Urinary PGE2 Excretion Research Articles

Renal effects of nadolol in cirrhosis.

The effects of nadolol on renal haemodynamics and function, and on the renin-angiotensin-aldosterone system and on renal prostaglandin production were studied in eighteen cirrhotics. After 1 month of treatment, nadolol had significantly decreased cardiac output by 25% without affecting arterial pressure, renal plasma flow or renal vascular resistance. Glomerular filtration rate, filtration fraction and the proportion of the cardiac output delivered to the kidneys were significantly increased. The renin-angiotensin-aldosterone system was suppressed and urinary PGE2 excretion was slightly increased. The latter effects were not correlated with those on renal haemodynamics and function.

Diabetes insipidus with renal resistance to vasopressin in the desoxycorticosterone-treated dog: a possible role for prostaglandins.

We examined the release of vasopressin and the renal response to exogenous vasopressin before and during desoxycorticosterone acetate (DOCA) administration in the dog. As treatment with DOCA produced potassium loss, urine volume increased, urinary osmolality decreased, and urinary PGE2 tended to increase. The increase in urine volume was accompanied by increases in serum sodium, in plasma osmolality and in plasma arginine vasopressin. The threshold for vasopressin release measured during polyuria was higher than control but the rate of vasopressin release was unchanged. The DOCA-induced polyuria was not affected by treatment with vasopressin which further increased plasma vasopressin. Treatment with indomethacin which corrected the increase in urinary PGE2 excretion but not the hypokalemia, restored the renal responsiveness to vasopressin, decreased the secretion of vasopressin, and corrected the polyuria and the hypernatremia. These findings suggest that DOCA-induced polyuria is attributable to a decrease in renal responsiveness to vasopressin which may be mediated in part by an increase in the renal synthesis of prostaglandins.

Congenital nephrogenic diabetes insipidus ? vasopressin and prostaglandins in response to treatment with hydrochlorothiazide and indomethacin

In four boys with congenital nephrogenic diabetes insipidus, plasma arginine-vasopressin (AVP) and urinary excretion of prostaglandins were studied in response to treatment with hydrochlorothiazide and indomethacin. An abnormal relationship between AVP and urine osmolality was demonstrated in all patients. In the first patient, treatment with indomethacin (3 mg/kg per day) resulted in a drop of the insulin and paraminohippurate clearances. In the other three patients urinary excretion of PGE2 was raised, and fell during treatment with hydrochlorothiazide (2 mg/kg per day) and indomethacin (2 mg/kg per day). Urine flow, free water clearance and osmolar clearance decreased during treatment. A combination of both drugs is more effective than hydrochlorothiazide alone and the effect appears to be additive.

Effects of Dietary Linoleic Acid on Blood Pressure and Renal Function in Subtotally Nephrectomized Rats

The effect of a high linoleic acid diet on blood pressure, renal function, and urinary prostaglandin excretion was studied in rats with decreased renal mass. Subtotally nephrectomized (5/6 nephrectomy) male rats received either a 15% linoleic acid (high linoleic acid, HLA) diet containing 20% safflower oil or a 0.28% linoleic acid (low linoleic acid, LLA) diet containing 20% coconut oil. Sham-operated rats were also placed on either HLA or LLA diet. The subtotal nephrectomized rats developed similar degrees of hypertension during the first 3 weeks after subtotal nephrectomy. However, 4 weeks after subtotal nephrectomy, the rats on HLA diet had significantly lower blood pressure than the rats on LLA diet [HLA 152 +/- 3 (mean +/- SE) mm Hg versus LLA 171 +/- 3 mm Hg]. This difference persisted until termination of the experiment at 7 weeks after subtotal nephrectomy (HLA 159 +/- 7 mm Hg versus LLA 192 +/- 6 mm Hg). The GFR measured 7 weeks after subtotal nephrectomy was significantly lower in both of the subtotally nephrectomized groups. However, the HLA subtotal nephrectomized rats had significantly higher GFR than the LLA-treated rats (HLA 0.23 +/- 0.05 ml/min 100 g versus LLA 0.12 +/- 0.02 ml/min/100 g, P less than 0.05). There was no difference in the GFR or blood pressure in the sham-operated rats treated with HLA or LLA diet. PGE2 excretion was lower in the two groups of subnephrectomized rats, but there was no difference between the HLA and LLA treated rats. Urinary 6-ketoPGF1 alpha was not decreased by subtotal nephrectomy and there was no difference between the dietary groups. However, TXB2 excretion was higher in the groups with subtotal nephrectomy, but there was no difference between the two dietary groups. In conclusion, the HLA diet attenuates the rise in blood pressure after subtotal nephrectomy in the rat and preserves renal function. There was no difference in urinary excretion of PGE2, 6-keto-PFG1 alpha, or thromboxane B2 between the two dietary groups.

Effects of acute and chronic dosing of NSAIDs in patients with renal insufficiency

Administration of nonsteroidal anti-inflammatory drugs (NSAIDs) to patients with chronically impaired renal function has been reported to cause abrupt and sustained reductions in renal plasma flow (RPF), glomerular filtration rate (GFR), and solute and water excretion in association with decreased renal prostanoid production. However, the time course of these acute effects and whether they are sustained during chronic exposure to the NSAIDs are unknown. Accordingly, using standard clearance and balance techniques, we investigated the effects of acute (zero to four hours) and chronic (five days) oral administration of two different NSAIDs on renal function in patients with stable, mild to moderate chronic renal insufficiency (CRI) and in normal subjects. In patients, acute oral administration of ketoprofen (K) and indomethacin (I) resulted in significant decreases in GFR (K: from 36 +/- 3 to 20 +/- 4 ml/min, P = 0.001; I: from 37 +/- 6 to 30 +/- 7 ml/min, P = 0.032; in RPF (K: from 194 +/- 21 to 146 +/- 21 ml/min, P = 0.002; I: from 222 +/- 33 to 147 +/- 18 ml/min, P = 0.016); and in urinary PGE2 excretion (K: from 0.60 +/- 0.25 to 0.08 +/- 0.02 ng/min, P = 0.05; I: from 0.34 +/- 0.06 to 0.18 +/- 0.06 ng/min, P = 0.042). Fractional excretion of sodium chloride and fractional free water clearance (CH2O/CIn) also decreased significantly after both agents. In normal subjects, GFR and RPF were not significantly decreased after acute dosing, whereas urinary PGE2 and fractional excretions of NaCl and free water decreased significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Captopril on the Urinary Excretion of Prostanoids and Kallikrein in Spontaneously Hypertensive Rats

The possible roles of vasodilatory prostanoids and the kallikrein-kinin system in the antihypertensive action of the angiotensin-converting enzyme (kininase II) inhibitor captopril were examined in spontaneously hypertensive rats. Captopril (20, 50 or 100 mg/kg daily orally) reduced blood pressure markedly and dose-dependently. It also increased water consumption and urine excretion, measured on the 5th day of treatment. The 24-hr urinary excretion of PGE2 was not changed, whereas that of PGF2 alpha and TxB2 tended to be enhanced. A clear increase, significant with all doses of captopril, occurred in the urinary excretion of 6-keto-PGF1 alpha. Kallikrein excretion in urine was suppressed by the two larger doses of captopril. The markedly augmented urinary excretion of 6-keto-PGF1 alpha, the stable metabolite of vasodilatory prostacyclin (PGI2), suggests that increased prostacyclin production may participate in the antihypertensive mechanism of captopril. Vasodilatory kinins can also contribute, since the captopril-induced decrease in kallikrein may reflect accumulation of kinins due to their reduced metabolism.

Different excretion pattern of urinary PGE 2 and 6-keto-PGF 1α in two kidney-one clip goldblatt rats

Changes in blood pressure and 24 hour urinary excretion of PGE 2 and 6-keto-PGF 1α have been studied during ten weeks after renal artery clipping or sham operation in rats. From the second week on, systolic blood pressure was significantly increased in the two kidney-one clip rats as compared to controls. Maximal differences were reached in the 10th week after the operation (145 ± 8 vs 116 ± 3.2 mm Hg; p<0.001). Urinary PGE 2 levels showed markedly elevated values versus controls from the 6th week on (p<0.001). However, no significant changes in urinary 6-keto-PGF 1α excretion were observed between the groups during the whole experimental period. These findings suggest that renal PGE 2 may be involved in the pathophysiology of blood pressure control in the two kidney-one clip model, whereas, 6-keto-PGF 1α seems not to be altered after renal artery clipping.

Increased urinary excretion of PGE2 during inappropriate antidiuresis induced by DDAVP

Increased urinary prostaglandin E excretion (UPGE2V) and renal production of PGE2 have been implicated in the mediation of escape from inappropriate antidiuresis induced by vasopressin (AVP). AVP-induced increases in PGE2 have been linked to its pressor activity. We examined the effects of the non-pressor AVP analogue, 1,desamino-8-D-arginine vasopressin (DDAVP), on UPGE2V in a rat model of inappropriate antidiuresis in which the escape response is not apparent. A dose of DDAVP known to cause antidiuresis (10 ng/hr), was given by osmotic minipump to rats during a water diuresis established by ad libitum ingestion of 5% dextrose in water (D/W). This dose of DDAVP reduced plasma sodium (P[Na+] ) to 127 +/- 2 mEq/liter within 24 hr. P[Na+] in controls given 5% D/W alone was 151 +/- 2. In the first eight hr after DDAVP, UPGE2V was fivefold higher than in control animals, an increase which was sustained for 48 hrs. Plasma renin (PRA) was threefold higher in control rats compared to rats that had received DDAVP, consistent with volume expansion in the latter. Despite declines in P[Na+] and PRA and increased UPGE2V in DDAVP treated rats, evidence of escape from inappropriate antidiuresis (secondary decline in Uosm or rise in urine volume (V) or P[Na+] ) was lacking. Moreover, DDAVP induced similar fivefold increases in UPGE2V when given to fluid deprived rats, demonstrating that increases of UPGE2V during inappropriate antidiuresis were not mediated by volume expansion. Administration of indomethacin to volume repleted DDAVP treated rats did not significantly increase Uosmol or decrease V compared to values observed in rats receiving DDAVP alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal prostaglandins E2 and F2α throughout normal human pregnancy

Abstract. Twenty‐five normal pregnant women were studied sequentially at 4‐week intervals, beginning from weeks 8–16 until delivery. In eighteen women the study was repeated 6 weeks after delivery. The 24‐h urinary excretion of PGE2 and PGF2α plasma renin activity (PRA), plasma aldosterone and fractional excretion of sodium (FENa) were measured at each visit. PGE2 and PGF2α, increased progressively throughout pregnancy (867 ± 81 and 1048 ± 94 ng 24 h‐1 respectively, before week 15 and 1581 ± 175 and 2625 ± 305 ng 24 h‐1, respectively, after week 35) and returned to normal values 6 weeks after delivery (748 ± 107 and 1503 ± 165 ng 24 h‐1, respectively). PRA and aldosterone increased in a similar fashion, but values of prostaglandins did not correlate with those of PRA or aldosterone. PGE2 correlated directly with FENa but this correlation was weak. These results may suggest that tubulo‐interstitial prostaglandins play a role in the regulation of sodium homeostasis during pregnancy.

Effect of salt loading on blood pressure and eicosanoid metabolism of spontaneously hypertensive rats fed a fish oil enriched diet.

This study investigated the effects of dietary modification of prostaglandin (PG) synthesis on blood pressure regulation in spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats under conditions of normal and elevated salt intake. After an initial period of 4 weeks on either a 2-series PG 'inhibitory' diet of fish oil (maxEPA) or a control diet of saturated fat, half of each group received 1.5% saline for 1 week. Blood pressures were unaffected by diet during the period of normal salt intake, but following salt loading, the maxEPA-fed SHR showed a blood pressure increase (mean = 21 mmHg) relative to the EPA-fed rats on water. Rats on maxEPA showed impaired ability to generate serum thromboxane and diminished excretion of urinary 6-keto-PGF1 alpha and PGE2. SHR on water showed greater serum TXB2 generating capacity than WKY, but diminished urinary PGE2 excretion. Thus, the increased blood pressure observed in the salt-loaded SHR on the maxEPA diet may be explained by reduced renal PG synthesis resulting in either mild sodium retention and/or increased vascular reactivity.

The effect of sodium bicarbonate on the flow-dependency of urinary prostaglandin excretion in man.

The influence of oral water loading on the excretion rate of prostaglandin (PG) E was investigated in healthy human subjects in a control study where the urine was acidic (pH 5.7) and after oral sodium bicarbonate, which made the urine mildly alkaline (pH 7.2). PGE was immediately extracted from urine and measured by a radioimmunoassay technique. After sodium bicarbonate (5 g) the urinary PGE excretion rate was some three-fold higher (P less than 0.01) than in the control study, in the absence of any significant difference in the urine flow (approximately 80 ml/h). In the control study (urine pH 5.7) the urinary PGE excretion rate increased significantly (P less than 0.01) as the urine flow rose in response to the oral fluid load. However, after sodium bicarbonate, PGE excretion did not alter after the fluid load despite a 10-fold increase in urine flow. Since after bicarbonate administration PGE excretion is independent of urine flow, mildly alkaline urine may represent a condition under which renal PGE synthesis can be effectively assessed from measurements of urinary PGE excretion, in the presence of changes in urine flow. In addition, the results are compatible with the hypothesis that, in man, PGE may be passively reabsorbed in the distal nephron, and a reduction in this reabsorption could contribute to or be responsible for the dependency of the excretion rate of PGE on urine flow.

Urinary excretion of TXB 2 after angiotensin converting enzyme inhibition in hypertensive patients

Urinary excretion of thromboxane B 2 (TXB 2), a stable metabolite of thromboxane A 2 (TXA 2), was measured by radioimmunoassay in 7 essential hypertensive patients before and after a converting enzyme inhibitor, SQ 14225, administration. When a single oral dose of SQ 14225 (50mg) was given to 7 patients with essential hypertension, urinary excretion of TXB 2 was increased significantly ( from 58.9 ± 18.1 to 116.1 ± 20.7 pg/min, mean ± SE, P < 0.02 ) with simultaneous increase in plasma renin activity, urine volume, urinary sodium, urinary potassium and urinary excretion of PGE (from 58.8 ± 12.8 to 135.1 ± 30.0 pg/min, mean ± SE, P < 0.05 ). These results indicate that SQ 14225 stimulates vasoconstricting TXA 2 production as well as vasodilating PGE production.

Urinary prostaglandins and renal function in chronic liver diseases.

Changes in urinary PGE2 and PGF2 alpha excretion in chronic liver diseases were observed in relation to renal hemodynamics and sodium balance. After equilibration on a 110-170-meq sodium diet, daily urine collections were analyzed for PGE2 and PGF2 alpha by a new extraction and radioimmunoassay method. PGE2 was significantly greater in cirrhotics than in healthy subjects and in chronic hepatitis. The value was greater in cirrhotics with ascites than in those without ascites (p less than 0.05). PGF2 alpha did not differ among the groups. In cirrhotics PGE2 was correlated negatively with creatinine clearance (Ccr)(r = -0.76, p less than 0.001). After administration of 200 mg indomethacin, a significant fall in Ccr was seen only in cirrhotics with ascites. The percentage fall in PGE2 after indomethacin correlated with that in Ccr (r = 0.89, p less than 0.05) and with that in urinary sodium excretion (r = 0.68, p less than 0.02). These results suggest that PGE2 is essential in the maintenance of renal function in liver cirrhosis with ascites.

Effects of Intravenous Aspirin on Prostaglandin Synthesis and Kidney Function in Intensive Care Patients

The effects of intravenous acetylsalicylic acid (1.0 g bolus) on renal function and prostaglandin synthesis were evaluated in a prospective, controlled study in eight patients in an intensive care unit. Four of these patients had congestive heart failure. Administration of acetylsalicylic acid caused significant antidiuresis (-56%), antinatriuresis (-82%), renin suppression (-26%) and decreased GFR (-41%). All of these changes were completely reversible within 1-2 hours and tended to be more pronounced in the patients with congestive heart failure. Urinary excretion of prostaglandin E2 was depressed profoundly (-93%) and did not return to more than 45% of control 6 h after the administration of acetylsalicylic acid. We conclude that intravenous acetylsalicylic acid affects kidney function in a manner similar to other prostaglandin synthesis inhibitors. Its effects are, however, short-lived. The inhibition of urinary PGE2 excretion outlasts GFR depression, antidiuresis, antinatriuresis and renin suppression by several hours.

The effect of suppression of prostaglandin synthesis on renal function in rats with intact and reduced renal mass

The present study was undertaken to assess the role of prostaglandin system in the compensatory response to reduced nephron population, respective to renal function and electrolyte excretion. Intact and 5 6 nephrectomized rats were divided in 4 groups: 1) rats pretreated with indomethacin, 2) rats pretreated with the vehicle of indomethacin, 3) rats pretreated with sulindac, and 4) rats pretreated with the vehicle of sulindac. In normal rats, indomethacin administration resulted in a mild decrease in creatinine clearance and a significant reduction of the urinary Na excretion. In the rats with reduced renal mass treated with indomethacin, the creatinine clearance did not differ from that in the control group. The 24 h urinary sodium excretion and the fractional excretion of sodium, however, were significantly lower in the indomethacin treated animals than in the control rats. No change in the creatinine clearance or in the sodium excretion was observed in all groups pretreated with sulindac. The urinary PGE 2 and thromboxane excretion was significantly lower in the indomethacin treated intact rats and the rats with reduced renal mass. Sulindac induced a slight decrease in urinary excretion of PGE 2 in intact rats. No significant change in urinary excretion of PGE 2 or thromboxane was seen after sulindac in the rats with reduced renal mass. The antinatriuretic effect of indomethacin was dissociated from changes in urine flow in all groups of animals, suggesting that the increase in Na reabsorption tool place in a water impermeable segment of nephron. These results suggest that the compensatory increase in urinary Na excretion per nephron in rats with reduced nephron population at least partly depends on an intact prostaglandin synthesis.

URINARY PROSTAGLANDIN (PG) EXCRETION IN PRIMARY AND SECONDARY HYPERTENSION

Hypertension may be due to volume overload, the pressor effect of circulating agents such as renin or, theoretically, to reduced levels of circulating vasodilator agents. Certain prostaglandins, e.g. PGE2 are known vasodilators. The renal medulla is known to be a source of PGE2, kidney damage could therefore result in reduced production and hence contribute to the development of hypertension. Experimental work suggests that there is decreased production of PGE2 in areas of induced renal scarring. We have previously established a normal range for the 24 hour urinary excretion of PGE2, PGF2α, 6 keto PGF1α and thromboxane B2 (TXB2) and have shown that relating the values obtained to urinary creatinine (Cr) is the most useful index of PG excretion. We therefore studied a group of children with secondary hypertension (due to reflux nephropathy or renovascular disease) and compared them with normal children and with children with primary hypertension. 24 hour urine collections were obtained from hypertensive children at diagnosis, and random urine specimens collected at follow-up clinic visits. No differences were found between hypertensives and normals in the PG:Cr ratios for PGF2α, 6 keto PGF1α and TXB2. However, PGE2:Cr ratios were substantially reduced in children with secondary hypertension when compared with normal (7.7 vs 17.5 ng/mmol Cr). Children with essential hypertension had PGE2:Cr ratios at the lower end of the normal range. Our data demonstrate reduced PGE2 excretion in secondary hypertension, which may be a contributory factor in its development.

Renal prostanoids after unclipping the denervated one-kidney, one-clip hypertensive rat.

The contribution of the renal nerves in maintaining blood pressure and modulating renal prostanoid synthesis was examined in established (less than 8 wk in duration) one-kidney, one-clip (1K,1C) hypertension in the rat. Systolic blood pressure was measured for 7 days after renal denervation, at which time the renal artery clip was removed. Twenty-four-hour urinary excretion of PGE2 and 6-keto-PGF1 alpha (stable degradation product of PGI2) was determined before and after denervation and unclipping. Compared with sham-denervated rats, denervation (n = 15) resulted in a small but significant fall in blood pressure (from 216 +/- 4 to 182 +/- 4 mmHg after 48 h) and an increase in urinary 6-keto-PGF1 alpha (from 31 +/- 4 to 43 +/- 5 ng/24 h after 24 h). There was no change in PGE2 excretion. Seven days after surgery, blood pressures were similar in denervated (202 +/- 4 mmHg) and sham-denervated (211 +/- 5 mmHg) rats and fell to a similar extent 24 h after unclipping (142 +/- 3 and 147 +/- 4 mmHg, respectively). Urinary 6-keto-PGF1 alpha increased from 25 +/- 5 to 74 +/- 11 in denervated and 21 +/- 2 to 72 +/- 9 ng/24 h in sham-denervated rats in the 24 h after unclipping. PGE2 excretion increased approximately twofold over this period. These findings indicate that the renal nerves have only a minor role in established hypertension in the 1K,1C rat and that the reversal of hypertension and stimulation of renal prostanoid synthesis following unclipping is not dependent on neural mechanisms.

Role of prostaglandins and angiotensin II in experimental glomerulonephritis

Moderate autologous nephrotoxic serum nephritis (NSN) in rats causes no reduction in GFR despite a reduction in ultrafiltration coefficient (Kf) to less than one-half of normal. An increase in intraglomerular hydraulic pressure maintains GFR, but the signal and efferent mechanisms for this adaptation remain unknown. Indomethacin and saralasin were used to study the possible roles of prostaglandins and angiotensin II (A-II) in the adaptation to NSN. Indomethacin decreased renal blood flow (RBF) in NSN (-8.6%, P less than 0.001), but not in controls. Renal vascular resistance (RVR) increased in NSN (+ 9.6%, P less than 0.01), but decreased in controls (-5.6%, P less than 0.01). GFR decreased in NSN (-22.3%, P less than 0.01), but increased in controls (+ 10.3%, P less than 0.001). Urinary PGE2 excretion decreased markedly both in NSN and controls. With combined treatment using indomethacin and saralasin, RBF increased in NSN (+ 22.4%, P less than 0.001), but did not change in controls. RVR decreased in NSN (-21.5%, P less than 0.001), but was unchanged in controls. GFR remained unchanged both in NSN and controls. With saralasin alone, RBF increased both in NSN (+ 21.4%, P less than 0.001) and in controls (+ 14.4%, P less than 0.001). RVR decreased both in NSN (-21.8%, P less than 0.001) and controls (-18.7% P less than 0.001). GFR increased (+ 12.3%, P less than 0.05) in NSN, but did not change in controls. Urinary PGE2 excretion was increased in NSN compared to controls, decreased markedly in NSN after either indomethacin or saralasin infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of age, sex and potassium excretion on urinary prostaglandins in children.

Measurement of urinary 6-ketoprostaglandin (PG) F1 alpha and PGE2 excretion in 83 healthy children, aged 5-15 years, revealed that supervised 4 h urine collections under mild water diuresis provided more consistent results than overnight 12 h urine collections. Males had higher urinary excretion of 6-keto-PGF1 alpha but not of PGE2 compared with females. Urinary potassium was related to 6-keto-PGF1 alpha in both 4 and 12 h urine collections and urinary sodium to 6-keto-PGF1 alpha in 4 h collections only. In the sexes combined multiple regression analyses revealed age as the only significant influence on prostanoid excretion (P = 0.001). Thus age and sex and dietary potassium intake need to be considered in studies of urinary prostanoids in children.

Interaction of renal prostaglandins with the renin-angiotensin and renal adrenergic nervous systems in healthy subjects during dietary changes in sodium intake.

In six healthy subjects the role of renal prostaglandins (PG) in modulating the actions of the renin-angiotensin and renal adrenergic nervous systems on renal function was investigated. During high dietary sodium intake (350 mmol/day) for 4 days no changes in urinary excretion of PGE2, PGF2 alpha, noradrenaline or adrenaline were noted, whereas plasma renin activity (PRA) and urinary aldosterone excretion were suppressed. After 4 days of low sodium intake (35 mmol/day) urinary excretion of PGE2, aldosterone and noradrenaline, as well as PRA, had significantly increased. Inhibition of PG synthesis with indomethacin (2 mg/kg body weight) had no effects on renal function on day 5 of high sodium intake. Despite suppression of PRA and urinary aldosterone, indomethacin significantly reduced p-aminohippurate (PAH) clearance, glomerular filtration rate (GFR) and urinary sodium excretion on day 5 of low sodium intake, when urinary noradrenaline excretion remained high. The results point to the crucial role of the renal adrenergic nervous system in controlling renal vascular resistance and sodium conservation in healthy subjects during low sodium intake, which is unmasked when renal PG synthesis is blocked by indomethacin. Enhanced renal PG synthesis during sodium restriction therefore not only attenuates the vascular and tubular effects of the renin-angiotensin system but, more importantly, also those of the highly stimulated renal adrenergic nervous system.