations of urinary excretion rates (U PGE2 V) cannot be made unless the distribution of PGE2 between renal venous plasma and urine is known. Therefore, in the present study on intact kidneys of anesthetized dogs both urinary excretion of PGE2 and the renal venous output (the product of plasma flow and venous concentration of PGE2) was determined during low and high rates of renal PGE2 synthesis. PGE2 was measured in urine and arterial and renal venous plasma by radioimmunoassay during the following conditions: (1) Hydropenia. In the control condition U PGE2 V averaged 0.041 +/- 0.012 pmol/g . min and varied between 4 and 70% of the total PGE2 output. With infusion of arachidonic acid (AA, 160 micrograms/kg . min) into the renal artery total PGE2 output increased from 0.18 +/- 0.03 to 3.23 +/- 0.51 pmol/g . min, whereas arterial concentrations of PGE2 were unchanged. The urinary fraction still varied between 6 and 46% of total renal PGE2 output. (2) High urine flows caused by mannitol, saline or saline and ethacrynic acid (ECA) infusion. These procedures did not stimulate total renal PGE2 output and the urinary fraction varied between 4 and 49%. ECA combined with saline infusion increased the urinary fraction significantly to 34.7 +/- 4.0%. AA increased the total PGE2 output as during hydropenia, but the urinary fraction fell to 13% in 13 dogs and was unchanged at about 8% in six dogs. On average the urinary fraction of total PGE2 output was significantly lower than in hydropenia. Thus, the urinary fraction of total renal PGE2 output is not constant, and urinary excretion of PGE2 does not give reliable information about renal synthetic rates of prostaglandins.

Glomerulotubular balance and prostaglandin synthesis.

We have tested a hypothesis proposed to explain glomerulotubular balance (GTB) as a consequence of variations in prostaglandin synthesis. Arachidonic acid (40 micrograms x kg-1 x min-1) infused into the renal artery of anesthetized dogs raised renal blood flow (RBF) by 41 +/- 5% in hydropenic and by 24 +/- 11% in volume-expanded dogs, but the absolute changes were similar. The infusion of arachidonic acid after the administration of indomethacin (10 mg x kg-1) had no effect on RBF. Arachidonic acid infusion increased the excretion of sodium and chloride in hydropenic dogs but not after the administration of ethacrynic acid in volume-expanded dogs. During continued infusion of ethacrynic acid, the glomerular filtration rate (GFR) was lowered by suprarenal aortic constriction and raised by carotid constriction. A linear relationship between electrolyte reabsorption and GFR (GTB) was observed when GFR was varied between 20 and 110% of control. GTB and tubular reabsorption at comparable GFR were not significantly altered during arachidonic acid infusion or after indomethacin administration. In all experimental settings, bicarbonate, chloride, and sodium reabsorption were altered in molar ratios of 1:2:3 during variations in GFR. We conclude that GTB is independent of variations in prostaglandin synthesis.

Segmental distribution of vascular resistances during ureteral occlusion. The vasoconstrictive effects of angiotensin and CaCl2 differ from those of catecholamines and renal nerve stimulation.

UNLABELLED: Examinations of renal autoregulation and renin release suggest that alpha-adrenergic agonists, in contrast to other vasoconstrictors, preferentially constrict the preglomerular arteries. To examine this hypothesis, experiments were performed in anesthetized dogs during ureteral occlusion. At a ureteral pressure (UP) of 100 mmHg the afferent arterioles are dilated and mechanical constriction of the renal artery does not alter intrarenal vascular resistances. Whereas angiotensin and CaCl2 infused into the renal artery reduced renal blood flow (RBF) by 25-30% without reducing UP, renal nerve stimulation reduced RBF and UP in proportion. During angiotensin and catecholamine infusion, measurements of UP and intrarenal venous pressure permitted calculations of preglomerular, efferent vascular and intrarenal venous resistances. Until RBF was reduced by 25%, angiotensin raised both preglomerular and efferent vascular resistances, whereas norepinephrine and the alpha-adrenergic agonists, phenylephrine and methoxamine, raised preglomerular more than efferent vascular resistance. When RBF was reduced by more than 25%, all vasoconstrictors showed a similar pattern with large increments both in preglomerular and efferent vascular resistances. CONCLUSIONS: Humoral and nervous stimulation of alpha-adrenergic receptors reduce glomerular capillary pressure by preferentially constricting the preglomerular arteries and may affect renal autoregulation and renin release by reducing the transmural pressure of the afferent arterioles.