Comparative Effect of PGE2 and PGI2 on Renal Function
Abstract Rapid degradation of prostacyclin (PGI2) inherent to its molecular structure has long been a major limitation in assessing the natriuretic effect of this prostaglandin. The recent availability of the stable PGI2 analogue iloprost now allows for a comparative study with prostaglandin E2 (PGE2). In the present study conducted in six anesthetized dogs, the intrarenal effects of two consecutive doses (1 and 4 ng · kg−1 · min −1) of PGE2 on renal blood flow, glomerular filtration rate, and urinary sodium excretion were compared with the effects of two identical doses of iloprost. The selected doses of PGE2 were those producing a maximal natriuretic and vasodilator response without affecting mean arterial pressure. A washout period was allowed between administration of PGE2 and iloprost. PGE2 infusion significantly increased fractional sodium excretion from 0.69±0.1 to 2.79±1.1% and 4.27±1.2%% (P<.05), respectively. These changes in fractional sodium excretion induced by PGE2 were associated with significant increases in renal blood flow from 151.1±62 to 185±64.3 and 185.6±64.3 mL/min (P<.05), respectively; however, no significant alterations were seen in glomerular filtration rate, from 29.5±9.4 to 35.2±12.2 and 32.7±7.8 mL/min (NS), and mean arterial pressure, from 117.6±26 to 113.9±24.1 and 112.3±24.1 mm Hg (NS) during control and PGE2 infusion. At identical doses, sequential infusion of PGI2 had no effect on renal blood floww and glomerular filtration rate, producing natriuresis only at the highest dose, a fractional sodium excretion from 0.69±0.1 to 0.8±0.28 mm Hg (NS) and 1.05±0.34% (P<.05), respectively. In conclusion, the present study confirms that PGE2 exerts a natriuretic effect during increases in renal blood flow. In contrast, PGI2 had no hemodynamic effect, and the natriuresis was markedly blunted.
Prostaglandin E2 and PGI2 are important mediators of the renal effects of the arachidonic acid cascade.1 The presence of PGE2 is necessary for the full expression of pressure-induced natriuresis because after blockade of prostaglandin synthesis, the excretion of sodium is restored by intrarenal infusion of PGE2 but remains depressed during infusion of PGI2.2 3 Similarly, renin release appears to be stimulated by the synthesis of PGI2 rather than of PGE2. This finding has fostered the notion that preglomerular function is under the control of PGI2, whereas postglomerular function is mediated by PGE2.4 Determination of the relative potency of PGI2 and PGE2 to induce natriuresis is very important in defining the role of prostaglandins in other physiological maneuvers, such as extracellular volume expansion, sympathetic withdrawal, etc. A simple pharmacological approach to assess the natriuretic effects of equivalent doses of PGI2 and PGE2 is precluded by the rapid, nonenzymatic conversion of PGI2 to 6-keto-PGF1α at pH 7.4.5 Iloprost, a synthetic stable PGI2 analogue, circumvents the methodological limitation attributed to PGI2 degradation.6 This study was therefore undertaken to compare the effects elicited by intrarenal infusion of PGE2 and iloprost on renal hemodynamics and sodium and water excretion at doses that do not affect MAP.
The present study, which had approval of the Institutional Animal Care and Use Committee, was performed in six male mongrel dogs with a body weight ranging from 18.1 to 22.4 kg. The animals had free access to water and were fed standard pelleted dog food that provided ≈50 mmol sodium per day. The dogs were fasted for 10 hours before surgery, then anesthetized with 30 mg/kg IV of sodium pentobarbital, and ventilated according to the nomogram of Kleinman and Radford.7 The right femoral artery was catheterized for continuous blood pressure monitoring and blood sample withdrawal. The femoral vein was cannulated for continuous infusion of inulin and additional anesthesia. An electromagnetic flow probe was placed on the left renal artery for continuous blood flow monitoring (Carolina Medical Electronics). A curved 23-gauge needle was inserted into the renal artery downstream from the flow probe to infuse saline solution at a rate of 0.4 mL/min during basal and washout periods, as well as to allow for intrarenal administration of PGE2 and iloprost during the experimental periods. Urine was collected in a graduated test tube from a catheter placed in the left ureter.
After the surgical procedure, a priming dose of 1.0 mL/kg body wt of 1.6% inulin solution was followed by a sustaining infusion of 0.05 mg · kg−1 · min−1. Following a 45-minute equilibration, a 15-minute control period (PB) was started. This period was immediately followed by a 30-minute intrarenal infusion of PGE2 at a rate of 1 ng · kg−1 · min−1. During the last 15 minutes of the infusion (PE1), the effects of this dose were evaluated. At the end of this period, a higher dose of PGE2 (4 ng · kg−1 · min−1) was started for an additional 30 minutes. The effects of this dose were evaluated during the last 15 minutes of this period (PE2). At least 30 minutes was allowed for washout of the drug before the above-mentioned sequence of periods was repeated with iloprost, a stable PGI2 analogue (Schering AG). Iloprost was infused at the same doses (1 and 4 ng · kg−1 · min−1), and the effects of this drug were measured during the respective PI1 and PI2 periods. Inasmuch as the sequence of drug infusions was not reversed or time control effects of iloprost or PGE2 evaluated, the effects of PGE2 on the subsequent response to iloprost or time-dependent changes in kidney function cannot be excluded.
PGE2 was initially dissolved in absolute ethanol followed by a 5% Na2CO3–saline solution, whereas iloprost was dissolved in saline solution. The concentrations of both drugs were adjusted to maintain a constant-volume infusion rate (0.4 mL/min) throughout the study. The doses of PGE2 or iloprost were derived from pilot studies that had demonstrated small effects on sodium excretion (<1 ng · kg−1 · min−1), whereas at >4 ng · kg−1 · min−1 there was a significant fall in MAP.
Plasma and urinary Na+ and K+ were determined with a flame photometer (Instrumentation Laboratory). GFR was calculated by measurement of inulin clearance; plasma and urine inulin concentrations were determined by the anthrone method.8
Comparisons between the different periods were performed by two-tailed paired t test, and a value of P<.05 was considered significant. Values in the figures are expressed as mean±SEM, whereas those in the text are reported as mean±SD.
Intrarenal infusion of either PGE2 or iloprost did not significantly alter MAP levels, as depicted at the top of Fig 1⇓. The average values for this parameter during the basal period were 117.6±26.1 mm Hg, whereas the maximum range of values during PGE2 and iloprost infusions was 112.3±24.1 (PE2) and 109.0±24.6 mm Hg (PI2), respectively. As shown in Fig 1⇓, although neither drug significantly increased GFR, the pattern of responses was quite similar to that of RBF. On the contrary, while both doses of PGE2 elevated RBF from 151.1±61.7 to 185.6±64.3 and 190.6±58.5 mL/min (P<.05 versus PB), no significant change (NS) was induced by either dose of iloprost (153.1±31.8 and 162.4±35.8 mL/min, respectively), as shown at the bottom of Fig 1⇓.
Fig 2⇓ shows changes induced by prostaglandin infusion on urinary flow, Na+ and K+ excretion (UNa+V and UK+V), and FENa. Intrarenal infusion of 1 and 4 ng · kg−1 · min−1 of PGE2 significantly increased urinary flow from 0.16±0.05 to 0.89±0.3 and 1.22±0.5 mL/min, respectively. Similar and proportional effects were exerted by PGE2 on urine and FENa. UNa+V increased from 42.1±20.2 to 182.3±62.1 and 235.0±83.4 μmol/min with the two doses of PGE2, whereas FENa increased from 0.69±0.11% to 2.79±1.1% and 3.27±1.2%. In parallel to these changes, urinary K+ excretion increased from basal values (19.2±4.4 μmol/min) to 40.3±10.2 and 44.7±11.0 μmol/min, respectively.
In addition to the significant increase in RBF (Fig 1⇑), intra-arterial infusion of iloprost induced slight elevations in urinary flow, Na+ and K+ excretion, and FENa, as shown in Fig 2⇑. The elevations obtained in these last parameters attained statistical significance (P<.05 versus PB) with the highest dose of iloprost. At this dose (4 ng · kg−1 · min−1), urine flow averaged 0.50±0.18 mL/min and UNa+V 94.2±42.1 μmol/min. However, the maximum response of these four urinary parameters (urine flow, UNa+V, UK+V, and FENa+) obtained with iloprost was significantly lower (P<.01) when compared with any of the doses of PGE2.
Increases in renal perfusion pressure are accompanied by significant and proportional elevations of sodium excretion. This pressure-induced natriuresis allows the kidney to participate in the control of MAP.9 The demonstration that nonsteroidal anti-inflammatory drugs abolished pressure natriuresis2 and that this effect was restored by intrarenal infusion of PGE2 but not PGI2 indicated that the presence of PGE2 is necessary for this full natriuretic effect.3 However, it is not known whether the efficacy of PGI2 was compromised by rapid conversion to PGF1α at physiological pH. Furthermore, PGI2 but not PGE2 exerts a specific effect on renin release from isolated afferent arterioles.4 These findings are consistent with the notion that PGI2 influences the regulation of preglomerular circulation, whereas PGE2 mediates sodium excretion.5 Refoyo et al10 demonstrated that under basal conditions, the highest concentration of both PGE2 and PGI2 in renal slices was in the innermost zone of the renal medulla, decreasing exponentially toward the renal cortex. These levels were significantly decreased by incubation with indomethacin, thus indicating that prostaglandins were being continuously formed in the excised renal tissue. Furthermore, incubation with arachidonic acid and bradykinin stimulated the formation of PGE2 in all zones of the kidney, but these maneuvers only increased the level of PGI2 in the outer medulla and in the renal cortex. These observations indicate that there may be an innermost medullary function influenced by PGE2 or that PGI2 influence is mainly exerted in the outer medulla and cortex.10 Roman and Lianos11 demonstrated that increments in papillary RBF increased renal interstitial hydrostatic pressure throughout the kidney. This may stimulate the synthesis of prostaglandins in the papilla, which then diffuse toward the cortex and thereby decrease sodium reabsorption in different nephron segments.
In conclusion, at doses that do not evoke changes in MAP, both PGE2 and iloprost are natriuretic, suggesting that the threshold to increase sodium excretion is lower than the one to modify systemic blood pressure. However, PGE2 produced significantly higher elevations in RBF and sodium and water excretion than did a fourfold higher dose of iloprost. The diuresis and kaluresis elicited by both PGE2 and iloprost are likely the result of the concomitant natriuresis.
The major findings of this article are that (1) intrarenal infusion of PGE2 at a dose of 1 and 4 mg · kg−1 · min−1 produces a 22% and 26% increment (P<.05), respectively, of RBF, while identical doses of the PGI2 synthetic analogue iloprost failed to produce vasodilatation and (2) these renal hemodynamic changes induced by the two doses of PGE2 were accompanied by a 4.3- and 5-fold increment in urinary Na+ excretion. In controls, only the highest iloprost dose induced a 15% elevation of urinary Na+ excretion.
Selected Abbreviations and Acronyms
|FENa||=||fractional sodium excretion|
|GFR||=||glomerular filtration rate|
|MAP||=||mean arterial pressure|
|RBF||=||renal blood flow|
This work was supported by National Institutes of Health grant HL16496 (to J.C.R.) and by the Mayo Foundation. Iloprost was kindly supplied by Dr Frank MacDonald from Schering AG, Berlin, Germany.
Reprints requests to J.C. Romero, MD, Department of Physiology and Biophysics, Mayo Clinic, Rochester, MN 55905.
- Received March 15, 1997.
- Revision received April 15, 1997.
- Accepted April 30, 1997.
Schlondorff D. Renal prostaglandin synthesis: sites of production and specific actions of prostaglandins. Am J Med. 1986;81(suppl 2B):1-11.
Frölich JC. Prostaglandin in hypertension. J Hypertens. 1990;8(suppl 4):573-578.
Griglewsky RJ, Stork G. PGI2 and its stable analogue iloprost. In: Prostaglandins. Griglewsky RJ, Stork G, eds. Berlin, Germany: Springer-Verlag; 1987.
Kleinman LT, Radford EP. Ventilation standards of small mammals. J Appl Physiol. 1964;19:360-362.
Fürh J, Kaczmarczyk J, Krietgen B. Eine einfache colorimetrische methode zur inulinbestimmung füur nierenclearance untersuchgen bei stoffweschelgesunden und diabetikem. Klin Wochenschr. 1955;33:129-730.
Selkurt EE, Womack I, Dailey WN. Mechanism of natriuresis and diuresis during elevated renal arterial pressure. Am J Physiol. 1965;209:95-99.
Refoyo A, Bolterman RJ, Bentley MD, Finksen-Olsen MJ, Sandberg SM, Romero JC. Distribution of prostaglandins E2 and 6-keto-PGF1α production in the canine kidney. Hypertension. 1990;15(suppl I):I-107-I-111.
Roman RJ, Lianos E. Influence of prostaglandins on papillary blood flow and pressure-natriuretic response. Hypertension. 1990;15:29-35.