The effect of sodium intake on rabbit renal prostaglandin E2 and thromboxane A2: dissociation from the renin-angiotensin system

The effects of chronic alterations in dietary sodium intake on urinary prostaglandin (PG) E2 and thromboxane (TX) B2 was investigated in the rabbit. Sodium restriction, over a 15-day period, reduced daily urinary PGE2 and TXB2 in concordance with urinary flow (V) and sodium excretion (UNa+V), but increased plasma renin activity (PRA) and plasma aldosterone concentration (PAC). Sodium repletion, on the other hand, increased urinary PGE2 and TXB2 in proportion to the rise in V, but reduced PRA and PAC. During both sodium diets PGE2 and TXB2 correlated positively with V and negatively with PRA. It is concluded that chronic sodium intake produces opposite changes in the renal prostaglandin and the renin-angiotensin systems.     

Effect of Sar1-Ileu8-angiotensin on renal prostaglandin E2 biosynthesis and excretion

To test the hypothesis that renal prostaglandin (PG) biosynthesis is regulated by angiotensin (AII), rabbits were given prolonged treatment with the AII analogue, Sar1-Ileu8AII (200 micrograms/kg/4 hr, subcutaneously), for 2 days during a low, normal, and high sodium intake. Sodium restriction augmented plasma renin activity (PRA), which was associated with a rise in basal renal PGE2 synthesis and urinary excretion, whereas sodium supplementation attenuated PRA with a decrease in renal PGE2 synthesis and urinary excretion. Sar1-Ileu8AII administration, with either a low, normal, or high salt intake, suppressed PRA. Sar1-Ileu8AII injection with a low sodium intake also suppressed renal PGE2 synthesis and excretion that was associated with a fall in blood pressure, suggesting an antagonistic action of this agent on vascular beds and renal PGE2 synthesis. On the other hand, with a high sodium intake Sar1-Ileu8-AII increased renal PGE2 synthesis and excretion as well as blood pressure, revealing an agonistic action of this compound under these conditions. The results suggest that exogenous AII analogue may act as an antagonist or agonist depending on sodium intake and endogenous AII levels, renal PGE2 synthesis is dependent on AII levels, either endogenously produced or exogenously administered (as an AII agonist), and the action of AII analogue on vascular beds and renal PGE2 synthesis does not appear to parallel its action on renin-AII feedback regulation at the juxtaglomerular cell especially under conditions of high sodium intake.     

Sulindac is not renal sparing in man

We investigated the claimed renal-sparing effect of the cyclooxygenase inhibitor sulindac. Fifteen normal women following a diet of 50 mEq salt a day were randomly assigned to 5 days of either placebo, sulindac, 200 mg b.i.d., or indomethacin, 25 mg q.i.d., after first serving as their own controls. Renal effects were assessed by the excretion rate of prostaglandin (PG) E2 (an index of renal PG synthesis), sodium balance, plasma renin activity (PRA), and the response to furosemide. Systemic effects were assessed by collagen-induced platelet aggregation and thromboxane B2 formation and by the urinary excretion of a systemically formed metabolite of PGF2 alpha (PGF-M). Both sulindac and indomethacin resulted in a positive sodium balance and a reduction in 24-hour urinary PGE2 excretion (range -49% to -86%). Basal PRA was decreased by indomethacin only, but the increases in PRA and in urinary PGE2 excretion in response to furosemide were inhibited by both sulindac and indomethacin. Sulindac reduced the natriuresis induced by furosemide, and indomethacin reduced the rise in inulin clearance after furosemide. Thus the two nonsteroidal anti-inflammatory drugs had similar effects on the kidney. Indomethacin had a greater effect than sulindac on the inhibition of collagen-induced platelet aggregation and thromboxane synthesis and the two drugs had equivalent effects on the reduction of PGF-M excretion. Peak plasma drug concentration of indomethacin (1.9 +/- 0.4 microgram/ml) and sulindac sulfide (7.7 +/- 1.9 microgram/ml) were those associated with clinical efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of oxprenolol and indomethacin on renin and aldosterone of normal subjects during low sodium diet

Abstract. To study the mechanisms underlying renin and aldosterone increase during low sodium diet, eight normal subjects were studied during normal sodium diet (5 g of NaCl per day) for 5 days, after 4 days of low sodium diet, and, on continuing low sodium diet, after randomized treatment with oxprenolol (100 mg), indomethacin (200 mg) and oxprenolol + indomethacin (100 + 200 mg) each given for 24 h with a 48 h interval between each treatment.
Renin (PRA) increased significantly after low sodium diet and the increase was inversely related to urinary sodium excretion.
Both oxprenolol and indomethacin significantly reduced PRA to values similar to those during normal sodium intake, while the combination of the two drugs showed a net additive effect on PRA. PRA decrements after either oxprenolol or indomethacin were significantly related to PRA values after low sodium diet while no correlation was present between PRA values after oxprenolol and indomethacin.
Aldosterone excretion showed a trend similar to that of PRA, being related to PRA on normal and low sodium diet, and to a lesser extent after drug treatment. These studies suggest that both the sympathetic nervous system and prostaglandins may play a permissive role in the regulation of renin and aldosterone of normal subjects on low sodium diet.     

Effects of angiotensin-converting enzyme inhibition on renal dysfunction induced by moderate potassium depletion in healthy women

Summary. The role of the renin-angiotensin system in renal hypokalaemic dysfunction has been investigated by evaluating the effects of the angiotensin(AT)-converting enzyme inhibition by enalapril. Healthy women were studied either in normal potassium balance (N3, n= 6) or moderate potassium depletion (KD3, n= 6). Potassium depletion (KD) was induced by low potassium dietary intake (10 mmol per day) and natriuretic treatment associated with replacement of net NaCl and water losses; the cumulative potassium deficit achieved was 214 54 mmol. The renal function and the urinary excretions of some prostanoids (PGE₂, 6-keto-PGF_lα, TxB₂) were evaluated during hypotonic polyuria (oral water load) and subsequent moderate antidiuresis (lysine-8-va-sopressin (LVP) low-dose infusion). Paired studies were performed in absence (control) and presence of enalapril. Basal plasma renin activity (PRA) and urinary aldosterone excretion were determined before the water load of control studies. Renal dysfunction typical of chronic KD occurred in the KD3 group, i.e. increase in PRA, decrease in creatinine clearance, depression of the diuretic response to water load, inhibition of distal fractional chloride reabsorption, and blunted efficacy of LVP in increasing the urinary solute concentration. The urinary prostanoid excretions were reduced. Basal urinary aldosterone excretion was not changed significantly. In KD3 group enalapril decreased mean arterial pressure (MAP), increased the plasma potassium concentration, improved the diuretic response to water load and corrected the impairment of the distal fractional chloride reabsorption. Despite the decrease in MAP enalapril did not affect significantly the creatinine clearance. Neither urinary prostanoid excretions nor the renal response to LVP were affected by the drug. The data suggest that in KD the increased activity of the renin-angiotensin system affected the renal function both through direct effects and through effects dependent on the angiotensin-supported secretions of aldosterone and probably of vasopressin. Finally, by comparing the effects of enalapril and indomethacin in experimental groups with an equivalent degree of KD, evidence is provided in favour of the interaction between renin-angiotensin and prostanoid systems in controlling the glomerular filtration rate and the salt and water handling by renal tubules.,     

Effects of 1-Sar-8-Ile-angiotensin II on urinary prostaglandin excretion in patients with essential hypertension

To investigate the interaction between the renin angiotensin aldosterone system and the renal prostaglandin (PG), urinary excretion of PGE, urinary excretion of main urinary metabolite (MUM) of PGF2a, urinary excretion of aldosterone, and plasma renin activity were measured before and after infusion of 1-Sar-8-Ile-Angiotensin II, a specific competitive inhibitor of angiotensin II, in 18 patients with essential hypertension under normal and low sodium diets. The values of urinary sodium excretion in these patients before the infusion of the peptide were 160.8 +/- 13.3 and 27.0 +/- 2.7 mEq per day on normal and low sodium diet, respectively. On normal sodium diet, urinary excretion of PGE was found to correlate with the level of plasma renin activity before the infusion (r = 0.6977, p less than 0.01), and it was decreased slightly from 0.37 +/- 0.05 ng/min to 0.26 +/- 0.04 ng/min after the infusion of the antagonist. On low sodium diet, urinary excretion of PGE was not significantly changed by the infusion of the peptide and showed no correlation with the level of plasma renin activity before the infusion, while urinary excretion of PGE showed a significant correlation with the excretion of urinary aldosterone (r = 0.6719, p less than 0.02). Excretion of PGF2aMUM decreased after the infusion of this peptide on both sodium diets, but the changes were not statistically significant. The present data suggest that angiotensin II influences the synthesis or release of renal PG in patients with essential hypertension on normal sodium diet, but not when they are on low sodium diet.     

Effective role of the renin-angiotensin system in the control of prostanoid synthesis and renal function in healthy women with moderate salt depletion

Summary. The interaction between moderate salt depletion and urinary excretions of prostanoids (PGE₂, 6-keto-PGF_1α and TXB₂), as well as the effective role of the activated renin-angiotensin system (RAS), in the control of renal function and urinary prostanoid excretions have been investigated in healthy women. Salt depletion (SD, n = 8) was induced by low sodium chloride dietary intake (≤60 mmol per day) and combined treatment with natriuretic and potassium sparing drugs. The cumulative sodium deficit was 381 ±55 mmol. The renal function and urinary excretion of prostanoids were evaluated during hypotonic polyuria (oral water load) and subsequent moderate anti-diuresis (lysine-8-vasopressin (LVP) low-dose infusion). Basal plasma renin activity (PRA) and urinary aldosterone excretion were determined, before the water load, in both the SD group and control studies in normal balance of sodium and potassium (N, n = 20). Paired studies were performed in the absence and in the presence of enalapril in the same SD group, as well as in a subgroup, with normal sodium and potassium balance, previously studied (N3, n = 6).     

Renal prostaglandins in cirrhosis of the liver

Urinary prostaglandin excretion was studied in 42 patients with liver cirrhosis and in nine control subjects on restricted sodium intake and on bed rest. Creatinine clearance (CCr), sodium excretion (UNaV), plasma renin activity (PRA) and plasma aldosterone were also evaluated. Patients without ascites and ascitic patients without renal failure showed increased urinary excretion of immunoreactive 6-ketoprostaglandin F1 alpha (i6-keto-PGF1 alpha), prostaglandin E2 (iPGE2) and thromboxane B2 (iTXB2) when compared with controls, while immunoreactive PGF2a (iPGF2 alpha) levels did not differ from those in the control group. Patients with functional renal failure (FRF) presented a significant reduction of vasodilator prostaglandins but urinary excretion of iTXB2 was higher than in controls. On the whole, cirrhotic patients with higher urinary excretion of prostaglandins had normal or nearly normal PRA and aldosterone levels. i6-keto-PGF1 alpha and iPGE2 inversely correlated with PRA and aldosterone. The relationship between i6-ketoPGF alpha alpha and CCr was found to be highly significant in cirrhotic patients but not in the control group. On the other hand, iPGE2 significantly correlated with UNaV and with the fractional excretion of sodium (FENa). We concluded that: (a) enhanced renal prostaglandin synthesis in cirrhosis, inversely related to PRA and aldosterone, may be dependent on volume status; and (b) preserved renal function in these patients is associated with the ability to synthesize prostacyclin and PGE2.     

Renal prostanoids: physiological relevance in healthy salt-depleted women

The effective role played by prostanoids in the control of renal function has been investigated in healthy women with salt depletion. Salt depletion (SD2 group, n = 6) was induced by low sodium chloride dietary intake (≤60 mmol per day) and combined treatment with natriuretic and potassium-sparing drugs. At the end of the depletive treatment, the cumulative sodium deficit was 513 ± 56 mmol. The renal function and urinary excretions of prostaglandin (PG) E₂, 6-keto-PGF_1α (6KPGF) and thromboxane (Tx) B₂ were evaluated during hypotonic polyuria. The basal values of plasma sodium and potassium concentrations, plasma renin activity (PRA) and urinary aldosterone excretion were determined before the induction of hypotonic polyuria. Paired studies were performed in the absence (control) and presence of indomethacin both in the SD2 group and in a previously studied group (N2, n = 6) of healthy women in normal sodium and potassium balance. Women in normal balance received 100 mg i.m. of indomethacin, salt-depleted women received only 50 mg (because 100 mg of the drug produced a prolonged anuria). In the SD2 vs. N2 group in the absence of treatment the following significant differences were found: (a) higher basal values of PRA and urinary aldosterone excretion; (b) higher urinary excretions of 6KPGF and TxB₂ but not of PGE₂; (c) lower values of urinary flow rate, creatinine clearance, absolute and fractional excretions of sodium and chloride, plasma osmolality and plasma electrolyte concentrations. The effects of the indomethacin have been assessed as percentage variations by using paired data for each experimental group. In the SD2 vs. N2 group the reduction in urinary excretions of 6KPGF, TxB₂ and potassium as well as in creatinine clearance were not significantly different. On the other hand, the following were significantly different: (a) the lower reduction in PGE₂ excretion; (b) the higher reduction in urinary flow rate and in C_H2O; (c) the reductions in absolute and fractional excretions of sodium and chloride, and the increase in plasma potassium concentration, significant in the SD2 group but not in the N2 group. The data suggest that: (1) when stimulated by salt depletion the renal biosynthetic pathways of PGI₂ and TxA₂ showed greater sensitivity to indomethacin inhibition; (2) the effects of the neurohormonal systems activated by salt depletion were either modulated or mediated by renal prostanoids.     

Hormonal and renal responses to neutral endopeptidase inhibition in normal humans on a low and on a high sodium intake

Abstract. Hormonal and renal effects of candoxatril, a neutral endopeptidase 24.11 inhibitor, were investigated in eight subjects equilibrated on a low sodium diet (10 mmol sodium per day) and a high sodium (350 mmol per day) diet. After candoxatril treatment, plasma ANP increased to a maximum at 2–4 h and declined to baseline within 24 h. The increases were relatively greater on the high sodium diet, which was also associated with increases in urinary sodium, with highest values at 4h. On the low sodium diet, the magnitude of the changes was significantly lower (24 h cumulative sodium excretion was 11.4± 5.5 mmol on the low sodium diet and 73.1± 25.6 mmol on the high sodium diet; P < 0.01). There were no significant effects on urinary potassium excretion, creatinine clearance or haematocrit. After candoxatril treatment there were reductions in PRA, especially on the low sodium diet. On either diet there were no effects on systemic blood pressure. These results demonstrate that dietary sodium intake is an important determinant of the renal and hormonal responses to neutral endopeptidase inhibition.     

Response of urinary angiotensin to challenges of the renin-angiotensin system

Angiotensin has an intrarenal action which may not parallel its action in the general circulation. We investigated whether the urinary excretion rates of angiotensin I and II (UV-AI, UV-AII) can be used as a marker of renal production. We therefore measured UV-AI, UV-AII, plasma angiotensin I and II (PAI, PAII), and plasma renin activity (PRA) in healthy subjects under conditions influencing the renin-angiotensin system: captopril injection (n = 7), enalapril treatment (n = 9), furosemide infusion on high and low sodium intake (n = 6), indomethacin treatment (n = 8), and head-out water immersion (three sodium intakes). After captopril (acute) and enalapril (chronic), PAI and PRA increased, PAII decreased, but neither UV-AI nor UV-AII changed. During furosemide infusion, PAI, PAII, PRA, as well as UV-AI and UV-AII increased. During indomethacin treatment, PAI, PAII, and PRA decreased, whereas UV-AI and UV-AII did not change consistently. Sodium restriction increased PAI, PAII, and PRA, but did not alter UV-AI and UV-AII. Head-out immersion decreased PAI, PAII, and PRA, but did not change UV-AI and UV-AII. The relative constancy of the urinary AI and AII excretion rates makes it doubtful whether urinary angiotensins reflect changes of renal angiotensin production.     

Acute renal effects of sulindac and indomethacin in chronic renal failure

The effects of 2 days of oral dosing with sulindac (200 mg twice a day) or indomethacin (75 mg twice a day) on glomerular filtration rate, urinary excretion of prostaglandin E2, sodium homeostasis, and other renal function parameters were investigated in eight patients with chronic stable impaired renal function. Indomethacin reduced creatinine clearance (from 41.0 +/- 7.9 to 30.3 +/- 6.3 ml/min) and increased serum levels of creatinine and beta 2-microglobulin. Sulindac had no effect on any of these parameters. Both drugs induced depression of urinary prostaglandin E2 excretion; this depression was greater after indomethacin. Urinary sodium excretion fell from 144.4 +/- 18.7 to 85.5 +/- 9.7 mmol/24 hr after indomethacin and from 131.7 +/- 11.6 to 103.4 +/- 13.3 mmol/24 hr after sulindac. Body weight increased 1.2 kg after indomethacin but was not changed by sulindac. Plasma renin activity was reduced from 2.3 +/- 0.8 to 1.7 +/- 0.6 nmol/L/hr by sulindac and from 2.8 +/- 0.8 to 1.5 +/- 0.5 nmol/L/hr by indomethacin. Urinary N-acetyl-beta-glucosaminidase and kallikrein excretion was not changed by either drug. Our data suggest that sulindac affects renal prostaglandin E2 synthesis and sodium excretion in patients with severe renal failure to a lesser extent than does indomethacin. Sulindac still seems to be the drug of choice in this group of patients, but glomerular filtration rate, body weight, and electrolyte balance should be carefully monitored.     

Effect of sulindac on prostaglandin synthesis in human and in cultured rat renal and vascular smooth muscle cells.

To examine the hypothesis that sulindac does not inhibit renal prostaglandin (PG) synthesis, we investigated the effects of sulindac and other nonsteroidal anti-inflammatory drugs on PG synthesis in human and in cultured rat renal and vascular smooth muscle (VSM) cells. In 7 patients with chronic glomerular disease, creatinine clearance and proteinuria were not changed by sulindac but were significantly reduced by diclofenac sodium. However, urinary excretion of PGE2 was decreased by both drugs. In cultured glomerular mesangial (GM), renal papillary collecting tubule (RPCT) and VSM cells from mesenteric artery, indomethacin, tiaprofenic acid, aspirin and ibuprofen inhibited both basal and arachidonic acid (AA)-stimulated PG synthesis dose-dependently. Although sulindac sulfoxide, at the same concentrations, inhibited both basal and AA-stimulated PGE2 synthesis in RPCT cells, it was less potent to inhibit PGI2 synthesis in VSM cells or PGE2 synthesis in GM cells. Active form sulindac sulfide inhibited PG synthesis in all types of cells but its inactive form sulfone did not. We conclude that sulindac inhibits renal PG synthesis but has little effect on renal function. This may be explained by its relatively weak potency on glomerular or vascular PG synthesis inhibition possibly due to the different biotransformation of the sulfoxide to the active sulfide in these cells.     

Effects of sulindac and indomethacin on renal prostaglandin synthesis

We compared the effects of sulindac and indomethacin, the effects of two nonsteroidal anti-inflammatory drugs, on renal prostaglandin synthesis and renal function. Sulindac, 200 mg twice daily, indomethacin, 25 mg four times a day, or placebo were taken by 15 normal female subjects (five in each of three treatment groups). Indomethacin decreased renal excretion of prostaglandins PGE2, PGF2 alpha, and 6-keto-PGF1 alpha, but sulindac and placebo had no effect on renal prostaglandin excretion. Concomitant with the reduction of renal prostaglandin synthesis in the indomethacin group, sodium and chloride excretion decreased; sulindac and placebo had no discernible effects on urine electrolytes. Extrarenal cyclooxygenase activity, as assessed by platelet thromboxane beta 2 release, was inhibited by both sulindac and indomethacin. Plasma renin activity and plasma aldosterone levels fell in all groups as a result of positive sodium balance, but the decrements of aldosterone were greater after indomethacin and sulindac. None of the treatments altered glomerular filtration rate or renal plasma flow in these normal women. We conclude that in normal women renal prostaglandin synthesis and prostaglandin-dependent tubular functions such as Na and Cl reabsorption are relatively unaffected by doses of sulindac (200 mg twice daily) that inhibit nonrenal cyclooxygenase. This may reflect the capacity of oxidative enzymes in the kidney to convert the active sulfide metabolite of sulindac to the inactive prodrug sulindac sulfoxide.     

Inhibition of prostaglandin synthesis by indomethacin interacts with the antihypertensive effect of atenolol

The interaction of inhibition of prostaglandin (PG) synthesis by indomethacin (75 mg/day) with the antihypertensive effect of atenolol (50 mg b.i.d.) was studied in 11 untreated otherwise healthy men 35 to 45 years old with essential hypertension. Atenolol for 3 weeks decreased supine blood pressure (BP) from 157/109 mm Hg during placebo to 148/97 mm Hg. Indomethacin alone for 1 week slightly increased BP and antagonized the antihypertensive action of atenolol. Atenolol reduced plasma renin activity (PRA) to 40% but did not modify either the urinary excretion of vasodilatory PGs (PGE2 and prostacyclin measured as 6-keto-PGF1 alpha) or plasma kininogen and urine kallikrein. Indomethacin suppressed PRA to 27% and PG excretion to approximately 70% but did not markedly change plasma kininogen and urine kallikrein excretion. The decreased excretion of 6-keto-PGF1 alpha, the metabolite of the main vasodilatory prostanoid prostacyclin, correlated with the increased BP measured in standing subjects. The effects of indomethacin were practically the same when given with atenolol as when given alone. We conclude that the slight increase in BP by indomethacin in essential hypertension is associated with the reduced production of vasodilatory PGs but not with alterations in activities of the renin-angiotensin or kallikrein-kinin systems.     

Time-course and relationship of the early changes in renal sodium excretion and aldosterone secretion during dietary sodium restriction in normal man

1. The fall in renal sodium excretion after dietary sodium restriction is prompt and reproducible. The importance of increased aldosterone secretion during the early phase (within 48 h) of this response is unclear. Using two indirect measures of aldosterone secretion (in urine and saliva), we have tried to relate changes in excretion and concentration of this hormone to renal sodium excretion during the abrupt transition from a normal (approximately 150 mmol/day) or high (260 mmol/day) to a low (5-25 mmol/day) sodium intake in 11 and seven male volunteers, respectively. 2. All subjects showed reduced renal sodium excretion within 36 h of dietary restriction, but the times at which increases in renal aldosterone excretion, saliva aldosterone concentration and plasma renin activity became statistically significant varied widely (8-72 h, 2.5- greater than 62.5 h and less than 4- greater than 38 h for renal aldosterone secretion, saliva aldosterone concentration and plasma renin activity, respectively). Circadian fluctuations in saliva aldosterone concentration were apparent and increased in amplitude during sodium restriction. 3. Urine flow rate tended to increase on the first day of sodium restriction and this reached statistical significance in the group initially on a high sodium intake (64.0 +/- 8.8 to 84.3 +/- 11.2 ml/h, P less than 0.01); although the pattern of urine flow did correlate with plasma arginine vasopressin concentration (r = -0.49, P less than 0.01), there was no significant decrease in mean plasma arginine vasopressin concentration [1.15 (0.92-1.44) to 0.90 (0.72-1.12) pmol/l, P = 0.08; geometric mean and 95% confidence limits].(ABSTRACT TRUNCATED AT 250 WORDS)     

Urinary prostaglandin and sodium metabolism in patients with essential hypertension

Urinary prostaglandin E (PGE) excretion as an indicator of renal PGE, urinary aldosterone excretion, plasma renin activity, urinary sodium excretion, and urinary potassium excretion were measured after sodium depletion in 15 patients with essential hypertension to investigate the interaction between renal PGE and sodium metabolism. Following sodium depletion, urinary PGE excretion decreased, whereas urinary aldosterone excretion and plasma renin activity increased. Significant positive correlations were found between urinary PGE excretion and urinary sodium excretion (r=0.41, p less than 0.01) or urinary sodium excretion-urinary potassium excretion ratio (r = 0.43, p less than 0.005). These results support the hypothesis that the renal PGE may play an important role in the regulation of sodium metabolism and this action of PGE is independent of the renin-aldosterone system.     

Urinary kallikrein and plasma renin activity as determinants of renal blood flow. The influence of race and dietary sodium intake.

We investigated the relationship of the kallikrein-kinin system and the renin-angiotensin system in the regulation of blood pressure, salt and water excretion, and renal blood flow. Normotensive and hypertensive black and white men were studied during unresticted sodium intake as well as on a 10-meq/day sodium intake; potassium intake was held constant throughout the study (80 meq/day). During unrestricted sodium intake, urinary kallikrein activity was greater in white normotensives than white hypertensives or black normotensives. There was no difference (P greater than 0.05) between white and black hypertensives or between black normotensives and black hypertensives. All groups had greater urinary kallikrein activity on low sodium vs. unrestricted sodium intake, but the increase in black hypertensives was small, and they excreted significantly less kallikrein than the ogher groups on the low sodium diet. Plasma renin activity showed similar increments after sodium restriction in all groups. Urinary kallikrein activity correlated with renal blood flow in all groups except the black normotensives on low sodium intake. Renal blood flow could be correlated uniformly with log (urinary kallikrein activity/supine plasma renin activity) in all groups on either diet. Urinary sodium and potassium excretion and urine volume were not different among the groups. We conclude: (a) important racial differences exist in urinary kallikrein activity that are unrelated to sodium or potassium excretion or urine volume; (b) dietary sodium restriction further delineates racial differences and suggests alternative pathophysiologic mechanisms for huma hypertension; (c) urinary kallikrein activity correlates with renal blood flow; and (d) our data support the concept that the kallikrein-kinin system and the renin-angiotensin system contribute to the regulation of renal blood flow and may account for racial differences in renal vascular resistance.     

The contribution of PGI2 to the effects of captopril in conscious dogs in differing states of sodium balance

There is some evidence that increased prostaglandin synthesis may mediate some of the effects of the angiotensin converting enzyme inhibitor captopril. The potential role of prostaglandin (PG)I2 in this process was assessed by measurement of changes in urinary 6-keto-PGF1 alpha excretion after captopril in eight sodium replete and depleted conscious dogs. In sodium replete animals captopril induced a small decrease in blood pressure, transient increases in effective renal plasma flow and urinary 6-keto-PGF1 alpha excretion, and progressive increases in plasma renin activity (PRA) and urinary sodium excretion. By contrast, during sodium depletion captopril induced a large decrease in blood pressure, a transient increase in effective renal plasma flow and urinary 6-keto-PGF1 alpha excretion, an early large but transient increase in PRA and small progressive increase in sodium excretion. The time course of changes after captopril suggested that increased PGI2 synthesis may contribute to the transient decrease in renal vascular resistance. The increase in PRA during sodium depletion was not associated with any change in urinary 6-keto-PGF1 alpha excretion.     

Urinary noradrenaline excretion and renal function in normal and hypertensive 50-year-old men.

1. Sympathetic nervous system activity, measured by urinary noradrenaline excretion, was determined in a group of untreated hypertensive subjects (n = 35), a reference group (n = 80) and a normotensive group (n = 51), all derived from a random population sample of 50-year-old men. It was compared with casual and resting blood pressure, urinary sodium excretion, urinary cretinine concentration and glomerular filtration rate. Hypertension was defined as systolic pressure greater than 175 or diastolic greater than 115 mmHg on two separate occasions. Normotension was defined as systolic pressure less than 160 and diastolic pressure less than 95 mmHg. 2. There was no difference in the average excretion of noradrenaline during the day or night between the reference, normotensive and hypertensive groups. None of the hypertensive patients had values for urinary noradrenaline excretion during the day above the range found in normotensive subjects, indicating that hypertension with increased sympathetic nervous system activity is uncommon when hypertension in defined as above. 3. No correlation between urinary noradrenaline excretion during the day and blood pressure was found in the reference group or in the normotensive group. In the hypertensive group, there was a negative correlation between urinary noradrenaline excretion and blood pressure after rest. This finding might indicate that factors other than sympathetic nervous system activity determine the level of blood pressure in hypertensive subjects. 4. In the hypertensive group, urinary noradrenaline excretion during the day was positively correlated with both urinary sidium excretion during the day and glomerular filtration rate. Urinary noradrenaline excretion per 24 h was positively correlated with urinary sodium excretion during the same time. High resting blood pressure, low urinary sodium excretion, low glomerular filtration rate and a reversed diurnal rhythm of urinary excretion characterized hypertensive patients with low urinary noradrenaline excretion, indicating more severe hypertension in these hypertensive patients with reduced sympathetic nervous system activity.