Renal Prostaglandin System Research Articles

Novel biomarkers in acute heart failure: MR-pro-adrenomedullin.

First isolated from human pheochromocytoma cells, adrenomedullin (ADM) is a peptide hormone with natriuretic, vasodilatory, and hypotensive effects mediated by cyclic adenosine monophosphate (cAMP), nitric oxide, and renal prostaglandin systems. ADM expression occurs in many tissues and organ systems, including cardiovascular, renal, pulmonary, cerebrovascular, gastrointestinal, and endocrine tissues where it acts as a circulating hormone and a local autocrine and paracrine hormone. ADM plasma concentrations are increased in hypertension, chronic renal disease, and heart failure. As ADM is unstable in vitro, it is necessary to measure its mid-regional pro-hormone fragment, the levels of which correspond to ADM concentration (MR-proADM). The prognostic potential of MR-proADM was recently demonstrated in the Biomarkers in Acute Heart Failure (BACH) trial. In this trial of 568 acute heart failure patients, MR-proADM was superior to both brain natriuretic peptide (BNP) and NT-proBNP in predicting mortality within 14 days. MR-proADM also provided significant additive incremental predictive value for 90-day mortality when added to BNP and NT-proBNP.

Adrenomedullin: Potential in physiology and pathophysiology

Adrenomedullin (ADM), a 52-amino acid ringed-structure peptide with C-terminal amidation, was originally isolated from human pheochromocytoma. ADM mediates vasodilatory and natriuretic properties through the second messenger cyclic adenosine 3′,5′-monophosphate (cAMP), nitric oxide and the renal prostaglandin system. ADM immunoreactivity and its gene are widely distributed in cardiovascular, pulmonary, renal, gastrointestinal, cerebral and endocrine tissues. ADM is also synthesized and secreted from vascular endothelial and smooth muscle cells. When injected intravenously, ADM increases flow rates predominantly in organs in which the ADM gene is highly expressed, suggesting that ADM acts as a local autocrine and/or paracrine vasoactive hormone. In addition, ADM is a circulating hormone and its plasma concentration is increased in various cardiorenal diseases such as hypertension, chronic renal failure and congestive heart failure. Current evidence suggests that ADM plays an important role in fluid and electrolyte homeostasis and cardiorenal regulation, however further investigations are required to address the importance of ADM under various physiological and pathophysiological conditions.

RENAL DOPAMINERGIC MECHANISMS AND HYPERTENSION: A CHRONOLOGY OF ADVANCES

Dopamine (DA) has been shown to influence kidney function through endogenous synthesis and subsequent interaction with locally expressed dopamine receptor subtypes (D1, D5 as D1 -like and D2, D3, and D4 as D2 -like). DA, and DA-receptor specific agonists and antagonists can alter renal water and electrolyte excretion along with renin release when infused systemically or intrarenally. Such effects are brought about by a combination of renal hemodynamic and direct tubular effects evoked along the full length of the nephron. The cellular mechanisms that direct these dopamine-mediated renal electrolyte fluxes have recently been clarified and include alterations in adenylyl cyclase, phospholipase C, and phospholipase A1 activity. The dopaminergic system also interacts directly with the renal kallikrein-kinin, prostaglandin and other neurohumoral systems. Aberrant renal dopamine production and/or dopamine receptor function have been reported in salt-dependent and low-renin forms of human primary hypertension as well as in genetic models of animal hypertension, including the SHR and Dahl SS rat. DA D1 or D3 receptor knockout mice have been shown to develop hypertension.

Comparative Hypertensionology-Renal Dopaminergic Activity in Experimental Hypertensive Rats

In our laboratory, it had been found that the renal natriuretic and depressor systems are suppressed in essential hypertension, and that suppression of the dopaminergic system may be primary and dominant in this condition. Moreover, close relationships among the renal dopamine, kallikrein-kinin, and prostaglandin systems have also been found. Therefore, we attempted to evaluate the pathogenetic and pathophysiological role of renal dopamine in connection with renal kallikrein-kinin and prostaglandin systems in various experimental hypertensive models.Two kidney 1 clip hypertensive rats (2K1C), 5/6 reduced renal mass hypertensive rats (5/6 RRM), deoxycorticosterone acetate-salt hypertensive rats (DOCA-salt), spontaneously hypertensive rats/Izumo (SHR/Iz), Dahl salt sensitive hypertensive rats/John Rapp (Dahl/Jr), Dahl/Iwai (Dahl/Iw), and respective controls were employed in this study. Urinary excretions of free dopamine (uDA), kallikrein (uKAL), and prostaglandin E2 (uPGE2) were measured before, during and after treatment in each of these hypertensive models.In these experimental hypertensive models, renal dopamine in DOCA-salt and SHR/Iz, and renal kallikrein in 2K1C, 5/6 RRM and two types of Dahl strains were primarily and dominantly suppressed in the renal natriuretic and depressor systems. Renal dopamine was transiently suppressed in Dahl/Jr, and PGE2 was suppressed in the two types of Dahl strains. Compensatory augmentation of renal kallikrein was found in DOCA-salt and SHR/Iz, and that of PGE2 was found in 5/6 RRM and DOCA-salt. Although these three renal natriuretic depressor systems are suppressed in Dahl/Jr, the dominantly suppressed system is not renal dopamine but renal kallikrein.Thus, it was summarized that, 1) decreased renal dopamine production is important in the pathogenesis of human essential hypertension, 2) pressor mechanisms of experimental hypertensive rats are different from human essential hypertension, 3) decreased renal dopamine is important in DOCA-salt and SHR/Iz,4) decreased renal kallikrein is the dominant mechanism in the pathogenesis of 2KlC, 5/6 RRM, DahllJr and DahllIw hypertensive rats, and 5) we have to be careful when considering human essential hypertension through results taken from experimental rat hypertensive models.

Effect of high potassium diets on the vascular and renal prostaglandin system in stroke-prone spontaneously hypertensive rats

High potassium (K) diets are known to have a protective effect on the endothelium and the kidney against hypertensive injury independent of blood pressure change. Vasodepressor prostaglandins (PGs) have been shown to be cytoprotective in various tissues. This study investigated the effect of high K diets on the vascular and renal eicosanoid system in stroke-prone spontaneously hypertensive rats (SHRsp). Eicosanoid production by the aorta and eicosanoid content in the renal cortex were examined in SHRsp rats fed high NaCl diets containing either 0.5% K (normal) or 2.1% K (high). Although the high K diet did not affect the blood pressure, SHRsp on the high K diet had less thickening of the aortic wall than SHRsp on the normal K diet (−15%, p < 0.001). The aortic strip of the high K SHRsp produced less vasodepressor PG than that of the normal K SHRsp when they were incubated in a medium (PGI 2 −45%, p < 0.003; PGE 2 −34%, p < 0.001). Furthermore, when the aorta was perfused in a chamber at hypertensive pressure, again the high K aorta showed reduced PGI 2 production as compared with the normal K aorta (intravascular side −52%, p < 0.01). Eicosanoid content in the renal cortex was not significantly different between the normal K and the high K SHRsp (PGI 2 79 vs 87 ng/g dry weight; PGE 2 214 vs 233 ng/g dry weight). Thus, the high K diet reduced vascular eicosanoid production but did not alter eicosanoid content in the renal cortex. The reduced vascular eicosanoid production in the high K SHRsp may reflect the reduced necessity for cytoprotective vasodepressor PG against vascular injuries.

Protective effect of cicletanine on hypertension-induced decreases in the renal kallikrein-kinin and prostaglandin systems in stroke-prone spontaneously hypertensive rats.

We investigated the effect of two oral (p.o.) doses of cicletanine (5 and 30 mg/kg/day) for 4 weeks on urinary excretion (UKE), renal concentration (RKC) of kallikrein, and prostaglandin E2 (PGE2) and 6-keto-PGF1 alpha urinary excretion of stroke-prone (SP) spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) rats submitted to a high sodium intake (1%). Both doses of cicletanine induced a significant antihypertensive effect in treated SHR as compared with hypertensive untreated controls (HC). After 4-week treatment, a significant difference in mortality was observed between normotensive controls (NC) (0%) and HC (84%). Both doses of cicletanine reduced the mortality of hypertensive animals (8% SHR with 5 mg and 24% SHR with 30 mg vs. 84% in HC). Whereas UKE and RKC were decreased in HC during the progression of untreated hypertension from week 1 to week 4, both doses of cicletanine administration significantly prevented this decrease. Consistently with maintenance of UKE during the course of hypertension, the level of tissue kallikrein was higher in hypertensive cicletanine-treated than in untreated SHR. This increased RKC was associated with a significantly higher rate of kallikrein biosynthesis. The increased level of the urinary excretion and tissue concentration of PGE2 and 6-keto-PGF1 alpha in cicletanine-treated SHR as compared with untreated animals was also of interest. This protective effect on PG excretion correlated with that on kallikrein excretion. The results confirm the efficiency of cicletatine as an antihypertensive treatment. The antihypertensive action includes protective effects on potential vasodepressor kallikrein-kinin and prostaglandin systems.(ABSTRACT TRUNCATED AT 250 WORDS)

Pathophysiology and treatment of ascites and the hepatorenal syndrome

Ascites indicates the accumulation of fluid in the peritoneal cavity, due to a wide range of causes. These causes can be classified according to the presence of portal hypertension, severe blood dyscrasia and peritoneal disease. Cirrhosis is the most frequent cause of ascites. The occurrence of ascites in cirrhosis is due to portal hypertension, which is responsible for the increase in hydrostatic pressure at the sinusoidal level and the alterations of splanchnic and systemic haemodynamics. These latter include increased splanchnic inflow, reduced systemic resistance and increased plasma volume and cardiac output. Portal hypertension also plays a major role in determining sodium retention, which occurs in the setting of increased RAA system and SNS activity. The mechanisms by which portal hypertension leads to the activation of antinatriuretic factors and sodium retention are not completely understood; three main hypotheses have been proposed to explain this relationship, namely the underfilling, the overflow and the peripheral arterial vasodilatation theories. In patients with cirrhosis and ascites, there is an overall activation of the renal prostaglandin system, which probably acts to maintain renal haemodynamics and GFR by counteracting the vasoconstricting effects of AII and noradrenaline on renal circulation. In advanced stages, ascites may become refractory to medical treatment and renal function shows a progressive impairment and eventually acute renal failure, the so-called HRS, due to a marked vasoconstriction of the renal arteries and the opening of the intrarenal-arteriovenous (A-V) shunts. In this condition, the reduced renal synthesis of vasodilating prostaglandins is probably of pathogenic importance. Treatment of ascites is usually based on bed rest, low-sodium diet and administration of aldosterone antagonists and loop diuretics. A sequential treatment of ascites based on the progressive addition of more potent drugs is the best way to relieve ascites while avoiding potentially dangerous side-effects. Patients who fail to respond to the above manoeuvres are said to have refractory ascites. Current treatment of this latter condition is mainly based on therapeutic paracentesis and the application of the LeVeen shunt, but long-term results are unsatisfactory.

Effects of short-term treatment with naproxen on kidney function in insulin-dependent diabetic patients with microalbuminuria

The renal effects of the prostaglandin synthesis inhibitor naproxen was investigated in eight patients with incipient type I diabetes nephropathy. The patients were treated with 1000 mg naproxen daily for 4 days in a placebo-controlled double-blind cross-over study. Naproxen reduced urinary prostaglandin E2 (PGE2) excretion by 60%, from 276 ng/24 h to 110 ng/24 h (P<0.05). Plasma renin activity (PRA) was reduced by 45% (F<0.05). Glomerular filtration (GFR) (single bolus 99mTc-DTPA technique) and effective renal plasma flow (ERPF) (131I-Hippuran clearance) were unchanged by naproxen. Microalbuminuria and renal albumin clearance was unchanged as was also urinary excretion of sodium, glandular kallikrein and β2-microglobulin (β2-M). Our results show that albumin excretion in incipient diabetic nephropathy is not solely dependent on the renal prostaglandin system. The difference in action between naproxen in this study and indomethacin in previous reports, could be caused by renal actions of indomethacin independent of the prostaglandin system.

Effects of short-term treatment with naproxen on kidney function in insulin-dependent diabetic patients with microalbuminuria

The renal effects of the prostaglandin synthesis inhibitor naproxen was investigated in eight patients with incipient type I diabetes nephropathy. The patients were treated with 1000 mg naproxen daily for 4 days in a placebo-controlled double-blind cross-over study. Naproxen reduced urinary prostaglandin E2 (PGE2) excretion by 60%, from 276 ng/24 h to 110 ng/24 h (P less than 0.05). Plasma renin activity (PRA) was reduced by 45% (P less than 0.05). Glomerular filtration (GFR) (single bolus 99mTc-DTPA technique) and effective renal plasma flow (ERPF) (131I-Hippuran clearance) were unchanged by naproxen. Microalbuminuria and renal albumin clearance was unchanged as was also urinary excretion of sodium, glandular kallikrein and beta 2-microglobulin (beta 2-M). Our results show that albumin excretion in incipient diabetic nephropathy is not solely dependent on the renal prostaglandin system. The difference in action between naproxen in this study and indomethacin in previous reports, could be caused by renal actions of indomethacin independent of the prostaglandin system.

The Role of the Renal Dopaminergic and the Prostaglandin Systems in Renal Uric Acid Metabolism in Patients with Essential Hypertension

The present study aimed to elucidate the role of renal dopaminergic and prostaglandin (PG) systems in renal uric acid metabolism in essential hypertension. Mean arterial pressure (MAP), heart rate (HR), endogenous creatinine clearance (Ccr), serum uric acid (SUA), urinary excretions of uric acid (UUAV) and sodium (UNaV), fractional excretions of uric acid (FEUA) and sodium (FENa), plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were measured before and after intravenous injection of a dopamine receptor antagonist, metoclopramide (MCP: 8 mg/m2.BSA), or before and after a single oral administration of prostaglandin synthesis inhibitor, indomethacin (IM: 75 mg), in 34 mild-to-moderate essential hypertensives (EHT). MCP injection or acute oral administration of IM caused significant decreases of UNaV and FENa in each group, whereas MAP, HR and SUA did not change in either group. Significant decreases in Ccr, UUAV and FEUA and increases in PRA and PAC were demonstrated by MCP injection, while no significant changes in these parameters were revealed by IM administration. There was a significant positive correlation between delta UUAV and delta Ccr or delta FEUA in both groups. In addition, a close positive correlation between delta UUAV and delta UNaV as well as between delta FEUA and delta FENa was found in the MCP group, but not in the IM group. On the other hand, no significant correlation was observed between delta UUAV and delta PRA or delta PAC in either MCP or IM administration. The decreases of UUAV and FEUA were significantly greater in MCP than in IM administration, despite similar changes in Ccr, UNaV and FENa between the two procedures. These data suggest that the endogenous renal dopaminergic system may contribute to renal uric acid metabolism, which is rather closely related to sodium handling in essential hypertension than the prostaglandin system. Furthermore, the attenuated renal dopaminergic activity may contribute to the elevation of serum uric acid level in patients with essential hypertension.

The effects of ibuprofen and indomethacin on renal function in the presence and absence of frusemide in healthy volunteers on a restricted sodium diet.

1. Since salt depletion stimulates the renal prostaglandin system to maintain renal function, the effects of indomethacin and ibuprofen upon renal haemodynamics, electrolyte excretion and renin release were examined in eight healthy male volunteers on a salt restricted diet, before and after frusemide administration. 2. Neither indomethacin (50 mg) nor ibuprofen (400 mg and 800 mg) affected renal blood flow, glomerular filtration rate or electrolyte excretion before frusemide. 3. Renal blood flow and glomerular filtration rate were significantly increased in the first 20 min after frusemide. These changes were significantly attenuated by indomethacin compared with placebo and ibuprofen 400 mg. Frusemide-induced diuresis but not natriuresis was inhibited by all treatments. 4. Both nonsteroidal agents inhibited equally the rise in renin activity seen after frusemide. 5. In this group of healthy volunteers on a salt restricted diet, ibuprofen and indomethacin had no detrimental effects on renal function in the absence of frusemide. The changes in renal haemodynamics due to frusemide were suppressed more by indomethacin than by ibuprofen, probably reflecting the more potent nature of indomethacin as an inhibitor of prostaglandin synthesis.

Influence of prostaglandins on papillary blood flow and pressure-natriuretic response.

The present study examined whether renal prostaglandins influence the pressure-natriuretic response by altering medullary hemodynamics or renal interstitial pressure. The diuretic and natriuretic responses to changes in renal perfusion pressure were compared in control rats (n = 15) and in rats receiving either meclofenamate (2 mg/kg, n = 9) or indomethacin (2 mg/kg, n = 4). In control rats, urine flow and sodium excretion increased from 10 +/- 2 to 118 +/- 10 microliters/min/g kidney wt and from 1.8 +/- 0.3 to 21.0 +/- 1.5 mueq/min/g kidney wt, respectively, when renal perfusion pressure was increased from 109 to 167 mm Hg. Urinary excretion of prostaglandin E2 and thromboxane B2 increased significantly by 152% and 190%, respectively. Meclofenamate lowered thromboxane B2 and prostaglandin E2 excretion and prevented the increase in eicosanoid excretion produced by elevations in perfusion pressure. The pressure-diuretic and pressure-natriuretic responses of rats given meclofenamate or indomethacin were approximately half of those observed in the control rats. Papillary blood flow increased 21% and renal interstitial pressure rose from 5.0 +/- 0.7 to 8.2 +/- 0.7 mm Hg in control rats when pressure was elevated from 100 to 150 mm Hg. Meclofenamate and indomethacin lowered papillary blood flow and renal interstitial pressure and blunted the increases in these values produced by elevations in perfusion pressure. These results support the view that renal prostaglandins modulate the pressure-natriuresis relation by altering renal medullary hemodynamics and suggest that an intact renal prostaglandin system is necessary for the full expression of the medullary hemodynamic and natriuretic responses to increases in renal perfusion pressure.

Effects of rhein on renal arachidonic acid metabolism and renal function in patients with congestive heart failure

In a randomized double-blind cross-over study the effects of rhein (administered as diacetyl-rhein 50 mg b.d. for 5 days) and placebo on renal arachidonic acid metabolism and renal function have been compared in 12 elderly patients (mean age 75.2 years) with congestive heart failure, whose renal function was known to be dependent on the integrity of the renal prostaglandin system. Rhein like placebo, did not induce any change in the urinary excretion of prostaglandin (PG) E2, 6-keto-PGF1 alpha and thromboxane (TX) B2, nor did it affect creatinine clearance, blood urea, urine output, natriuresis, body weight, plasma renin activity or plasma aldosterone concentration. Separate analysis of the results obtained in the 5 patients receiving diuretic treatment did not show any significant effect of rhein as compared with placebo on the parameters investigated. Serum TXB2 concentration during whole blood clotting, as an index of platelet arachidonic acid metabolism, also showed no significant difference when DAR and placebo were compared. It is concluded that in patients with congestive heart failure rhein does not inhibit renal or platelet eicosanoid metabolism, nor does it modify renal function, sodium excretion or the renal response to diuretics.

Systemic haemodynamics, renal and platelet function during chronic propranolol administration in patients with compensated cirrhosis.

Chronic propranolol administration is followed by some haemodynamic alterations, which may impair renal function. It has also been suggested that it may reduce platelet production of proaggregatory thromboxane (TX) A2. We therefore evaluated cardiac index (CI), systemic vascular resistance (SVR), creatinine clearance, daily sodium excretion under controlled sodium intake, platelet aggregation and platelet TXA2 production during whole blood clotting in eight patients with cirrhosis, portal hypertension and no ascites, before and after 3 months of propranolol administration. Liver function was also assessed by evaluating the galactose elimination capacity (GEC) and galactose clearance (Cgal). The expected, significant reduction of CI and increase of SVR was observed. Creatinine clearance and sodium balance were unchanged throughout the study. Furthermore, the renal prostaglandin system, as reflected by urinary prostaglandin E2 and TXB2 excretion, was also unaffected by the drug. No modification of platelet aggregation, platelet TXA2 production during whole blood clotting, GEC and Cgal was observed. We conclude that chronic propranolol administration is followed by alterations of CI and SVR, but it does not impair renal function and platelet aggregation in patients with cirrhosis, portal hypertension and no ascites. The maintenance of renal function during beta-adrenergic blockade is not due to an increased renal production of vasodilating prostaglandins.

The pathophysiological role of renal dopamine, kallikrein kinin and prostaglandin systems in essential hypertension.

In order to clarify the relationship and the pathophysiological role of renal dopamine, kallikrein-kinin and prostaglandin systems in essential hypertensives, the effects of dopamine on these systems and renal sodium handling were investigated. Basal levels of kallikrein, kinin and prostaglandin E2 in essential hypertensives were significantly lower than those in normotensives. Those of kallikrein and kinin were obviously more suppressed in the low renin group than in the normal renin group, but no significant difference in prostaglandin E2 was found in either subgroup. Urinary dopamine excretion was significantly lower in the low renin essential hypertensives, while no significant difference was found between normotensives and normal renin essential hypertensives. Kallikrein activity and prostaglandin E2 were significantly increased in essential hypertensives by dopamine infusion, and no significant difference was found in kallikrein-quantity and kinin between normotensives and essential hypertensives after the infusion. These increases of kallikrein and kinin were significantly higher in the low renin group than in normal renin group, but those of prostaglandin E2 were not. Urine volume, urinary sodium excretion and fractional excretions of sodium and inorganic phosphorus were all increased in both normotensives and essential hypertensives after dopamine infusion. The increases of these were significantly greater in essential hypertensives than in normotensives, and greater in the low renin group than the normal renin group. From these results, it was suggested that the dopamine, kallikrein-kinin and prostaglandin E2 system have a close relationship with each other, and the suppression of these systems may contribute to the pathophysiology of essential hypertension, especially in the low renin group.

Participation of the Prostaglandin System in Furosemide-Induced Changes of Renal Function in Anesthetized Rats

The possible mediation of the endogenous prostaglandin and kallikrein-kinin systems of changes in renal function induced by furosemide was studied in anesthetized rats. Increasing doses of furosemide infusion (0.03, 0.1, and 0.3 mg/kg/min) caused dose-related diuresis, natriuresis, kaliuresis, and decreased renal blood flow and urinary osmolality without any significant changes in mean arterial blood pressure. Pretreatment with the prostaglandin synthetase inhibitor indomethacin resulted in marked reduction of the water and sodium excretion induced by furosemide. It also blunted renal vasoconstriction and renin release by furosemide, but the glomerular filtration rate was not affected. Pretreatment with aprotinin, a kallikrein inhibitor, failed to affect the renal response to furosemide. The results indicate that the renal prostaglandin system, but not the kallikrein-kinin system, participates in the effect of furosemide on renal functions mainly through electrolyte transport inhibition in the renal tubule.

Altered renal and platelet arachidonic acid metabolism in cirrhosis

Urinary excretion rates of prostaglandin (PG) E2, PGF2α, 6-keto-PGF1α, and thromboxane (TX) B2 were evaluated in three groups of cirrhotic patients [without ascites (group 1, 13 cases), with ascites and normal renal function (group 2, 15 cases), and with ascites and renal failure (group 3, 5 cases)]and in 14 healthy controls. All urinary arachidonate metabolites were significantly increased in group 2 patients. Patients with renal failure showed lower PGE2, PGF2α, and TXB2 values than those from group 2; PGF2α values were also lower than controls. Platelet TXA2 production during whole blood clotting was significantly reduced in all groups of patients. Administration of low-dose aspirin and sulindac, two cyclooxygenase inhibitors selectively sparing renal cyclooxygenase activity, effectively inhibited platelet TXA2 production without affecting urinary TXB2 excretion, thus ruling out platelets as a possible source of urinary TXB2. We conclude that patients with ascites and normal renal function show an overall activation of the renal PG system. Renal production of vasodilating PGE2 and PGI2 may be involved in supporting renal function in these patients. A reduced platelet synthesis of proaggregatory TXA2 also occurs in cirrhotic patients. This may play a role in the bleeding tendency of cirrhosis.

Urinary Prostaglandin E2 Excretion after the Resumption of Renal Function Post Renal Transplantation

Previous studies have demonstrated that the renal prostaglandin system participates in the recovery from ischemic events, in diuresis and in natriuresis. This study was undertaken to probe renal prostaglandin E2 synthesis during the first and second weeks after renal transplantation. Urinary prostaglandin E2 excretion was greatly elevated immediately after transplantation, compared to the second week, and differences in urine PGE2 concentration were also significant. This suggests that enhanced prostaglandin synthesis accompanies the resumption of renal function after transplantation.

High potassium intake selectively increases urinary PGF2 alpha excretion in the rat.

This study was designed to investigate relationships between dietary potassium and the renal prostaglandin system in rats. The potassium content of the diet was 0.162 mmol/g during the control period and 0.004, 0.162, 1.351, or 2.702 mmol/g during the experimental period. Relative to control data in rats fed a 0.162 mmol/g potassium diet, the urinary excretion of 6-keto-PGF1 alpha was not affected by high potassium intake but increased (P less than 0.05) by 25% in rats fed a low potassium diet for 13 days and was associated with reduction of plasma potassium and with elevation of both plasma renin and net release of 6-keto-PGF1 alpha from renal inner medulla slices incubated in Krebs solution. The excretion of PGF2 alpha was not affected by low potassium intake but increased (P less than 0.05) by about twofold in rats fed a potassium-rich diet (1.351 and 2.702 mmol/g) for 13 days and was associated with elevation of plasma potassium concentration, renal prostaglandin 9-keto-reductase activity, and urinary excretion of kallikrein and vasopressin. The urinary excretion of PGE2 was not altered in rats fed either low or high potassium diets. Altogether, these results indicate selective influence of dietary potassium on the urinary excretion of prostaglandins in the rat.

Prostaglandins in the sodium excretory response to altered renal arterial pressure in dogs.

Acute variations in renal arterial pressure are associated with corresponding alterations in absolute and fractional sodium excretion even under conditions of highly efficient autoregulation of renal blood flow (RBF) and glomerular filtration rate (GFR). Since prostaglandins recently have been implicated in the regulation of sodium excretion, we investigated the hypothesis that the renal prostaglandin system participates in "pressure natriuresis." Anesthetized sodium-replete dogs were subjected to partial carotid artery constriction to elevate systemic arterial pressure. Under these control conditions, sodium excretion was 103 +/- 18 mueq/min (n = 17) and urinary prostaglandin E2 excretion averaged 4.6 +/- 1.5 ng/min (n = 8). Decreases in renal arterial pressure within the auto-regulatory range reduced sodium excretion (2.1%/mmHg) and prostaglandin E2 excretion (1.7%/mmHg), whereas GFR and RBF were not affected. There was a significant correlation between the changes in sodium and prostaglandin E2 excretion rates (r = 0.932, P less than 0.01). In nine dogs treated with indomethacin, sodium excretion was reduced by 70% while GFR and autoregulatory capability were unaffected. There was a marked attenuation of the effect of changes in arterial pressure on sodium excretion, with this parameter exhibiting changes averaging 0.6%/mmHg (P less than 0.001). These observations suggest that the renal prostaglandin system may exert an important influence on the pressure-natriuresis mechanism.