This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Montanari, A. Articles by Dall’Aglio, P. Search for Related Content PubMed PubMed Citation Articles by Montanari, A. Articles by Dall’Aglio, P.

(Hypertension. 1997;30:557.)
© 1997 American Heart Association, Inc.

Articles

Angiotensin II Blockade Does Not Prevent Renal Effects of L-NAME in Sodium-Repleted Humans

Alberto Montanari; Enrico Tateo; Elena Fasoli; Daniela Giberti; Patrizia Perinotto; Almerico Novarini; Pierpaolo Dall’Aglio

From the Istituto di Patologia Medica (A.M., E.T., D.G., P.P., P.D’A.), and Istituto di Semeiotica Medica (E.F., A.N.), University of Parma, Parma, Italy.

Correspondence to Alberto Montanari, MD, Istituto di Patologia Medica, Via Gramsci 14, I-43100 Parma, Italy. E-mail montalbr{at}ipruniv.cce.unipr.it

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Abstract In seven healthy, young subjects on a 240 mmol sodium diet, mean arterial pressure (MAP), renal hemodynamics, and renal handling of Na and exogenous Li were measured at baseline and during short-term nitric oxide (NO) blockade with a 90-minute infusion of 3.0 µg · kg^-1 · min^-1 of N^G-L-arginine methyl ester (L-NAME). The infusion was performed twice: after a 3-day pretreatment with either placebo or 50 mg losartan to block Ang II receptors. With placebo, L-NAME produced no change in MAP from 0 to 45 minutes (period 1) and only a 5% increase at 45 to 90 minutes (period 2) of infusion. Effective renal plasma flow (ERPF, PAH clearance) and glomerular filtration rate (GFR, inulin clearance) declined by 11.7% and 8.0%, respectively in period 1 and by 14.6% and 11.6%, respectively, in period 2. Calculated renal vascular resistance (RVR) increased by 13.0% to 20.6%. Fractional excretion of Na (FE_Na) and Li (FE_Li) fell by 30.0% and 21.0%, respectively, in period 1 and by 44.2% and 31.1% in period 2. All these variations were significant versus baseline. With losartan, the rise in MAP at 45 to 90 minutes was completely abolished, whereas all changes in ERPF, GFR, RVR, FE_Na, and FE_Li in response to L-NAME were the same as those observed with placebo. The present data show that NO blockade with low-dose systemic infusion of L-NAME produces renal vasoconstriction, reduced GFR, and increased tubular Na reabsorption independent of changes in MAP. Reduced FE_Li indicates an effect of NO on the proximal tubule. Since these changes are not prevented by losartan, we conclude that in Na-repleted humans, renal vasoconstriction and Na-retaining effects of inhibition of basal NO production are not due to the unopposed action of endogenous Ang II.

Key Words: L-NAME • human • kidney • nitric oxide • angiotensin II • hemodynamics

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Nitric oxide is a short-lived, free radical molecule with potent vasodilatory effects. It is generated by the vascular endothelium through the action of NOS on its substrate L-arginine. Infusion of L-arginine–substituted compounds with specific inhibitory effects on NOS, such as L-NMMA, L-NAME, and L-NNA, leads in animals and humans to increase in MAP and in vascular resistance in many organs including the renal circulation.^{1 2 3 4 5 6 7 8 9} In the kidney, NOS inhibition has been shown in rats, dogs, and humans to produce decrease in ERPF and RBF, less pronounced fall in GFR, and thus a rise in FF.^{1 2 4 5 6 7 8 9} In both animals and humans, marked elevations in MAP due to NOS inhibition are followed by natriuresis while Na retention occurs when MAP is unaltered or only slightly increased.^{1 2 3 4 5 6 7 8 9}

Renal responses to systemic or intrarenal NOS blockade closely resemble the action of exogenous Ang II.⁹ Thus, the hypothesis has been advanced that the actions of NOS blockade in the kidney might derive at least in part from removal of renal vasodilatory tone due to the basal generation of NO leading to renal vasoconstriction and Na retention by the unopposed effect of endogenous Ang II.

Conflicting results have been reported about the interactions between NO and endogenous Ang II in the renal circulation. Ohishi et al¹⁰ have shown that both afferent and efferent rat arterioles pretreated with Ang II antagonists had a reduced vasoconstrictor response to NO inhibition. Similarly, in micropuncture studies in rats De Nicola et al¹¹ have reported interactions between NO and endogenous Ang II at the glomerular level based on the effects of losartan upon hemodynamic changes secondary to NOS inhibition. Sigmon and colleagues^{12 13 14} have found a blunted increase in renal vascular resistance (RVR) in response to NO inhibition in anesthetized rats with suppressed renin-angiotensin system. In contrast, Baylis et al⁹ have observed no effect of both inhibition of Ang II synthesis with captopril and Ang II blockade with losartan on renal vasoconstriction due to L-NAME infusion in conscious rats. Similar results have been reported by Deng et al^{15 16} in anesthetized rats.

Until now, no studies have been made in humans on the relationship between tonic NO-dependent regulation of renal hemodynamics and endogenous Ang II. Thus, we have conducted the present study in healthy, Na-repleted humans to investigate the renal effects of acute NOS blockade with systemic, low-dose infusion of L-NAME during placebo or short-term Ang II blockade with losartan.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Subjects
Seven healthy subjects, one male and six females, chosen among the medical staff of Istituto di Patologia Medica at the University of Parma, participated in the study after the protocol had been approved by the ethics committee of our institution and written informed consent had been obtained by each subject. The following inclusion criteria were used. All the subjects were aged less than 40 years; had no evidence or history of disease of heart, liver, kidneys or endocrine organs; had not abused alcohol or drugs; and were not currently under medical treatment. Prior to the study all subjects had a clinical examination, blood pressure measurement, electrocardiogram, and laboratory screening. Clinical data and laboratory results are given in Table 1.

View this table: [in this window] [in a new window]   Table 1. Basic Clinical and Laboratory Characteristics of 7 Healthy Subjects Participating in the Study

Experimental Procedure
Each subject underwent two L-NAME infusion studies, the first after a 3-day placebo treatment, the second after a 3-day 50-mg per day losartan oral treatment. Placebo or losartan tablets were taken at 10 PM. In women experiments were performed around the midpoint of the menstrual cycle. Before each experiment subjects were maintained for 5 days on a controlled diet providing 240 mmol Na, 80 mmol K, and 1800 to 2400 kcal per day. At 10 PM of the day prior the study, each subject received 8 mmol lithium (Li) as carbonate salt, the exogenous Li being used as an approximate marker of proximal tubular reabsorption.^{17 18 19 20}

After an overnight fast, infusion experiments were initiated at 8 AM. After a blood sample was drawn for the control of para-aminohippuric acid (PAH) and inulin measurement and hematocrit, a plastic indwelling catheter was placed into an antecubital vein and a priming dose of 3.000 mg/1.73 m² body surface area inulin (Inutest 25% solution) and 600 mg/1.73 m² of PAH (20% solution) was injected. Then an infusion of PAH and inulin in saline solution was initiated using a 50-mL syringe precision pump (Perfusion Secura, Braun) at a rate adjusted to obtain plasma levels around 1.5 mg/dL for PAH and 20 mg/dL for inulin. The infusion continued throughout the entire study, which was performed with the subjects in a sitting position. A second indwelling catheter for blood sampling was immediately placed at the contralateral arm and kept patent by constant infusion of 1.0 mL/h of saline solution.

After 60 minutes of equilibration (-45 minutes time), subjects emptied their bladders; then a 45-minute baseline clearance period was initiated. After 45 minutes, subjects then voided a pump infusion of 3.0 µg · kg^-1 · min^-1 of L-NAME in saline solution was initiated and maintained until the end of the study. Two further 45-minute clearance periods were performed (0 to 45 minutes and 45 to 90 minutes, respectively) then the experiment was stopped.

A 300-mL tap water load was administered hourly throughout the study in order to ensure an appropriate urine flow. Blood pressure and pulse rate were measured every 5 minutes using an automatic monitoring device (TM 2421, A and D Co Ltd). Samples from urine volume excreted during each clearance period were taken for Na, Li, and NO₂ + NO₃ sum (UNO_xV). Samples for plasma PAH and inulin were drawn every 15 minutes during the entire study. Samples for plasma Na and Li were taken at -45, 0, +45 and +90 minutes.

Calculations
A satisfactory steady state of plasma concentration of PAH and inulin was obtained with our infusion technique.^{17 18} The variability in plasma PAH and inulin measured throughout infusion was of the same order of magnitude as the coefficient of variability found in duplicate analysis of single plasma samples (2.4% for PAH and 3.6% for inulin). Thus, ERPF and GFR were calculated without measuring PAH and inulin in urine according to Schnurr et al.^{17 18 21} For this purpose, PAH and inulin were measured in the infusate, and infusion rates were calculated by multiplying their concentrations for the volume of infusion solution per min. By dividing the infusion rate for each measured plasma concentration, we obtained four values in the baseline period and three in each L-NAME period for both ERPF and GFR.

The mean values were used in the expression of data for each clearance period. Filtration fraction (FF) was calculated by dividing GFR for ERPF, RBF by dividing ERPF for (1-hematocrit) and RVR from MAP and RBF. Clearances of Li (C_Li) and Na (C_Na) were calculated with standard formula using the mean plasma value between the beginning and the end of each period. Baseline plasma Li ranged 0.10 to 0.18 mmol · L^-1 according to the subject body size. Fractional excretion of Li and Na (FE_Li and FE_Na) were obtained by dividing C_Na and C_Li for GFR.

Study Drugs
PAH (20% solution) was purchased from J. Monico, Venice, Italy and Inutest by Laevosan Gesellschaft, Linz, Austria. Commercially available 50-mg losartan tablets (Lortaan; Merck, Sharp, and Dohme) were used. Pharmaceutical grade L-NAME was obtained by Clinalfa, Läufelfingen, Switzerland.

Analytical Methods
Na was measured by flame photometry and Li by atomic absorption spectrophotometry; plasma and infusate PAH and inulin were measured as previously described^{17 18} ; and UNO_x was measured according to the method of Gilliam et al²² with minor changes.

Statistical Methods
Data are expressed as the mean±SEM. ANOVA was used to compare the results obtained in different study periods in the same experiment and paired Student’s t test for the results of the same study period between the two experiments.

	Results

Top Abstract Introduction Methods Results Discussion References

 
No adverse effect due to losartan or L-NAME administration was observed. Table 2 summarizes the results of our experiments for MAP and renal hemodynamics. L-NAME infusion after placebo was followed by a slight but significant rise in MAP, which was evident however only after 45 minutes of L-NAME infusion (Fig 1). Renal hemodynamics was widely altered by L-NAME even at 0 to 45 minutes when MAP was unchanged. In that period GFR diminished by about 8% (Fig 1) and ERPF declined by 11.7% (Fig 2). FF rose slightly but significantly and RVR increased by 13%. All these changes were more pronounced, although not significantly, in the second infusion period, when RVR was 20.6% higher than that calculated at baseline. Baseline MAP and renal hemodynamic values were not modified by losartan pretreatment. On the contrary, the increase in MAP observed at the 45- to 90-minute period was completely abolished by the previous Ang II blockade (Fig 1).

View this table: [in this window] [in a new window]   Table 2. Effects of Infusion of 3.0 µg · kg -1 · min-1 of L-NAME on MAP and Renal Hemodynamics in 7 Healthy Subjects Pretreated With Placebo or 50 mg Losartan for 3 Days

View larger version (25K): [in this window] [in a new window]   Figure 1. Effect of 3.0 mg · kg-1 · min-1 infusion of L-NAME on mean arterial pressure (MAP, mm Hg) and glomerular filtration rate (GFR, mL/min 1.73 m2) in seven healthy subjects after a 3-day treatment with placebo or losartan 50 mg per day. Mean±SEM. *P<.001 versus baseline; P<.001 versus placebo 0 to 45 minutes and versus losartan 45 to 90 minutes.

View larger version (26K): [in this window] [in a new window]   Figure 2. Effect of 3.0 mg · kg-1 · min-1 infusion of L-NAME on effective renal plasma flow (ERPF, mL/min 1.73 m2) and renal blood flow (RBF, mL/min 1.73 m2) in seven healthy subjects after a 3-day treatment with placebo or losartan 50 mg per day. Mean±SEM. *P<.001 versus baseline.

In Table 3 we show the effect of L-NAME on renal handling of Na and Li and renal excretion of NOx. Both absolute and fractional (Fig 3) excretion of Na and Li declined progressively during L-NAME, with values of U_NaV, FE_Na, C_Li and FE_Li even significantly lower in the 45- to 90-minute period in comparison with 0 to 45 minutes. These changes were not prevented by losartan. Baseline UNOxV was not modified by losartan. L-NAME infusion produced a similar marked decrease in UNO_xV with placebo and losartan.

View this table: [in this window] [in a new window]   Table 3. Effects of Infusion of 3.0 µg · kg-1 · min-1 of L-NAME on Renal Handling of Na and Li and on Urinary Excretion of NO2 Plus NO3 (N0x) in 7 Healthy Subjects Pretreated With Placebo or 50 mg Losartan for 3 Days

View larger version (24K): [in this window] [in a new window]   Figure 3. Effect of 3.0 mg · kg-1 · min-1 infusion of L-NAME on fractional renal excretion of Na (FENa) and Li (FELi) in seven healthy subjects after a 3-day treatment with placebo or losartan 50 mg per day. Mean±SEM. *P<.001 versus baseline; P<.005 versus 0 to 45 minutes losartan; #P<.05 versus 0 to 45 minutes placebo; P<.001 versus 0 to 45 minutes.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The aim of the present study in humans was to investigate whether the basal NO-dependent vasodilator tone exerts its action on renal hemodynamics and Na handling by counterbalancing the effects of endogenous Ang II. Systemic low-rate infusion of L-NAME was adopted to minimize any confounding effect of changes in MAP on the L-NAME-induced variations at the renal level. Actually, animal studies have shown that simultaneous elevations in renal perfusion pressure produce wide alterations in both renal hemodynamic and tubular responses to NOS inhibition. Such alterations include marked increase in both afferent and efferent arteriolar tone, while local intrarenal NOS inhibition leads to much smaller changes in afferent tone and no variations in efferent tone.^{2 5} In addition the antinatriuretic action of NOS inhibition, which may be evident even at doses of inhibitor devoid of any renal hemodynamic effect⁸ is blunted or reversed, with consequent natriuresis, dependently on the magnitude of simultaneous rise in MAP, probably as the result of a "pressure-natriuresis" mechanism.⁸ Since with our experimental design a slight increase in MAP was seen only after at least 45 minutes of L-NAME infusion, our findings show that substantial renal vasoconstriction, reduction in GFR, and elevation in FF result from NOS inhibition in humans independently of any changes in MAP. This indicates a greater sensitivity of the kidney in comparison with other vascular tissues to NOS blockade in agreement with that observed previously in dogs and rats.^{6 23 24}

U_NaV was considerably decreased during L-NAME, in spite of a relatively smaller decline in GFR, with a consequent reduction in FE_Na. In addition, not only C_Li but also FE_Li declined substantially. Taken together, these results suggest an effect of NO on Na reabsorption at the tubular level, the drop of FE_Li pointing to an important action on the proximal tubule. Because of the well-known limitations of Li as a marker of proximal reabsorption due to the possibility that a portion of Li delivered from the proximal tubule is reabsorbed at more distal tubular sites,^{17 18 19 20} some caution should be taken in interpreting C_Li-derived data. Our subjects, however, were Na repleted and received a substantial although not maximal water load during infusion. Since these experimental conditions should have been able to minimize any distal Li reabsorption,^{19 20} our data would indicate a substantial, although not exclusive, effect of NOS inhibition on proximal tubular reabsorption, in agreement with the results of Bech et al⁴ in human studies with L-NMMA infusion.

Recent observations^{25 26} have shown that both NOS expression and NO concentration in renal medullary tissue are much higher than in cortical tissue. On this basis it can be suggested that NO produced in the renal medulla rather than in the renal cortex plays a major role in renal Na handling as well as in medullary blood flow regulation.²⁶ These findings can argue against the proximal tubule as an important site of NO-dependent modulation of tubular Na reabsorption. On the other hand, the increase in proximal reabsorption we show in response to L-NAME might be a consequence not only of a direct effect of cortical NOS inhibition on the proximal tubule, but also of changes in glomerular hemodynamics and in peritubular physical forces. These include a reduced filtered load, an increased FF with elevation in peritubular oncotic pressure or a fall in peritubular hydrostatic pressure owing to glomerular vasoconstriction. In addition our data do not exclude an effect of NO on distal Na reabsorption since FE_Na declined by 44% and FE_Li by 31% with L-NAME infusion.

Changes in renal hemodynamics and tubular function due to L-NAME were accompanied by a 25-30% to 55-60% reduction in the excretion rate of NO₂+NO₃ (UNO_xV). UNO_xV is generally considered a good marker of NO generation in the body.^{27 28} Although it is known that UNO_xV is markedly blunted by intrarenal infusion of NOS inhibitors,²⁹ one cannot assume that changes in UNO_xV such as those we show reflect precisely the entity of NOS blockade in the kidney. Actually UNO_xV is widely influenced by a number of factors other than renal NO production. These include the rate of systemic NO generation, the amount of filtered and then reabsorbed NO_x as well as dietary nitrate intake and other metabolic sources of nitrate.^{27 28 29} More importantly for the purpose of the present study, baseline UNO_xV and its decline during L-NAME were the same after placebo and losartan, thus indicating that the overall NO_x metabolism and presumably the degree of NOS inhibition with L-NAME were not affected by Ang II blockade.

Baseline MAP, renal hemodynamics and tubular Na and Li handling were not changed by losartan pretreatment with respect to placebo. This agrees with previous observations of no systemic or renal effects of losartan in sodium repleted healthy humans.^{30 31}

Our subjects received the last dose of losartan ten hours before the start of infusion study in order to prevent any possible acute renal change due to a very recent drug administration. Studies in humans³² have shown that at this time from one single 50-mg administration the effect of pressor doses of Ang II is still substantially blunted by losartan owing to the long half-life of its main, pharmacologically active metabolite. In addition, it has been observed recently that one single dose of 50 mg losartan is able to prevent almost completely renal vasoconstriction secondary to low-rate infusion of Ang II in Na repleted humans.³¹ The "clinical" doses administered in the present as well as in other^{30 31 32} human studies (less than 1 mg/kg per day) are much lower than those used in animal studies to block AT₁ receptors (3 mg/kg in the study of Baylis et al⁹ ). However, since the above reported findings^{31 32} showed that clinical doses of losartan counteract effectively both systemic and renal effects of exogenous Ang II, after a 3-day pretreatment with 50 mg per day the pharmacological actions of losartan or of its metabolites upon AT₁ receptors should have been fully expressed during L-NAME infusion.

Losartan pretreatment completely abolished the slight but definite rise in MAP we observed from 45 to 90 minutes of L-NAME infusion. This is in keeping with previous studies showing that systemic hemodynamic changes elicited by acute or chronic NO blockade are effectively prevented or at least attenuated not only by Ang II receptor antagonists but also by calcium channel blockers, ACE inhibitors and ₁-adrenergic blocking agents.^{9 33 34 35 36}

At the renal level, however, hemodynamic and cation handling changes due to L-NAME infusion were not prevented by losartan. This indicates that, at least in Na repleted state, vasoconstriction and tubular Na retention following NOS inhibition in human kidney are not due to the unopposed effects of endogenous Ang II.

Our findings are in agreement with several previous animal studies showing no interactions in the kidney between basal NO production and endogenous Ang II. Baylis et al⁹ in salt-repleted, chronically instrumented, conscious rats showed that both losartan and captopril are unable to prevent renal vasoconstriction produced by systemic L-NAME. Very similar results are reported by Deng et al^{15 16} in anesthetized rats irrespectively of high or low Na intake. In these latter studies, the effects of Ang II blockade on the renal action of L-NAME were investigated in the presence of marked elevations in MAP. Under such an experimental condition, however, Ang II blockade could appear to be ineffective in preventing L-NAME–induced renal vasoconstriction because of prevailing contribution of a pressure-induced, Ang II-independent component superimposed to the renal vasoconstriction due to NOS inhibition itself. Since in our study there was no change in renal perfusion pressure, this possible confounding effect is ruled out.

A number of studies in rats and dogs have shown important interactions between NO and infused (not endogenous) Ang II in the control of renal hemodynamics. Ikenaga et al³⁷ have observed that basal NO production attenuates the vasoconstrictor effect of Ang II in both afferent and efferent arterioles in an in vitro blood perfused, nephron preparation. Parekh et al³⁸ have confirmed this result in anesthetized rats. Baylis et al³⁹ have shown a 10-fold amplification of renal vasoconstriction following systemic infusion of Ang II in response to simultaneous administration of L-NAME in rats. Similar results are reported by Deng et al¹⁶ and by Granger et al,⁶ Alberola et al,⁷ Snackenberg et al⁴⁰ in dogs receiving intrarenal infusion of both L-NAME and Ang II. L-NAME exerts its potentiating action mainly upon afferent arteriole, where Ang II itself elicits much less vasoconstriction than at the efferent level.⁴⁰ This suggests an important protective role of NO to maintain renal hemodynamics in the presence of an excess of intrarenal Ang II.⁴⁰ Baylis and Qiu⁴¹ have recently pointed out that important interactions between NO and Ang II may be observed in animal study not only when exogenous Ang II is administered, but also when intrarenal renin-angiotensin system is in some way stimulated by the experimental manipulation, such as anesthesia, acute surgical stress or preparation for micropuncture experiments. This may explain the results of several investigations performed with micropuncture^{11 41} or in whole, anesthetized rats^{12 13 14} showing that endogenous Ang II contributes to the glomerular hemodynamic response to acute systemic NOS inhibition. On the contrary, when Ang II in the kidney is reduced at the minimal level, such as in our Na-repleted healthy humans the effect of NOS inhibition are largely independent of Ang II.

In conclusion, in the present study we demonstrate that NO exerts in humans its tonic control on basal renal hemodynamics and tubular Na handling independently of endogenous Ang II. It is conceivable, however, that interactions between NO and Ang II become important under different experimental or pathophysiological conditions, such as volume depletion and renal hypoperfusion where renal function is largely influenced by elevated intrarenal concentrations of Ang II. This point deserves further elucidation in studies in humans.

	Selected Abbreviations and Acronyms

 

L-NMMA = NG-monomethyl-L-arginine L-NAME = NG-nitro-L-arginine methyl ester L-NNA = NG-nitro-L-arginine NOS = nitric oxide synthase MAP = mean arterial pressure ERPF = effective renal plasma flow RBF = renal blood flow GFR = glomerular filtration rate FF = filtration fraction

Received March 17, 1997; first decision April 17, 1997; accepted May 7, 1997.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Baylis C, Harton P, Engels K. Endothelial derived relaxing factor (EDRF) controls renal hemodynamics in the normal rat kidney. J Am Soc Nephrol. 1990;1:875-881.[Abstract]

2. Raij L, Baylis C. Nitric oxide and the glomerulus. Kidney Int. 1995;48:20-32.[Medline] [Order article via Infotrieve]

3. Haynes WG, Noon JP, Walker BR, Webb DJ. Inhibition of nitric oxide synthesis increases blood pressure in healthy humans. J Hypertension. 1993;11:1375-1380.[Medline] [Order article via Infotrieve]

4. Bech JN, Nielsen CB, Pedersen EB. Effects of systemic NO synthesis inhibition on RPF, GFR, U_Na, and vasoactive hormones in healthy humans. Am J Physiol. 1996:F845-F851.

5. Deng A, Baylis C. Locally produced EDRF controls preglomerular resistance and ultrafiltration coefficient. Am J Physiol. 1993;264:F212-F215.[Medline] [Order article via Infotrieve]

6. Granger JP, Alberola AM, Salazar FJ, Nakamura T. Control of renal hemodynamics during intrarenal and systemic blockade of nitric oxide synthesis in conscious dogs. J Cardiovasc Pharmacol. 1992;20(suppl 12):S160-S162.

7. Alberola AM, Salazar FJ, Nakamura T, Granger JP. Interactions between angiotensin II and nitric oxide in control of renal hemodynamics in conscious dogs. Am J Physiol. 1994;267:R1472-R1478.[Medline] [Order article via Infotrieve]

8. Lahera V, Salom MG, Miranda Guardiola F, Moncada S, Romero JC. Effects of N^G-nitro-L-arginine methyl ester on renal function and blood pressure. Am J Physiol. 1991;261:F1033-F1037.[Medline] [Order article via Infotrieve]

9. Baylis C, Engels K, Samsell L, Harton P. Renal effects of acute endothelial-derived relaxing factor blockade are not mediated by angiotensin II. Am J Physiol. 1993;264:F74-F78.[Medline] [Order article via Infotrieve]

10. Ohishi K, Carmines PK, Inscho EW, Navar LG. EDRF-angiotensin II interactions in rat juxtamedullary afferent and efferent arterioles. Am J Physiol. 1992;263:F900-F906.[Medline] [Order article via Infotrieve]

11. De Nicola L, Blantz RC, Gabbai FB. Nitric oxide and angiotensin II. Glomerular and tubular interaction in the rat. J Clin Invest. 1992;89:1248-1256.[Medline] [Order article via Infotrieve]

12. Sigmon DH, Carretero OA, Beierwaltes WH. Plasma renin activity and the renal response to nitric oxide synthesis inhibition. J Am Soc Nephrol. 1992;3:1288-1294.[Abstract]

13. Sigmon DH, Beierwaltes WH. Angiotensin II: nitric oxide interaction and the distribution of blood flow. Am J Physiol. 1993;265:R1276-R1283.[Medline] [Order article via Infotrieve]

14. Sigmon DH, Carretero OA, Beierwaltes WH. Angiotensin dependence of endothelium-mediated renal hemodynamics. Hypertension. 1992;20:643-650.[Abstract/Free Full Text]

15. Deng X, Welch WJ, Wilcox CS. Renal vasoconstriction during inhibition of NO of synthase: effects of dietary salt. Kidney Int. 1994;46:639-646.[Medline] [Order article via Infotrieve]

16. Deng X, Welch WJ, Wilcox CS. Role of Nitric Oxide in short-term and prolonged effects of Angiotensin II on renal hemodynamics. Hypertension. 1996;27:1173-1179.[Abstract/Free Full Text]

17. Montanari A, Vallisa D, Ragni G, Guerra A, Colla R, Novarini A, Coruzzi P. Abnormal renal responses to calcium entry blockade in normotensive offspring of hypertensive parents. Hypertension. 1988;12:498-505.[Abstract/Free Full Text]

18. Montanari A, Ragni G, Vallisa D, Giucastro G, Serventi M, Perinotto P, Colla R, Novarini A. Role of blood pressure in the natriuretic response to acute calcium channel blockade in humans. J Cardiovasc Pharmacol. 1991;17:724-730.[Medline] [Order article via Infotrieve]

19. Boer WH, Koomans HA, Dorhout Mees EJ, Gaillard GA, Rabelink AJ. Lithium clearance during variations in sodium intake in man: effects of sodium restriction and amiloride. Eur J Clin Invest. 1988;18:279-283.[Medline] [Order article via Infotrieve]

20. Kirchner KA. Lithium as a marker for proximal tubular delivery during low salt intake and diuretic infusion. Am J Physiol. 1987;253:F188-F196.[Medline] [Order article via Infotrieve]

21. Schnurr E, Lahmf W, Kuppers H. Measurement of renal clearance of inulin and PAH in the steady state without urine collection. Clin Nephrol. 1980;13:26-29.[Medline] [Order article via Infotrieve]

22. Gilliam MB, Sherman MP, Griscavage JM, Ignarro LJ. Spectrophotometer assay for nitrate using NADPH oxidation by Aspergillus nitrate reductase. Anal Biochem. 1993;212:359-365.[Medline] [Order article via Infotrieve]

23. Walder CE, Thiemermann C, Vane JR. The involvement of endothelium-deprived relaxing factor in the regulation of renal cortical blood flow in the rat. Br J Pharmacol. 1991;102:967-973.[Medline] [Order article via Infotrieve]

24. Slangen B, Weaver C, Baylis C. Renal effects of low dose nitric oxide (NO) inhibition in the rat. J Am Soc Nephrol. 1993;4:569A.

25. Mattson DL, Higgins DJ. Influence of dietary sodium on renal medullary nitric oxide synthase. Hypertension. 1996;27(pt 2):688-692.

26. Zou A-P, Cowley Jr AW. Nitric oxide in Renal cortex and medulla. An In Vivo Microdialysis study. Hypertension. 1997;29(pt 2):194-198.

27. Wennmalm A, Benthin G, Edlund A, Jungestern L, Kieler-Jensen N, Lundin S, Westfelt UN, Petersson A-S, Waagstein F. Metabolism and excretion of nitric oxide in humans: an experimental and clinical study. Circ Res. 1993;73:1121-1127.[Abstract/Free Full Text]

28. Süto T, Losonczy G, Qiu C, Hill C, Samsell Ruby J, Charon N, Venuto R, Baylis C. Acute changes in urinary excretion of nitrite and nitrate (U_noxV) do not predict vascular NO production. Kidney Int. 1995;48:1272-1279.[Medline] [Order article via Infotrieve]

29. Majid DSA, Godfrey M, Grisham MB, Navar LG. Relation between pressure natriuresis and urinary excretion of nitrate/nitrite in anesthetized dogs. Hypertension. 1995;25(pt 2):860-865.

30. Burnier M, Rutschmann B, Nussberger J, Versaggi J, Shaini S, Waeber B, Brunner HR. Salt-dependent renal effects of angiotensin II antagonist in healthy subject. Hypertension. 1993;22:339-347.[Abstract/Free Full Text]

31. Gandhi SK, Ryder DH, Brown NJ. Losartan blocks Aldosterone and renal vascular Responses to Angiotensin II in humans. Hypertension. 1996;28:961-966.[Abstract/Free Full Text]

32. Munafo H, Christen Y, Nussberger J, Shum LY, Borland RM, Lee RJ, Waeber B, Biollaz J, Brunner HR. Drug concentration response relationship in normal volunteers after oral administration of losartan, an angiotensin II receptor antagonist. Clin Pharmacol Ther. 1992;51:513-521.[Medline] [Order article via Infotrieve]

33. Qiu CB, Engels K, Baylis C. Angiotensin II and alpha (1)-adrenergic tone in chronic nitric oxide blockade-induced hypertension. Am J Physiol. 1994;266:R1470-R1476.[Medline] [Order article via Infotrieve]

34. Henrion D, Dowell FJ, Levy BI, Michel JB. In vitro alteration of aortic vascular reactivity in hypertension induced by chronic N^G-nitro-L-arginine methyl ester. Hypertension. 1996;28:361-366.[Abstract/Free Full Text]

35. Pollock DM, Polakowski JS, Divish BJ, Opgenorth TJ. Angiotensin blockade reverses hypertension during long-term nitric oxide synthase inhibition. Hypertension. 1993;21:660-666.[Abstract/Free Full Text]

36. Kung CF, Moreau P, Takase H, Luscher TF. L-NAME hypertension alters endothelial smooth muscle function in rat aorta: prevention by trandoprilat and verapamil. Hypertension. 1995;26:744-751.[Abstract/Free Full Text]

37. Ikenaga H, Fallet RW, Carmines PK. Basal nitric oxide production curtails arteriolar vasoconstrictor responses to Ang II in rat kidney. Am J Physiol. 1996;271:F365-F373.[Medline] [Order article via Infotrieve]

38. Parekh N, Dobrowolski L, Zou AP, Steinhausen M. Nitric oxide modulates angiotensin II and norepinephrine-dependent vasoconstriction in rat kidney. Am J Physiol. 1996;270:R630-R635.[Medline] [Order article via Infotrieve]

39. Baylis C, Harvey J, Engels K. Acute nitric oxide inhibition amplifies the renal vasoconstrictor actions of angiotensin II. J Am Soc Nephrol. 1994;5:211-214.[Abstract]

40. Schnackenberg CG, Clayton Wilkins F, Granger JP. Role of nitric oxide in modulating the vasoconstrictor actions of Angiotensin II in preglomerular and postglomerular vessels in dogs. Hypertension. 1995;26:1024-1029.[Abstract/Free Full Text]

41. Baylis C, Qiu C. Importance of nitric oxide in the control of renal hemodynamics. Kidney Int. 1996;49:1727-1731.

This article has been cited by other articles:

				C. Delles, A. U. Klingbeil, M. P. Schneider, R. Handrock, T. Schaufele, and R. E. Schmieder The role of nitric oxide in the regulation of glomerular haemodynamics in humans Nephrol. Dial. Transplant., June 1, 2004; 19(6): 1392 - 1397. [Abstract] [Full Text] [PDF]

				M. Graebe, L. Brond, S. Christensen, S. Nielsen, N. V. Olsen, and T. E. N. Jonassen Chronic nitric oxide synthase inhibition exacerbates renal dysfunction in cirrhotic rats Am J Physiol Renal Physiol, February 1, 2004; 286(2): F288 - F297. [Abstract] [Full Text] [PDF]

				M. Liang, T. J. Berndt, and F. G. Knox Mechanism underlying diuretic effect of L-NAME at a subpressor dose Am J Physiol Renal Physiol, September 1, 2001; 281(3): F414 - F419. [Abstract] [Full Text] [PDF]

				P. PERINOTTO, A. BIGGI, N. CARRA, A. ORRICO, G. VALMADRE, P. DALL'AGLIO, A. NOVARINI, and A. MONTANARI Angiotensin II and Prostaglandin Interactions on Systemic and Renal Effects of L-NAME in Humans J. Am. Soc. Nephrol., August 1, 2001; 12(8): 1706 - 1712. [Abstract] [Full Text] [PDF]

				A. Broere, A. H. Van Den Meiracker, F. Boomsma, F. H. M. Derkx, A. J. Man In'T Veld, and M. A. D. H. Schalekamp Human renal and systemic hemodynamic, natriuretic, and neurohumoral responses to different doses of L-NAME Am J Physiol Renal Physiol, December 1, 1998; 275(6): F870 - F877. [Abstract] [Full Text] [PDF]

				L.-T. Dijkhorst-Oei, J. J. Beutler, E. S.G. Stroes, H. A. Koomans, and T. J. Rabelink Divergent effects of ACE-inhibition and calcium channel blockade on NO-activity in systemic and renal circulation in essential hypertension Cardiovasc Res, November 1, 1998; 40(2): 402 - 409. [Abstract] [Full Text] [PDF]

				A. Montanari, E. Tateo, E. Fasoli, A. Donatini, B. Cimolato, P. Perinotto, and P. Dall'Aglio Dopamine-2 Receptor Blockade Potentiates the Renal Effects of Nitric Oxide Inhibition in Humans Hypertension, January 1, 1998; 31(1): 277 - 282. [Abstract] [Full Text] [PDF]

This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Montanari, A. Articles by Dall’Aglio, P. Search for Related Content PubMed PubMed Citation Articles by Montanari, A. Articles by Dall’Aglio, P.