Effect of L-arginine infusion in normotensive subjects with and without a family history of hypertension

BACKGROUND: Experimental studies have shown that nitric oxide (NO) generation in the kidney from L-arginine participates in the regulation of renal function. Our purpose was to study the effect of infusion of L-arginine (1, 5, and 10 mg/kg/min) on blood pressure (BP), renal hemodynamics, and urinary excretion of sodium and albumin in normotensive subjects with a family history of either severe hypertension (FHSH, N = 17) or mild hypertension (FHMH, N = 20) and in control subjects (N = 18) without a hereditary predisposition for hypertension. METHODS: The glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured by renal clearances of Cr51 ethylenediaminetetraacetic acid and paramino-hippurate. Renal tubular reabsorption of sodium was estimated by lithium clearance. To evaluate the effect of L-arginine infusion on the L-arginine/NO pathway, we measured the NO-metabolite nitrate in plasma, and urinary excretion of cGMP, the second messenger of NO. The derivative at an L-arginine dose of 7.5 mg/kg/min was used as a measure of sensitivity to L-arginine. RESULTS: There was no difference in baseline systolic BP between the groups, but diastolic BP was significantly higher in FHSH compared with control subjects (P < 0.05). L-arginine caused a significant increase in urine flow, urinary excretion of albumin and sodium, and lithium clearance in all groups. FHSH showed a significantly decreased sensitivity to L-arginine with respect to urine flow rate (P = 0029) compared with FHMH and control subjects. L-arginine caused a significant decrease in the GFR in FHSH (P < 0.02) and control subjects (P < 0.001), but in FHMH, the decrease did not reach statistical significance (P = 0.097). There was no difference in sensitivity to L-arginine with respect to BP, RPF, or GFR between the three groups. In all patients, there was a significant positive relationship between Delta urine flow rate or Delta urinary sodium excretion and Delta GFR during infusion of L-arginine (P = 0.003 and P = 0.03, respectively). Plasma nitrate and urinary cGMP decreased in all groups during the L-arginine infusion. CONCLUSION: L-Arginine infusion in normotensive subjects caused an enhanced urine flow rate and urinary sodium and albumin excretion and a slight reduction in GFR. The effect of L-arginine on the urine flow rate was significantly less pronounced in subjects with a family history of severe hypertension, which may indicate a tubular disturbance in hypertension.     

Renal tubular function in cirrhotic patients with ascites: special reference to lithium clearance following the human atrial natriuretic peptide administration]

Synthetic alpha-human atrial natriuretic peptide (alpha-hANP), 1 micrograms/kg, was intravenously given to 16 cirrhotic patients with ascites and 9 control subjects (CS) to investigate major factors responsible for sodium retention and refractory ascites. The following parameters were measured before and after alpha-hANP administration; such as lithium clearance (CLi) as an index of fluid delivery to the distal tuble, mean arterial pressure (MAP), urinary sodium excretion rate (UNaV), urine volume (V), glomerular filtration rate (GFR), effective renal plasma flow (ERPF), plasma renin activity (PRA), plasma aldosterone concentration (PAC), urinary excretion of prostaglandin (PG)E2, 6-keto-PGF1 alpha (6-k-PGF1 alpha), and thromboxane B2 (TxB2). Patients were divided following alpha-hANP administration into 2 groups as "good responders (GR)" and "poor responders (PR)", in which GR was defined as the group showing 2-fold-increase in UNaV. In contrast, PR had significant lower MAP (71.8 +/- 5.04 mmHg), GFR (21.3 +/- 3.90 ml/min), ERPF (158.0 +/- 43.8 ml/min), FELi (CLi/GFR; 12.6 +/- 1.26%), and higher PRA (8.72 +/- 0.99 ng/ml/h) and PAC (12.2 +/- 3.13 ng/dl) than GR. GR demonstrated almost same natriuretic response as CS with an increase of GFR and renal PGs synthesis, and a decrease of FELi despite reduction in blood pressure. However, alpha-hANP did not suppress PRA, PAC, and distal tubular reabsorption of sodium (FDRNa = 1-FENa/FELi) in cirrhotic patients, whereas suppressed in CS. UNaV correlated with FELi (r = 0.687, p = 0.01) and GFR (r = 0.777, p = 0.01). PRA correlated with FELi r = 0.669, p = 0.015), GFR (r = -0.634, p = 0.018), and MAP (r = 0.858, p = 0.001) only in cirrhosis. These results therefore indicated that hypotension caused by hemodynamic alteration and extremely stimulated renin release might effect on proximal tubular sodium reabsorption and GFR, leading to sodium retention and diuretic resistance in cirrhosis.     

Subpressor dose asymmetric dimethylarginine modulates renal function in humans through nitric oxide synthase inhibition

Increased blood concentrations of the endogenous nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine (ADMA) have been linked to high blood pressure and to cardiovascular mortality. We evaluated the effects of a subpressor ADMA dose on NO production, renal hemodynamics, sodium handling and active renin and noradrenalin plasma concentrations in 12 healthy subjects (age 26 +/- 1 year) using a double-blind placebo-controlled study design. Infusion of ADMA caused a significant decrease in plasma cyclic guanosine monophosphate (cGMP) levels, i.e. the second messenger of NO (from 6.1 +/- 0.4 to 4.3 +/- 0.3 pmol/l; p < 0.05). In parallel, effective renal plasma flow (ERPF) decreased while renovascular resistance (RVR) increased significantly (ERPF from 667 +/- 9 to 603 +/- 10 ml/min/1.73 m2; RVR from 79 +/- 2 to 91 +/- 2 ml/min/mm Hg; both p < 0.05 vs. baseline). Infusion of placebo did not cause significant changes in plasma cGMP levels, ERPF and RVR (cGMP from 5.7 +/- 0.5 to 5.9 +/- 0.6 pmol/l; ERPF from 665 +/- 12 to 662 +/- 11 ml/min/1.73 m2; RVR from 79 +/- 2 to 78 +/- 2 ml/min/mm Hg; all non-significant). Moreover, urinary sodium excretion was significantly lower with infusion of ADMA as compared with placebo infusion (128 +/- 8 vs. 152 +/- 7 micromol/min; p < 0.05). In contrast, blood pressure, active renin and noradrenalin plasma concentrations did not change significantly with either infusion protocol. Acute infusion of a subpressor ADMA dose modulates several aspects of renal function in humans without affecting the activity of the renin-angiotensin and sympathetic system. Whether chronic (intrarenal) NO synthase inhibition in individuals with increased ADMA blood levels may cause persistent renal vasoconstriction and sodium retention must be evaluated.     

Renal and metabolic effects of L-arginine infusion in kidney transplant recipients.

AIM AND METHODS: In order to investigate the role of kidney damage on renal response to L-arginine (L-Arg) infusion in transplant patients receiving cyclosporine A (CsA) treatment, we assessed systemic and glomerular hemodynamic variables, the fraction excretion of urinary sodium, albumin, cyclic GMP (as an index of nitric oxide (NO) production from L-Arg) and urea excretion (as an index of ureagenesis), and glucoregulatory hormone levels in five normal volunteers and 21 renal allograft recipients (aged 10-20 years) treated with CsA, 10 with normal renal function and 11 with chronic renal insufficiency. RESULTS: In the normal subjects, L-Arg infusion (290 mg/min/1.73 m2 for 1 h) significantly reduced mean arterial pressure (MAP) (76+/-7 to 70+/-5 mmHg) and renal vascular resistance (RVR), and increased GFR (103+/-9 to 122+/-7 min/1.73 m2), RPF, urinary cyclic GMP excretion (0.40+/-0.1 to 0.60+/-0.1 nmol/100 ml glomerular filtrate (GF)), and sodium and albumin excretion. Neither the patients with chronic graft dysfunction nor those with a normal graft responded to L-Arg infusion: RVR remained high, and MAP, GFR, RPF, fractional excretion of sodium and urinary excretion of albumin and cyclic GMP were unchanged in both groups of patients. Glucagon, insulin and urinary urea excretion rose significantly in controls and both patient groups. CONCLUSION: The hemodynamic effects of L-Arg infusion were inhibited in the patients, regardless of their degree of renal function, possibly because L-Arg-NO production was blunted.     

Significance of renal dopamine on pathogenesis of essential hypertension

In order to clarify the role of renal dopaminergic activity in renal sodium-water metabolism, the effects of oral administration of L-DOPA (400 mg), were studied on blood pressure (BP), plasma renin activity (PRA), plasma aldosterone concentration (PAC), urinary volume (UV), urinary excretion of sodium and lithium (UNa and ULi) in 11 normal subjects (N) and 32 patients with essential hypertension (EH). EH were divided into the salt sensitive (SS) and non salt-sensitive (NSS) groups by response of mean blood pressure (10% increase) after administration of NaCl. The change of UNa, PRA, and PAC after administration of NaCl were lower in SS than in NSS. After administration of L-DOPA, BP falled and UV, UNa, FENa, FELi and Ccr increased in both N and EH. The change of these factors were greater in SS as compared with those in NSS. These results suggest that in SS patients the suppression of water-sodium handling in the kidney might be due to depression of renal dopaminergic activity. Renal dopaminergic activity may play an important role in the pathogenesis of EH.     

Antihypertensive effect of a non-peptide angiotensin II receptor antagonist, MK954, in patients with essential hypertension]

We examined the chronic effects of MK954, a novel orally active angiotensin II receptor antagonist, on blood pressure and renal function in 8 patients with essential hypertension for 2-4 weeks. All patients, four men and four women, 48.0 +/- 15.3 year-old (mean +/- SD), were hospitalized and given normal sodium diet (NaCl 10 g/day). After a control period with placebo for one week, MK954 was administered orally at 8 AM every day. The initial dose of MK954 was 12.5 mg/day, then the dose was increased up to 100 mg/day until diastolic blood pressure fell below 90 mmHg. The average dose was 59.4 +/- 43.7 mg/day. Casual blood pressure in supine position decreased significantly from 161.0 +/- 6.6/95.0 +/- 3.5 mmHg to 145.8 +/- 8.1/83.3 +/- 3.7 mmHg without any change in pulse rate. Non-invasive ambulatory blood pressure monitoring revealed that once daily administration of MK954 lowered blood pressure for 24 hours but did not affect circadian rhythm or variability of blood pressure. Reduction of blood pressure was slightly greater during day time than during sleeping time. Unlike a peptide angiotensin II antagonist, there was no pressor action of MK954 as agonist. No significant alternations were observed in body weight, serum electrolytes, creatinine clearance, urine volume or urinary excretion of sodium. Plasma renin activity (PRA) rised significantly after MK954 treatment but plasma aldosterone concentration (PAC) did not change. The reasons why PAC was not reduced are unclear. The doses of MK954 employed in this study might be insufficient to inhibit adrenal angiotensin II receptor. In conclusion, MK954 has long acting hypotensive effect in essential hypertension without affecting renal function.     

Effect of indomethacin on renal function and plasma renin activity in dogs with chronic renovascular hypertension

The effect of indomethacin on plasma renin activity (PRA) and renal function was examined in conscious dogs with chronic renovascular hypertension before or after volume expansion. PRA did not change following the infusion of indomethacin: PRA was 5.18 +/- 1.46 ng/ml/h during control periods and was 5.01 +/- 0.95 ng/ml/h (p greater than 0.1) after 80 min of infusion of indomethacin. Mean arterial blood pressure (MABP) was 121.6 +/- 7.4 mm Hg during control periods and was 122.0 +/- 4.6 mm Hg (p greater than 0.1) after 80 min of infusion of indomethacin. Infusion of indomethacin into these dogs undergoing diuresis did not change inulin or p-aminohippuric acid clearance. Sodium excretion (UNaV) showed slight but not signifcant decreases with the infusion of indomethacin. UNaV was 109.3 +/- 25.7 muEq/min during control periods and was 69.6 +/- 21.0 muEq/min (0.05 less than p less than 0.1) after 80 min of infusion of indomethacin. The results suggest that renin release, sodium excretion, and blood pressure in the dog with chronic renovascular hypertension in uninfluenced by indomethacin.     

Nitric oxide synthesis inhibition does not impair water immersion-induced renal vasodilation in humans

Nitric oxide (NO) is tonically released in the kidney to maintain renal perfusion and adequate sodium and water clearance. Little is known about the role of NO in the renal adaptation to an acute volume challenge. This is important for our understanding of pathophysiologic conditions associated with impaired NO activity. This study examined the effects of NO synthesis inhibition on neurohumoral, renal hemodynamic, and excretory responses to head-out immersion (HOI). Seven healthy men underwent four 7-h clearance studies. One study served as a time control study (placebo infusion), and in one study N(G)-monomethyl-L-arginine (L-NMMA; 3 mg/kg priming dose + 3 mg/kg per h) was infused during hours 2 to 5. In a third and fourth clearance study, HOI was applied from hours 3 to 5, during infusion of either placebo or L-NMMA. To assess the degree of NO synthesis inhibition, the effect of L-NMMA on [(15)N]-arginine-to-[(15)N]-citrulline conversion rate was studied in four others. HOI decreased mean arterial pressure (MAP) from 87 +/- 3 to 76 +/- 2 mmHg and renal vascular resistance (RVR) from 82 +/- 6 to 70 +/- 7 mmHg. min/L, and increased sodium excretion (UNaV) from 110 +/- 27 to 195 +/- 29 micromol/min and flow (UV) from 14.4 +/- 1.4 to 15.8 +/- 1.4 ml/min. L-NMMA caused profound and sustained increases in MAP and RVR and decreases in UNaV and UV. HOI superimposed on L-NMMA infusion decreased the elevated MAP from 93 +/- 4 to 83 +/- 2 mmHg and RVR from 111 +/- 9 to 95 +/- 7 mmHg. min/L, and increased UNaV from 41 +/- 8 to 95 +/- 15 micromol/min and UV from 10.0 +/- 1.1 to 12.7 +/- 1.4 ml/min. The relative changes were not significantly different from the effects of HOI without L-NMMA infusion. HOI decreased plasma renin activity and aldosterone and increased plasma atrial natriuretic peptide and urinary cGMP. L-NMMA decreased urinary cGMP, but did not affect the plasma hormones or the changes induced by HOI. L-NMMA decreased the [(15)N]-arginine-to-[(15)N]-citrulline conversion rate to one-third of baseline. The results indicate that in a state of NO deficiency in humans, the kidney can still respond to an acute volume challenge with vasorelaxation, diuresis, and natriuresis.     

Insulin and hypertension--the mechanisms of high blood pressure during chronic insulin infusion

The purpose of this study was to assess the effects of chronic insulin infusion on blood pressure and urinary sodium excretion in Wistar rats. Fifteen Male Wistar rats weighing about 220 g were used. The rats were housed in metabolic cage and measured urine volume. Osmotic minipumps filled with insulin (0.57 U/day, Insulin group, n = 9) or saline (0.014 cc/day, Control group, n = 6) were implanted subcutaneously under ether anaesthesia, and blood pressure, urine volume, urinary sodium excretion (UNaV), plasma renin activity (PRA), plasma norepinephrine concentration (PNE) were measured for 4 weeks. In insulin group, there were no significant changes on plasma glucose levels, but systolic blood pressure rose significantly from 119 mmHg to 140 mmHg after 4 weeks. In this group, urine volume, UNaV, and PRA were significantly lower than those of control group and PNE was tended higher but not significant (P less than 0.1). Exogenous NE was given intravenously to assess the endogenous NE activity. Blood pressure elevation caused by exogenous NE in insulin group was suppressed significantly than that of control group. On the basis of these findings, we conclude that insulin can cause high blood pressure due to sodium retention and activation of endogenous NE.     

Effects of Prenalterol on Renal Function in Normal Man

The effects of prenalterol infusion, 0.5 microgram/kg/min, on renal function were studied in 10 male volunteers. Systolic blood pressure increased by 22 mmHg (P less than 0.01) and diastolic pressure decreased by 11 mmHg (P less than 0.01). Heart rate increased by 11 beats/min (P less than 0.01). Plasma catecholamine levels and plasma renin activity were not altered. Renal haemodynamics were unchanged. Urine flow rate and fractional free water excretion decreased by 29% and 45%, respectively (P less than 0.01). Fractional sodium excretion increased by 19% (P less than 0.01) and fractional potassium excretion fell by 33% (P less than 0.05).     

Paradoxical increase in nitric oxide synthase activity in hypercholesterolaemic rats with impaired renal function and decreased activity of nitric oxide.

BACKGROUND: We have shown that acute exposure of oxidized low-density lipoprotein (OX-LDL) induces vasoconstriction in renal vessels and reduces glomerular filtration rate (GFR) in an isolated perfused rat kidney model by decreasing the activity of nitric oxide (NO). L-arginine has a protective role against OX-LDl-induced vasoconstriction. Micropuncture studies have demonstrated that short-term diet-induced hypercholesterolaemia is associated with decreased GFR and renal blood flow and increased glomerular capillary pressure. This may be mediated by decreased activity of NO. METHODS: Rats were made hypercholesterolaemic by supplementing the standard chow with 4% cholesterol and 1% sodium cholate. A group of rats on hypercholesterolaemic diet also received L-arginine in the drinking water. After 4 and 6 weeks, blood samples and 24-h urine samples were collected for the measurement of biochemical parameters. After 6 weeks, all rats were subjected to isolated perfusion of kidneys at a constant pressure of 100 mmHg. During isolated perfusion, the unused contralateral kidney was taken for morphological studies and for assessing the activity of nitric oxide synthase enzyme by beta-NADPH diaphorase histochemistry. RESULTS: Rats fed a high-cholesterol diet had LDL levels 3-6 times greater than the rats fed standard chow. Rats that received L-arginine in the drinking water had serum L-arginine levels 5-6 times greater than control rats. At 6 weeks, creatinine clearance was significantly lower in the rats on the high-cholesterol diet compared to the rats on standard chow and rats on high-cholesterol diet plus L-arginine. Twenty-four-hour urinary total nitrate and nitrite excretion in the hypercholesterolaemic rats was 1.5-2 times greater than that of control rats. Twenty-four-hour urinary cGMP excretion was significantly lower in the rats on a high-cholesterol diet, but in the rats on high-cholesterol diet and L-arginine, 24-h urinary cGMP excretion was not significantly different from that of control rats. During isolated perfusion of kidneys, renal perfusate flow was found to be significantly reduced in the kidneys taken from the rats on a high-fat diet compared to controls. L-arginine supplementation in the drinking water almost completely reversed the effect of a high-fat diet. Inulin clearance was also significantly reduced in kidneys on a high-fat diet in contrast to controls but not in kidneys on high fat-diet and L-arginine. Basal cGMP excretion in urine was significantly lower in the kidneys taken from the rats on a high-fat diet compared to controls. L-arginine supplementation restored the basal cGMP excretion in these kidneys. NO synthase (NOS) enzyme activity as assessed by NADPH diaphorase activity showed that kidney sections taken from the rats on a high-fat diet showed more intense staining, indicating increased activity compared to the kidney sections taken from the rats on a normal diet. CONCLUSION: Though activity of NO is diminished in hypercholesterolaemic rats with impaired renal function, there is a paradoxical increase in NO production and NOS activity. L-arginine reverses the effects of a high-fat diet.     

Changes of vasoactive substances following embolization for renal cell carcinoma

Renal arterial embolization and subsequent nephrectomy or nephrectomy alone were performed in 34 patients with renal cell carcinoma. Renal arterial embolization caused a blood pressure elevation concomitant with an increase in plasma renin activity (PRA), urinary aldosterone excretion or urinary prostaglandin (PGE₂) excretion. Subsequent nephrectomy normalized hypertension and reduced the levels of these vasoactive substances. There were significant relationships between the increase in mean blood pressure and the increase in PRA, the increment in mean blood pressure and the increment in urinary aldosterone excretion, and the increase in PRA and increase in log urinary PGE₂ excretion following embolization. These evidences suggest that enhancement of the renin-angiotensin-aldosterone system participates in the development of hypertension following embolization, and increased PRA may play an important role in the release of urinary PGE₂.     

The effect of sodium restriction in renovascular hypertension

Six patients with angiographically proven renal artery stenosis were given a low salt diet, consisting of 10 mEq sodium per day for 4-6 days. Five patients showed a remarkable decrease in blood pressure (BP), from 169 +/- 12/107 +/- 4 to 131 +/- 12/84 +/- 5 mmHg, despite a rise in renin level. The decrease in BP was paralleled by a decrease in urinary sodium excretion. Restoration of the regular diet caused immediate elevation of blood pressure. We conclude that severe sodium restriction can reduce blood pressure in patients with renovascular hypertension.     

The role of the Na, K-ATPase inhibitor in renal sodium handling in patients with essential hypertension

The present study aimed to elucidate the role of Na, K-ATPase inhibitor in renal sodium metabolism in essential hypertension. Mean arterial pressure (MAP), heart rate(HR), urine volume (UV), urinary excretion of sodium (UNaV), endogenous creatinine clearance (Ccr), fractional excretion of sodium (FENa), plasma renin activity(PRA) plasma aldosterone concentration(PAC), plasma noradrenaline concentration (PNA) and urinary excretion of noradrenaline(UNA) were measured before and after intravenous injection of ouabain (0.1 mg/m2.BSA) in 12 normotensive(NT) and 22 mild-to-moderate essential hypertensive subjects(EHT). Following ouabain injection, UV, UNaV FENa significantly increased, but PRA decreased, in both NT and EHT. MAP, HR, Ccr, PNA, and UNA did not change significantly in either group. On the other hand, a significant decrease in PAC was observed in NT, but not in EHT. The changes of UNaV and FENa were significantly attenuated in EHT as compared to NT. No significant difference in change of MAP, HR, UV, Ccr, PNA, UNA, or PRA was demonstrated between NT and EHT. A significantly positive correlation was found between delta UNaV and delta FENa in both NT and EHT, while no significant correlation was observed between delta UNaV and delta MAP, delta UV, delta Ccr, delta PRA, delta PAC, delta PNA and delta UNA in either group. These results suggest that 1) Na, K-ATPase inhibitor clearly augments natriuresis by suppression of sodium reabsorption in renal tubules, 2) since this augmentation was attenuated, there is an elevation of endogenous Na, K-ATPase inhibitor(s) should be considered in EHT, and 3) an increase of the inhibitor might participate to the hypertensive mechanism in EHT.     

Effects of L-arginine and L-NAME on the renal function in hypertensive and normotensive subjects

BACKGROUND/AIM: Renal vasodilation in response to L-arginine has been reported to be diminished in hypertensive (HT) subjects. If this diminished renal vasodilator response indicates disturbance of the renal NO pathway, a diminished renal vasoconstrictor response to NO synthase inhibition may be present in HT subjects as well. The present study was conducted to compare the effects of L-arginine and N(G)-nitro-L-arginine methyl ester (L-NAME) on renal and systemic hemodynamics between HT and normotensive (NT) subjects. METHODS: The responses of renal and systemic vascular resistances (RVR and SVR) and plasma noradrenaline and renin (NOR and PRA) to systemic NO stimulation and inhibition were studied in patients with grade 1 essential HT and age- and sex-matched NT subjects. On separate occasions, after baseline values were obtained, 40-min randomly administered intravenous infusions of L-arginine (12.5 mg.kg(-1).min(-1)) or L-NAME (0.0125 mg.kg(-1).min(-1)) were given. RESULTS: Baseline values of RVR (129 +/- 21 and 162 +/- 10 resistance units) and SVR (15.1 +/- 4.3 and 21.6 +/- 5.1 resistance units) were higher (p < 0.01) in HT than in NT subjects, whereas the baseline values of NOR and PRA were similar. Infusion of L-arginine caused similar decrements in SVR (29 +/- 10 and 31 +/- 11%), but the decrease in RVR was smaller (22 +/- 8 and 35 +/- 12%, respectively; p < 0.05) in HT than in NT subjects. In response to L-NAME, the increments in RVR (66 +/- 10 and 61 +/- 25%) and SVR (36 +/- 21 and 34 +/- 18%) were similar in HT and NT subjects. In both groups, infusion of L-arginine was associated with similar increments, whereas infusion of L-NAME was associated with similar decrements in NOR and PRA. CONCLUSIONS: This study confirms the smaller renal vasodilator response to L-arginine in HT than in NT subjects. Whether this is caused by a disturbance of the renal NO pathway remains doubtful considering the observed similar L-NAME-induced increments in RVR and SVR in the two groups of subjects.     

Supplementation with a low dose of L-arginine reduces blood pressure and endothelin-1 production in hypertensive uraemic rats.

BACKGROUND: We documented recently that increased endothelin-1 (ET-1) production in blood vessels and glomeruli of uraemic rats plays a crucial role in the development of hypertension and the progression of chronic renal failure. Normally, biological effects and local production of ET-1 are attenuated by the immediate release of nitric oxide (NO). Increasing evidence suggest, however, that NO release is impaired in chronic renal failure. We investigated whether supplementation with L-arginine, the natural precursor of NO, improves NO synthesis in uraemic rats with reduced renal mass and modulates vascular and renal ET-1 production as well as blood pressure and renal failure progression. METHODS: One week after surgical renal mass reduction, the uraemic and sham-operated animals received either no treatment or 0.1% L-arginine in drinking water for 5 weeks. In another series of experiments, uraemic rats received 1% L-arginine for 5 weeks. Immunoreactive-ET-1 (ir-ET-1) levels in plasma, urine, and vascular and renal tissue preparations was measured by radioimmunoassay after sample extraction and purification. RESULTS: Before treatment, systolic blood pressure was significantly elevated in uraemic animals compared to sham-operated controls (156+/-7 vs 111+/-3 mmHg, respectively; P<0.01). Thereafter, systolic blood pressure increased further in uraemic-untreated rats (systolic blood pressure at week 5; 199+/-9 mmHg, P<0.01), whereas it remained similar in uraemic rats supplemented with 0.1% L-arginine (171+/-9 mmHg, NS). At the end of the study, serum creatinine and urea, proteinuria and ir-ET-1 excretion were significantly augmented, while creatinine clearance was reduced in uraemic animals compared to the controls. Ir-ET-1 level was also increased in glomeruli as well as in thoracic aorta, mesenteric arterial bed, and pre-glomerular arteries, and was associated with vascular hypertrophy as assessed by tissue weight. In contrast, ir-ET-1 level was diminished in the renal papilla of uraemic rats. Treatment with 0.1% L-arginine significantly reduced proteinuria and urinary ir-ET-1 excretion (P<0.05) as well as ir-ET-1 level in glomeruli (P<0.01) and in thoracic aorta (P<0.05). These changes were associated with increased plasma NO metabolites NO2/NO3 levels in L-arginine-treated animals (P<0.01) and reduced aortic hypertrophy (P<0.05). In contrast, supplementation with 1% L-arginine had no effect on systolic blood pressure in uraemic rats, but exacerbated proteinuria and urinary ir-ET-1 excretion and increased serum urea (P<0.05) were observed. CONCLUSIONS: These results indicate that improvement of NO release with a low dose but not with a high dose of L-arginine significantly attenuates the development of hypertension and the progression of renal insufficiency in rats with reduced renal mass. These protective effects may be mediated in part by the reduction of vascular and renal ET-1 production.     

Sodium, renin, aldosterone, catecholamines, and blood pressure in diabetes mellitus

Interrelations among plasma renin activity (PRA), aldosterone and cortisole levels, 0lood volume, exchangeable sodium, urinary catecholamines, and blood pressure were studied in 35 normal subjects and 60 age-matched non-azotemic patients with diabetes mellitus (60% with hypertension, 15% with orthostatic hypotension). Basal PRA, plasma aldosterone, cortisol, blood volume, plasma potassium, and urinary electrolytes were comparable in diabetic and normal subjects. Diabetic patients, however, had a 10% increase in body sodium (P less than 0.01), and 8% of them showed normal postural PRA responses and subnormal aldosterone responses; 22% had subnormal PRA and normal aldosterone responses, and 17% had subnormal responses of PRA and aldosterone. Non-PRA-related aldosterone responses could not be explained by ACTH or electrolytes. Orthostatic decreases in blood pressure correlated (P less than 0.01) with both catecholamine excretion and basal PRA. This suggests that in diabetes mellitus, body sodium is increased. Basal PRA and plasma aldosterone are usually normal, but their postural responses are frequently impaired. Absent aldosterone responses, despite normal PRA responsiveness, may reflect an adrenal abnormality or an ineffective form of renin. Marked postural aldosterone stimulation, unrelated to PRA, ACTH, or electrolytes, points to a potent unknown factor in aldosterone control. Low levels of free peripheral catecholamines and PRA may be complementary factors contributing to postural hypotension.     

Renal and endocrine effects of fenoldopam and metoclopramide in normal man

The effects of fenoldopam (FD), a selective dopamine-1 (DA1) agonist in doses from 0.05 to 0.50 micrograms/kg/min and of the aselective dopamine antagonist metoclopramide (MCP) on blood pressure (BP), sodium excretion and renal hemodynamics were investigated in 10 healthy volunteers. During FD infusion the diastolic BP fell 9 mm Hg with a rise in heart rate. During combined infusion of FD and MCP no changes in BP occurred. Effective renal plasma flow rose for all doses of FD with a maximal increase of 36% and was not influenced by MCP infusion. Glomerular filtration rate remained unchanged. FD induced an increase in sodium and calcium excretion compared to placebo study, which was abolished by MCP. A marked rise of plasma renin activity during FD infusion was noted, blunted by MCP. MCP induced a marked increase of aldosterone, sustained, but blunted, during subsequent FD infusion, suggesting a DA1-mediated influence on aldosterone secretion. During infusion of FD alone, an increased urinary dopamine excretion was observed. We conclude that FD induces: (1) systemic and renal vasodilation and (2) natriuresis by direct stimulation of DA1 receptors in the proximal tubule, which is (partially) counteracted by a rise of plasma renin activity and subsequently of aldosterone.     

Role of renal prostaglandin E2 in chronic renal disease hypertension

The role played by renal prostaglandin E2 in the maintenance of hypertension in chronic renal disease has been investigated through studying the response of body weight, blood pressure, glomerular filtration rate (GFR), 24-hour natriuresis, plasma renin activity (PRA), plasma aldosterone and urinary PGE2 excretion to the administration of indomethacin (2mg/kg daily, during 3 days). A group of 37 patients diagnosed as having chronic renal parenchymatous disease with creatinine clearance above 25 ml/min was included in the study. 21 of them were hypertensive (BP greater than 160/95). 27 normotensive volunteers were also studied and considered as the control group. The initial study disclosed similar levels of PGE2, PRA and plasma aldosterone in volunteers, normotensive patients and hypertensive patients, although the sodium intake was lower in the last two groups. A positive correlation between PRA and urinary PGE2 was found both in normotensive (r = 0.507, p less than 0.01) and in hypertensive patients (r = 0.609, p less than 0.01). The administration of indomethacin induced a diminution of PRA, plasma aldosterone and urinary PGE2 levels together with an increase in diastolic blood pressure (p less than 0.05-0.01) in both volunteers and patients. The remaining parameters measured did not change in volunteers or in normotensive patients. On the contrary, in hypertensive patients, during indomethacin administration, lower values of creatinine clearance (p less than 0.005) and 24-hour natriuresis (p less than 0.05) together with an increase in body weight (p less than 0.01) were observed. These results point to the existence of a protective role of renal prostaglandin E2 upon renal function when hypertension appears in the course of chronic renal parenchymatous disease.     

Steroid-induced hypertension in patients with nephrotic syndrome

In 35 initially normotensive patients with chronic glomerulonephritis and lupus nephritis (including 27 patients with nephrotic syndrome; NS), blood pressure (BP), urinary sodium excretion, plasma renin activity (PRA), plasma aldosterone level (PA), urinary aldosterone excretion (Au and blood volume were measured before and during prednisolone treatment. In 7 patients (all with NS) steroid-induced hypertension has developed. The patients prone to develop hypertension were hypervolemic nephrotics with initial depression of PRA, PA, Au, and severe sodium retention. In these patients prednisolone did not produce diuresis of natriuresis nor did it decrease proteinuria. In normo- and hypovolemic patients prednisolone produced significant diuresis and natriuresis and failed to induce hypertension. Thus, two types of response to prednisolone could be observed in patients with NS.