Increase In Renal Plasma Flow Research Articles

Renal responses to nifedipine and captopril in hypertensive insulin-dependent diabetic men: a randomized cross-over study

The effects of nifedipine retard and captopril on renal haemodynamic parameters have been examined in a double blind randomised cross-over trial in 10 insulin-dependent diabetic males with hypertension (systolic pressure > 150 mmHg or diastolic pressure > 90 mmHg). The acute renal haemodynamic response to nifedipine retard 20 mg and captopril 25 mg was monitored at the start of therapy and again after 8 weeks treatment with nifedipine retard 20 mg b.d. and captopril 25 mg b.d. Blood pressure fell from 148/97 +/- 4/2 (SEM) during the run-in phase to 135/87 +/- 4/1.5 on nifedipine retard and to 131/83 +/- 5/1 on captopril. There was no difference between the initial renal response to the two agents; an increase in renal plasma flow and a non-significant decline in glomerular filtration rate resulted in similar decreases in filtration fraction. After 8 weeks therapy, neither drug had a significant effect on urinary albumin excretion. Baseline renal function did not differ and no acute changes in renal haemodynamics were seen after nifedipine. Following captopril there was no acute change in systemic blood pressure but RPF rose from 572 +/- 41 to 638 +/- 42 ml/min per 1.73 m2 (P < 0.05) and filtration fraction fell from 0.21 to 0.16 (P < 0.02). This sustained acute response of the renal circulation to angiotensin-converting enzyme (ACE) inhibition after chronic therapy may be relevant to the apparent renal protection afforded by ACE inhibitors in experimental nephropathies.

Effects of insulin on renal haemodynamics and the proximal and distal tubular sodium handling in healthy subjects.

The effects of insulin on renal haemodynamics and renal sodium handling were studied in 10 healthy males. Using the euglycaemic insulin clamp technique, insulin was infused on separate days resulting in two levels of hyperinsulinaemia (41 +/- 3 and 90 +/- 7 mU/l, respectively). Renal haemodynamics and the proximal and distal tubular sodium handling were studied using inulin, para-amino-hippuric acid, sodium and lithium clearances. Low- and high-dose insulin infusions were followed by a fall in sodium clearance from 1.6 +/- 0.1 ml/min to 1.2 +/- 0.1 and 1.0 +/- 0.1 ml/min, respectively. Both levels of hyperinsulinaemia resulted in increased distal tubular sodium reabsorption. The distal antinatriuretic effect of insulin was associated with dose- and time-dependent decline in proximal tubular sodium reabsorption. The changes in proximal tubular sodium handling occurred without any significant changes in natriuretic factors, such as renal dopamine and plasma atrial natriuretic peptide levels. However, hyperinsulinaemia resulted in time- and dose-dependent increases in renal plasma flow, and renal vasodilatation could, possibly via changes in renal interstitial pressure, have contributed to the fall in the proximal tubular sodium reabsorption. The results also suggest that decreased proximal sodium reabsorption may be a compensatory mechanism counteracting the insulin-induced sodium retention.

Role of endothelium-derived nitric oxide in the renal hemodynamic response to amino acid infusion.

The present study was performed in anesthetized rats to compare the renal hemodynamic responses to mixed amino acids (M-AA) with those to L-arginine (L-Arg) and to examine the effect of endothelium-derived nitric oxide (EDNO) synthesis blockade on the M-AA-induced rise in renal plasma flow (RPF) and glomerular filtration rate (GFR). Intravenous infusion of both M-AA (Ser, Gly, Ala, and Pro, 0.71 mmol.100 g-1.min-1) and L-Arg (0.71 mmol.100 g-1.min-1) increased RPF and GFR. Peak increases in RPF for M-AA and L-Arg were 39.7% (P less than 0.05) and 63.4% (P less than 0.01), whereas GFR increases were 33.6% (P less than 0.05) and 46.7% (P less than 0.01, respectively). Outer cortical blood flow (OCBF) was increased with both treatments. Sodium excretion and urine flow were increased more with L-Arg than M-AA (both P less than 0.01). Infusion of the nitric oxide synthesis inhibitor, nitro-L-arginine (N-L-Arg, 20 micrograms.100 g-1.min-1) increased mean arterial pressure but decreased RPF 48.4% (P less than 0.001), OCBF 39.5% (P less than 0.001), GFR 37.8% (P less than 0.01), urine flow 29.8% (P less than 0.01), and sodium excretion 40.9% (P less than 0.01). When M-AA was administered after N-L-Arg, significant increases in OCBF, RPF, and GFR were observed (P less than 0.01); there was also an enhancement of sodium excretion and urine flow (both P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Thromboxane-receptor blockade increases water diuresis in cirrhotic patients with ascites

This study was undertaken to investigate the role of increased renal thromboxane (TX) A2 production in modulating renal hemodynamics and sodium and water retention in cirrhotic patients with ascites. In a randomized, double-blind, placebo-controlled, crossover trial, 15 nonazotemic cirrhotic patients with ascites and elevated urinary TXB2 excretion received the thromboxane-receptor antagonist ONO-3708 (3 μg · kg−1 · min−1) in a 4-hour continuous infusion. Administration of ONO-3708 significantly blocked TXA2 receptors; bleeding time showed a twofold increase (432 ± 65 vs. 131 ± 17 seconds; P < 0.005), and platelet aggregation to U-46619 (an agonist of TXA2 receptors) was abolished in all patients studied. The drug induced a significant increase in free water clearance (3.06 ± 0.70 vs. 1.72 ± 0.57 mL/min; P < 0.001) and diuresis (4.74 ± 0.79 vs. 3.94 ± 0.66 mL/min; P < 0.05) compared with placebo, as well as a significant (14%) increase in renal plasma flow. The increases in both free water clearance and diuresis induced by ONO-3708 were directly related to basal urinary TXB2 excretion. These results suggest a role for renal TXA2 as a modulator of water handling in cirrhotic patients with ascites.

Stevioside effect on renal function of normal and hypertensive rats

Physiological and pharmacological experiments have suggested that Stevioside from the leaves of Stevia rebaudiana acts as a typical systemic vasodilator. The effect of Stevioside on renal function in both normal and with experimental renal hypertension rats (GII) was evaluated using clearance techniques. Stevioside provoked hypotension, diuresis and natriuresis in both the normal and hypertensive rats. Normal rats presented an increase in renal plasma flow (RPF) and glomerular filtration rate (GFR) constant following Stevioside administration. The last effect is in part due to vasodilation of both the afferent and efferent arterioles. Moreover, Stevioside infusion in hypertensive rats caused an increase in RPF and GFR. These data are consistent with impairment of a renal autoregulation mechanism in this experimental hypertensive model.

Enhanced renal response to intracerebroventricular angiotensins II and III in spontaneously hypertensive rats

The acute effects of intracerebroventricular (i.c.v.) administration of angiotensin III (ANG III) on blood pressure (BP) and renal function were investigated in spontaneously hypertensive rats (SHR, n = 31) and Wistar-Kyoto (WKY) normotensive rats ( n = 6). ANG II was also administered to the same rats for comparison of its renal effect. BP and renal clearance responses were measured before and during ANG injections. The results showed that i.c.v. injections of 1, 5 and 50 pmol of ANG III did not significantly alter BP in SHR, but a high dose of ANG III (50 pmol) caused a vasopressor effect (7 +- 4mmHg) in WKY rats. There were significant increases in renal plasma flow (RPF), glomerular filtration rate (GFR), urine flow, absolute and fractional excretions of sodium and potassium, osmolar clearance and free water reabsorption rate following i.c.v. administration of ANG III in both SHR and WKY rats. However, the enhancement in renal responsiveness to ANG III was greater in SHR than in the WKY group. At 5 pmol of ANG III, the peak increases in GFR (96 ± 23%), diuresis (316 ± 102%) and natriuresis (712 ± 281%) in SHR were significantly greater than those in WKY rats (40 ± 13%, 152 ± 89%, 229 ± 130%, resp.). The renal effect of central ANG III was blocked by i.c.v. ANG III antagonist, [Ile 7]-ANG III, but was enhanced by bestatin, an ANG III metabolic enzyme inhibitor. I.c.v. administration of ANG II at 50 pmol increase BP in both SHR and WKY rats (14 ± 13and10 ± 3mmHg, resp.). Greater diuretic and natriuretic responses to ANG II were also noted in SHR than in WKY rats. These results indicate that central ANG III is an active as ANG II in modulating renal function. Furthermore, the enhanced renal response to i.c.v. ANGs II and III in SHR suggests a hyperactive central RAS implicated in BP and body fluid regulation in this genetic hypertensive strain.

The effect of high-dose nifedipine on renal hemodynamics of cyclosporine-treated renal allograft recipients.

Cyclosporine has been shown to reduce renal perfusion and to decrease glomerular filtration rate. Experimental studies suggest that nifedipine might reverse this renal vasoconstrictive effect of cyclosporine. We studied renal hemodynamics of 5 cyclosporine-treated renal transplant recipients before and after 2 weeks of therapy with high-dose nifedipine (up to 120 mg/day). Pretreatment GFR and renal plasma flow (RPF) were decreased. Following administration of nifedipine, RPF increased by 18% (P less than 0.01), while GFR did not change. Filtration fraction decreased by 10.5% (P less than 0.01). Mean arterial pressure declined from 111 +/- 5 to 96 +/- 3 mmHg (P less than 0.01). Renal vascular resistance dropped by 25% (P less than 0.01). Calculated postglomerular plasma flow increased by 20.5% (P less than 0.01). Urinary albumin excretion rate was unaffected. Cyclosporine whole blood levels were unchanged. The increase in RPF and in postglomerular plasma flow suggests that high-dose nifedipine might lessen cyclosporine-induced glomerular and interstitial ischemia in renal allograft recipients.

Glomerular function in Pima Indians with noninsulin-dependent diabetes mellitus of recent onset.

Differential solute clearances were used to characterize glomerular function in 20 Pima Indians with noninsulin-dependent diabetes mellitus (NIDDM) of less than 3 yr duration. 28 Pima Indians with normal glucose tolerance served as controls. In the diabetic group, the glomerular filtration rate (GFR, iothalamate clearance) exceeded the control value by 15% (140 +/- 6 vs. 122 +/- 5 ml/min, P less than 0.01). A corresponding 12% increase in renal plasma flow (RPF) was not statistically significant and did not account fully for the observed hyperfiltration, suggesting a concomitant elevation of the ultrafiltration pressure or coefficient. The median albumin excretion ratio in NIDDM exceeded control by almost twofold (10.1 vs. 5.8 mg/g creatinine), a trend which just failed to achieve statistical significance (P = 0.06). Fractional clearances of dextrans of broad size distribution were also elevated in diabetic subjects, significantly so for larger dextrans of between 48 and 60 A radius. A theoretical analysis of dextran transport through a heteroporous membrane revealed glomerular pores in NIDDM to be uniformly shifted towards pores of larger size than in controls. We conclude that an impairment of barrier size selectivity combined with high GFR elevates the filtered protein load in NIDDM of recent onset. We propose that enhanced transglomerular trafficking of protein may predispose to sclerosis of glomeruli in those Pima Indians with NIDDM who ultimately develop diabetic nephropathy.

Disassociation between glomerular hyperfiltration and extracellular volume in diabetic rats

The relationship of the development of glomerular hyperfiltration in diabetes to changes in extracellular fluid volume has not been previously examined. To accomplish this task, male Wistar rats were chronically cannulated in the bladder, femoral artery and vein. Control measurements of glomerular filtration rate (GFR), renal plasma flow (RPF), extracellular fluid volume (ECF), and urinary sodium excretion were performed on two separate days prior to infusion of streptozotocin (65 mg/kg body wt i.v.). After infusion of streptozotocin, the IDDM rats were separated into two groups: untreated IDDM group of rats and IDDM rats treated with insulin at doses sufficient to normalize blood glucose (Ultralente, 2 to 8 IU/day). A third group of normal non-diabetic rats served as time controls. Measurements of renal function occurred at 1, 4, 7, 11, and 15 days after infusion of streptozotocin. Blood glucose in the non-diabetic measurement period averaged 137 +/- 30 mg/dl and increased from 412 +/- 55 after 24 hours in the untreated diabetic rats to 533 +/- 33 mg/dl after 15 days of IDDM. The time controls and the insulin-treated diabetic rats did not differ in blood glucose values at the time measurements were performed. Glomerular filtration rate increased from 1.0 +/- 0.1 to 1.7 +/- 0.1 ml/min/100 g body wt by day 15 in the untreated diabetic rats with significant increases in GFR within 24 hours. GFR of both time controls and the insulin-treated IDDM rats did not significantly vary during the time of the study. The increase in GFR in the untreated IDDM group was associated with a concomitant increase in RPF.(ABSTRACT TRUNCATED AT 250 WORDS)

Systemic and renal actions of dopexamine and dobutamine during endotoxin shock in the rat

Acute renal failure is a complication of endotoxin shock caused by decreased renal blood flow and nephrotoxic effects of endotoxin. We hypothesized that dopexamine (DX), a new dopamine and β2 receptor agonist that lacks α-adrenergic vasoconstrictor action, might prevent acute renal failure during shock by its vasodilator action on the renal circulation and not as a result of a concomitant increase in cardiac output (CO). We thus compared the action of DX with that of dobutamine (DB; β1-agonist, no renal effects) administered in such a dose that it caused a similar increase in CO. Shock was induced in anesthetized (sodium pentobarbital) rats by infusion (2 mL/kg/h) of endotoxin ( Escherichia coli 0127138, 10 mg/kg) from t = 0 to t = 60 minutes; experiments ended at t = 135 minutes. Dopexamine (3.10 −8 mol/kg/min; DX group, n = 8) or DB (10 −8 to 10 −7 mol/kg/min; DB group, n = 8) was infused from t = −30 to t = 135 minutes; a third group only received endotoxin (ES group, n = 8). Glomerular filtration rate (GFR) and renal plasma flow (RPF) during shock were calculated from plasma double exponential disappearance rate from t = 90 to t = 135 minutes of 125I thalamate and 131I hippurate, respectively. In renal biopsies, we also measured lactate, glucose, ATP, phosphocreatine concentration (CrP), energy charge ([ATP + 0.5 ADP]/[ATP + ADP + AMP]) and the number of leukocytes per 50 glomeruli at t = 135 minutes. In the ES group, CO was low (approximately 55 mL/min) and serum lactate was high (approximately 5 mmol/L, indicative of shock); RPF and GFR were 1.28 ± 0.31 and 0.46 ± 0.07 mL/min/100 g body weight, respectively. Cardiac output in the DX and DB groups was higher (by approximately 45%) than in the ES group due to a greater stroke volume, but RPF and GFR were significantly higher only in the DX group (by 140% and 76%, respectively). Dopexamine and DB improved renal metabolism to the same extent; the accumulation of leukocytes during endotoxemia was not prevented in either group. The major action of DX thus seems to be an increase in RPF that cannot be attributed to restored CO alone, but also to decreased renal vascular resistance. Acute renal failure was prevented by DX in this way.

Response of insulin-like growth factor I and renal hemodynamics to a high- and low-protein diet in the rat.

An increase in plasma insulin-like growth factor I (IGF-I) levels by growth hormone injection or IGF-I infusion can raise renal plasma flow and glomerular filtration rate. However, it is not known whether a more physiological stimulus for IGF-I will also increase IGF-I in the kidney and whether the increase in renal or serum IGF-I is correlated with the increase in renal plasma flow and glomerular filtration rate. Male rats were pair fed either a high-protein (36% protein, N = 9) or a low-protein but isocaloric diet (9% protein, N = 9) for 10 to 14 days. Renal plasma flow and glomerular filtration rate were then estimated by clearance measurements, and IGF-I was measured in extracted serum, liver, renal cortical tissue, and glomeruli. Body weight gain and combined kidney weight were higher in high-protein rats as compared with low-protein animals (0.86 +/- 0.02 SEM versus 0.77 +/- 0.02 g/100 g body wt; P less than 0.05), but liver weights were not different. Serum, liver, and glomerular IGF-I levels were also higher in the high-protein rats as compared with the low-protein animals (serum, 1.12 +/- 0.03 versus 0.80 +/- 0.06 U/mL, P less than 0.05; liver, 183 +/- 17 versus 117 +/- 16 mU/g wet wt, P less than 0.05; glomeruli, 7.43 +/- 0.73 versus 4.81 +/- 0.59 mU/mg of protein, P less than 0.05). In contrast, the renal cortical IGF-I levels were not different in high-protein versus low-protein rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Thromboxane Synthesis Inhibitor Triflusal on Renal Hemodynamics in Microalbuminuric Diabetic Patients

Triflusal (2-acetoxy-4-trifluormethylbenzoic acid) is a platelet-antiaggregant drug that selectively inhibits thromboxane synthesis with little effect on prostacyclin production. In this study, we evaluated the effect of 5-day administration of 900 mg/day triflusal on glomerular filtration rate (GFR), renal plasma flow (RPF), urinary albumin excretion (UAE), thromboxane B2 (TXB2), 6-ketoprostaglandin F1 alpha (PGF1 alpha), and PGE2 in nine normotensive insulin-dependent diabetic patients with UAE between 30 and 103 micrograms/min. Plasma TXB2 and plasma renin activity (PRA) were also determined. After administration of triflusal, we observed a reduction in microalbuminuria (59 +/- 25 vs. 33 +/- 22 micrograms/min, P less than 0.01), an increase in RPF (648 +/- 119 vs. 722 +/- 134 ml.min-1 x 1.73 m-2, P less than 0.01), and a reduction in filtration fraction (0.24 +/- 0.04 vs. 0.20 +/- 0.03, P less than 0.01). Triflusal produced a significant reduction in both plasma TXB2 (130 +/- 39 vs. 52 +/- 32 pg/ml, P less than 0.02) and urine TXB2 (523 +/- 249 vs. 312 +/- 11 pg/min, P less than 0.02), without changes in PRA and UAE of 6-keto-PGF1 alpha and PGE2. Metabolic control and arterial blood pressure did not change during the study. These results suggest that platelet-antiaggregant therapy can reduce microalbuminuria in diabetic patients. This effect could be mediated by a reduction in the transglomerular hydraulic pressure through a vasodilation of efferent arterioles secondary to renal thromboxane synthesis inhibition.

Sodium and Water Excretion in Nephrotic Patients: Effects of Changes in Renal Haemodynamics

1. Eight nephrotic patients were studied in order to evaluate the effects of acute changes in renal plasma flow and glomerular filtration rate on renal solute and water handling, in the absence of plasma volume expansion. 2. The subjects were studied first after the administration of captopril, a manoeuvre that increased renal plasma flow without a significant change in glomerular filtration rate, and a second time after receiving combined therapy with captopril and ibuprofen, a manoeuvre that decreased glomerular filtration rate without a significant change in renal plasma flow. 3. After captopril therapy, despite the increase in renal plasma flow, there was no significant change in proximal sodium reabsorption (as estimated from fractional lithium reabsorption), urine volume or urine osmolality. 4. The decrease in glomerular filtration rate observed after the administration of captopril plus ibuprofen was associated with decreases in fractional excretion of sodium and urine volume, and an increase in urine osmolality. The changes in these parameters of tubular function were proportionate to the changes in glomerular filtration rate. Fractional proximal sodium reabsorption increased substantially. 5. These observations suggest that, in the absence of plasma volume expansion, an increase in renal plasma flow does not increase sodium or water excretion by the nephrotic kidney. Moreover, during acute decreases in glomerular filtration rate, glomerulotubular balance appears to be disrupted, resulting in disproportionately high rates of proximal tubule sodium reabsorption.

Effect of fenoldopam in dogs with spontaneous renal insufficiency

Fenoldopam administration orally or i.v. resulted in significant increases in paraaminohippuric acid (PAH) clearance in both four control dogs and four dogs with chronic renal failure. Oral fenoldopam resulted in significant plasma levels of fenoldopam sulfate metabolites. One metabolite, fenoldopam-8-sulfate, a potential inhibitor of organic anion transport, did not depress renal cortical slice accumulation of PAH. The data therefore indicate that in dogs with chronic renal failure, PAH clearance after fenoldopam administration is a reliable measure of renal plasma flow, and fenoldopam can result in an increase in renal plasma flow.

Ceranapril (SQ 29,852), an Orally Active Inhibitor of Angiotensin Converting Enzyme (ACE)

Ceranapril (SQ 29,852) is a new inhibitor of angiotensin I (AI) converting enzyme (ACE) belonging to the hydroxylphosphonate class. The purpose of the present report is to present the in vivo pharmacology of ceranapril in conscious animal models. In conscious, normotensive rats, ceranapril administered i.v. (ED50 = 63 nmol/kg) or p.o. (ED50 = 530 nmol/kg) inhibited an AI pressor response with potency equal to that of captopril. However, in conscious dogs, ceranapril was a relatively poor inhibitor of the AI pressor response after both i.v. (ED50 = 300 nmol/kg) and p.o. (ED50 = 18 mumol/kg) administration; in monkeys ceranapril was a good inhibitor of the AI pressor response after i.v. (ED50 = 60 nmol/kg) but not p.o. (ED50 = 18 mumol/kg) administration. In rats, the duration of ceranapril's inhibition of an AI pressor response was longer than an equimolar dose of captopril. Similarly, in SHR, ceranapril's blood pressure lowering effect had a longer duration than that of captopril. Ceranapril's ACE inhibitory effects were longer lasting in anephric rats than in sham rats, suggesting a renal route of excretion for ceranapril. Ceranapril administration to conscious female dogs resulted in significant increases in renal plasma flow and GFR. In SHR, doses of 23 and 68 mumol/kg resulted in significant blood pressure lowering that lasted 24 h. Oral doses of 2.3, 6.8, 23, and 68 mumol/kg in two-kidney, one-clip hypertensive rats resulted in significant and dose-related falls in arterial pressure, which again persisted for 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of intravenous amino acid infusion and dietary proteins on kidney function in cirrhosis

Acute intravenous amino acid infusion or a high-protein diet increases renal plasma flow and the glomerular filtration rate in healthy subjects. Conversely, a low-protein diet reduces renal plasma flow and glomerular filtration rate. The aim of this study was to investigate the effect of intravenous amino acid infusion and dietary proteins on kidney function in cirrhosis. Protocol 1: renal plasma flow and glomerular filtration rate were measured before and during intravenous administration of a 10% amino acid solution (0.043 ml/kg/min) to eight compensated cirrhotic patients (group 1), nine nonazotemic cirrhotic patients with ascites (group 2) and seven cirrhotic patients with ascites and functional renal failure (group 3). Amino acid administration induced a significant increase in renal plasma flow and glomerular filtration rate in all groups studied. Renal plasma flow and glomerular filtration rate increased by 16% and 14%, respectively, in group 1; 31% and 22% in group 2 and 25% and 21% in group 3. Protocol 2: Renal plasma flow and glomerular filtration rate were measured in nine cirrhotic patients with ascites after 11 days on a low-protein diet (0.5 gm/kg body weight/day) and also after the patients followed for 11 days a moderately high-protein diet (1.5 gm/kg body weight/day). The moderately high-protein diet was associated with a significant increase in renal plasma flow (12%) and glomerular filtration rate (13%) compared with values obtained while the patients followed the low-protein diet. Plasma glucagon levels increased markedly during the intravenous administration of amino acid and the intake of the moderately high-protein diet.(ABSTRACT TRUNCATED AT 250 WORDS)

The Renal Hemodynamic Response following a Meat Meal in Children with Chronic Renal Failure and in Healthy Controls

The renal hemodynamic response to a meat meal (2 g/kg BW) was studied in 11 healthy children and in 10 children with a mean plasma creatinine concentration of 2.6 +/- 0.1 mg/dl due to chronic renal failure (CRF) of various etiologies. In the healthy status, after a meat meal, the glomerular filtration rate (GFR) increased significantly from a baseline value of 119.0 +/- 5.0 to a peak of 159 +/- 5.8 ml/min x 1.73 m2; in CRF baseline GFR averaged 49 +/- 4.0 and at peak 76.6 +/- 7.2 ml/min x 1.73 m2 (p less than 0.005). The peak GFR response was reached earlier in healthy subjects than in CRF (p less than 0.05) and did not correlate with age or with baseline GFR. Renal plasma flow (RPF) in healthy controls increased from 532 +/- 32 at baseline to 646 +/- 42.9 ml/min x 1.73 m2 after the meal (p less than 0.005). Also in CRF after a meat meal there was a significant increase in RPF from 278 +/- 51 to 65 +/- 66 ml/min x 1.73 m2 (p less than 0.005). The filtration fraction was not affected. The percent increase over baseline values of GFR and RPF at the peak was significantly higher in diseased children. Renal reserve averaged 28.1 +/- 5.3 ml/min in diseased children and 39.7 +/- 5.2 ml/min (p less than 0.01). The data indicate that (1) a meat meal is a suitable method to recruit renal reserve in normal children and in children with chronic renal failure, and (2) the renal reserve is normal in chronic renal failure.

ACUTE EFFECTS OF INTRAVENOUS CYCLOSPORINE ON BLOOD PRESSURE, RENAL HEMODYNAMICS, AND URINE PROSTAGLANDIN PRODUCTION OF HEALTHY HUMANS

The acute renal failure associated with cyclosporine may result from vasoconstriction of intrarenal arterioles. To evaluate the mechanism of cyclosporine-induced nephrotoxicity, we acutely administered cyclosporine to eight healthy female volunteers with normal blood pressure and renal function. Cyclosporine (4 mg/kg) in 250 ml of 5% dextrose in water (D5W) was administered as a steady intravenous infusion over 6 hr. Glomerular filtration rate and renal plasma flow were measured by serum disappearance of 99m TcDTPA and 131I hippuran, respectively, during the last 3 hr of the infusion. D5W was given to the patients on separate days before the cyclosporine infusion to obtain control data. Systolic and diastolic blood pressure measured every hour during the infusions and renal vascular resistance were slightly higher during cyclosporine administration, but the increases were not statistically significant. Renal plasma flow was not affected by cyclosporine, being 479.6 +/- 24.9 ml/min during the control infusion and 463.3 +/- 12.7 ml/min during the cyclosporine infusion. However, glomerular filtration rate was reduced by cyclosporine in all patients (control, 108.8 +/- 2.5 ml/min, vs. cyclosporine, 91.1 +/- 2.2 ml/min, P less than .01), except one who demonstrated no significant change. Urinary excretion of thromboxane B2 during cyclosporine administration was markedly increased in all patients, being 39.9 +/- 8.2 ng/hr in the control period and 85.8 +/- 22.3 ng/hr during cyclosporine infusion (P less than .05), except for the one patient in whom no decrease in GFR was noted. There was no significant change in the urinary excretion rate for 6-keto-prostaglandin F1a or prostaglandin E during cyclosporine infusion. Serum averaged levels of peripheral renin activity, angiotensin II, and aldosterone did not change during with the cyclosporine administration compared with the control. All patients demonstrated a decrease in 24-h urinary excretion of sodium and potassium on the day of the cyclosporine infusion. Verapamil SR (240 mg daily for 7 days prior to cyclosporine infusion) did not reverse the reduction in glomerular filtration rate induced by cyclosporine; however, a significant reduction in renal vascular resistance and an increase in renal plasma flow (P less than .05) were noted when the volunteers were treated with both verapamil and cyclosporine compared with cyclosporine alone. Intravenous infusion of Cremophor EL, the vehicle to dissolve cyclosporine, demonstrated no significant effects on blood pressure, renal hemodynamics or urinary prostaglandin excretion.(ABSTRACT TRUNCATED AT 400 WORDS)

Natriuretic Effects of Calcium Antagonists

An important characteristic which distinguishes calcium antagonists from traditional vasodilators is their natriuretic rather than antinatriuretic action. Evidence that all classes of calcium antagonists have a natriuretic effect has been provided by intravenous administration in animal experiments. After single oral doses, all calcium antagonists have some natriuretic effect, but its extent differs with different compounds; dihydropyridines have a greater immediate natriuretic response than verapamil or gallopamil. Recent experiments by our group using the newer dihydropyridine derivative, isradipine, indicate that the natriuretic response may occur at even lower doses than the antihypertensive effect. Indeed, doses of 2.5mg, 5.0mg and 7.5mg of this compound caused an increasingly larger fall in blood pressure, while the natriuretic and diuretic effects peaked with the 2.5mg dose. The natriuretic effect is associated with no or a very small change in glomerular filtration rate and with a more consistent increase in renal plasma flow. The duration of the natriuretic action of calcium antagonists is debated. Our studies have shown that this action is evident during the first 2 days of administration of a dihydropyridine, and then seems to disappear; however, a small negative sodium balance persists, an observation that accounts for the absence of any increase in bodyweight or fluid volumes with long term administration of calcium antagonists, despite their vasodilating action. Recent data have shown that under long term treatment with isradipine sodium clearance was still increased a few hours after administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of Intrarenal Renin-Angiotensin System on Pressure-Natriuresis in Spontaneously Hypertensive Rats

The pressure-natriuresis relationships in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were characterized with or without intrarenal renin-angiotensin system (RAS) blockade. The pressure-natriuresis relationship in SHR was shifted toward higher pressure in comparison to WKY. The inhibition of intrarenal RAS by MK-422 (0.3 ug/kg/min) in SHR enabled to excrete more sodium at the same pressure (P less than 0.05), whereas no significant changes were observed in WKY. In SHR, during administration of Thi5,8, D-Phe7-bradykinin (50 micrograms/kg/min), the natriuretic responses to MK-422 were maintained. Intrarenal infusion of Sar1, Ile8-angiotensin (70 ng/kg/min) into SHR increased sodium excretion accompanied by an increase in renal plasma flow. Intrarenally administered angiotensin I (10 ng/kg/min) into WKY showed antinatriuretic effects with minimal changes in renal hemodynamics. These results indicate that alteration of intrarenal RAS in SHR might contribute to reset the pressure-natriuresis relationship.