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Deoxycorticosterone Suppresses the Effects of Losartan in Nitric Oxide—Deficient Hypertensive Rats

MARIA C. DE GRACIA^*, ANTONIO OSUNA^*, FRANCISCO O'VALLE, RAIMUNDO G. DEL MORAL, ROSEMARY WANGENSTEEN, CIPRIANO GARCIA DEL RIO and FELIX VARGAS

^* Experimental Unit, Nephrology Service, Hospital Virgen de las Nieves, Granada, Spain.
Department of Anatomical Pathology, Faculty of Medicine, Granada, Spain.
Department of Physiology, Faculty of Medicine, Granada, Spain.

Correspondence to Dr. F. Vargas, Departamento de Fisiología, Facultad de Medicina, E-18012, Granada, Spain. Phone: 34-958-243520; Fax: 34-958-246179; E-mail: fvargas{at}goliat.ugr.es

	Abstract

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Abstract. Chronic inhibition of the renin angiotensin system prevents increased BP and renal injury in N^G-nitro-L-arginine methyl ester (L-NAME) hypertension. However, a relationship between plasma renin activity and the protective effect of chronic angiotensin II (Ang II) blockade has not been established. With this background, this study was undertaken to evaluate how the chronic administration of deoxycortisone acetate (DOCA) modifies the effects of losartan on BP, renal injury, and other variables in L-NAME hypertensive rats. The following groups were used: Control, DOCA, L-NAME, L-NAME + losartan, L-NAME + DOCA, and L-NAME + DOCA + losartan. Tail systolic BP was measured twice a week. After 4-wk evolution, mean arterial pressure and metabolic, morphologic, and renal variables were measured. The final mean arterial pressure values were 116 ± 6 mmHg for control, 107 ± 2 mmHg for DOCA, 151 ± 5 mmHg for L-NAME, 123 ± 2 mmHg for L-NAME + losartan, 170 ± 3 mmHg for L-NAME + DOCA, and 171 ± 5.5 mmHg for L-NAME + DOCA + losartan. Losartan prevented microalbuminuria, hyaline arteriopathy, and glomerulosclerosis of L-NAME hypertension but was ineffective in L-NAME + DOCA—treated rats. Plasma protein was significantly reduced in the L-NAME + DOCA group when compared with control and L-NAME groups, whereas no significant differences were observed in the other groups. Plasma renin activity was suppressed in the DOCA (0.55 ± 0.2) and L-NAME + DOCA (0.60 ± 10.2) groups but unsuppressed in the L-NAME + DOCA + losartan group (5.8 ± 1). The conclusion is that DOCA blocks the preventive effect of losartan on the increased BP and renal injury of L-NAME hypertension, which suggests that DOCA transforms L-NAME hypertension into an Ang II—independent model of hypertension. These data also suggest that losartan prevents L-NAME hypertension by blocking the activity of systemic Ang II.

	Introduction

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Chronic inhibition of nitric oxide (NO) synthesis by N^G-nitro-L-arginine methyl ester (L-NAME) induces a dose- and time-dependent arterial hypertension (1,2,3). The mechanisms that underlie this effect are not completely elucidated, but there is considerable evidence to suggest that the renin angiotensin system (RAS) plays a major role in the pathogenesis of this experimental model. The participation of RAS is supported by data showing that chronic AT₁ receptor blockade or angiotensin-converting enzyme inhibition prevents the development of L-NAME hypertension and reverses it, as well as prevents or attenuates the arteriolar and glomerular injuries produced in this model of hypertension (2,4,5,6,7). However, a relationship between circulating RAS and the protective effect of chronic angiotensin II (Ang II) blockade has not been established.

The chronic administration of deoxycorticosterone acetate (DOCA) induces sodium retention and in the presence of a high salt intake produces a volume-dependent type of hypertension (8,9). This model of hypertension courses with suppressed plasma renin activity (PRA), whereas renal RAS is not suppressed in dogs (10) or rats (11). The administration of DOCA to normal rats without an increased saline intake suppressed PRA but did not increase BP (8,12,13).

The Ang II receptor antagonists exert antihypertensive effects in high- and normal-renin hypertension models (14). However, the acute and chronic administration of these inhibitors does not reduce BP in low-renin hypertensive (DOCA+salt) rats (11,14,15,16) or dogs (10), although it increases natriuresis (10) and ameliorates renal injury (11,15). With this background, we decided to evaluate how the chronic administration of DOCA modifies the effects of losartan, an AT₁ Ang II receptor antagonist, on BP, renal injury, and other variables in L-NAME hypertensive rats.

	Materials and Methods

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Male Wistar rats that were born and raised at the animal center of the University of Granada were used. The experiments were performed according to European Union guidelines for the ethical care of animals. Rats that initially weighed 200 to 250 g were randomly assigned to different experimental groups. All animals had free access to standard rat diet with a sodium content of 0.5% (rodent toxicology diet, B&K, Barcelona, Spain) and tap water ad libitum, except where stated.

Experimental Protocol
Effects of DOCA and Losartan on the Development of L-NAME Hypertension. The rats were randomly divided into six groups: control, L-NAME treated (NAME), DOCA treated (DOCA), L-NAME plus DOCA treated (NAME+DOCA), L-NAME plus losartan treated (NAME+LOS), and L-NAME plus losartan and DOCA treated (NAME+DOCA+LOS) (n = 8 in all groups). L-NAME and losartan were given in the drinking water at a concentration of 35 mg/100 ml and 20 mg/100 ml, respectively, resulting in a daily intake of approximately 25.4 and 14.5 mg/kg per d. The concentration of L-NAME and losartan in the NAME+DOCA, NAME+LOS, and NAME+DOCA+LOS groups was adjusted every 2 d, according to their respective fluid intake, to ensure that a similar dose of both substances was given. DOCA was administered subcutaneously at a dose of 12.5 mg/rat per wk. All treatments were started at the same time and were maintained for 4 wk.

Body weight and tail systolic BP (SBP) were determined twice a week during the course of the experiment. The SBP was measured by tail-cuff plethysmography in unanesthetized rats (LE 5001-Pressure Meter, Letica SA, Barcelona, Spain). At least seven determinations were made at every session, and the mean of the lowest three values within a range of 5 mmHg was recorded as the SBP level.

After the time course study, all animals were housed in metabolic cages with free access to food and their respective drinking fluids. After 2 d of adaptation, the food and water intake and urine values were gathered during two consecutive days. The values obtained on each experimental day were averaged for statistical purposes. The urinary variables measured were diuresis, natriuresis, kaliuresis, creatinine, and microalbuminuria.

After the metabolic study was completed, the femoral artery was cannulated. After a 24-h recovery period, direct BP and heart rate were recorded continuously for 60 min. The values obtained during each of the last 30 min were averaged to obtain the mean BP value. Blood samples from the femoral catheter were taken to determine plasma urea, creatinine, electrolytes, total protein, and PRA. Body weight, ventricular weight, and kidney weight were also measured at the end of the study.

Analytical Procedures. PRA was measured following the method of Haber et al. (17). The assay was performed with rat plasma obtained from blood collected in ice-chilled tubes containing sodium ethylenediaminetetraacetate (EDTA). Plasma was incubated at 37°C (pH 7.4) with protease inhibitors (3.4 mM 8-hydroxyquinolone sulfate, 0.25 mM EDTA, 0.1 mM phenylmethyl sulfonyl fluoride, 1.6 mM dimercaprol, and 5 mM sodium tetrathionate) for 2 h. The angiotensin I generated was measured using a RIA kit purchased from CIS Bio International (Gif-Sur-Yvette, Cedex, France). Sodium, potassium, urea, creatinine, and plasma protein were measured on the same day by an autoanalyzer (Beckman CX4, Fullerton, CA). Microalbuminuria was measured by nephelometry.

Histologic Techniques. For conventional morphology, buffered 4% formaldehyde-fixed, paraffin-embedded longitudinal tissue sections in the sagittal plane were stained with hematoxylin and eosin, Masson-Goldner trichromic stain, and periodic acid-Schiff stain. The presence of glomerular lesions (glomerulosclerosis, collapse, necrosis, and microaneurysm) was evaluated in at least 300 glomeruli per section. Tubular atrophy, tubular casts, and vascular alteration (stenosis and hyaline arteriopathy) were also evaluated. The morphologic study was done in a blinded fashion on 3-Fm sections using light microscopy. The values were expressed as the percentage of rats with lesions in each group, and the severity of lesions was calculated semiquantitatively using a 0 to 3+ scale (-, absence; +, mild [<10% of vessels, tubules, or glomeruli involved]; ++, moderate [10 to 25%]; +++, severe [>25%]).

Statistical Analyses
The evolution of tail SBP with time was compared using a nested design. When the overall difference was significant, Bonferroni's method with an appropriate error was used. The remaining variables measured at the end of the experimental period were compared with one-way ANOVA, and subsequent pairwise comparisons were made with the Newman-Keuls test.

	Results

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BP
Figure 1 summarizes the BP data. Figure 1A shows the evolution of the tail SBP measured by plethysmography, and Figure 1B shows the final mean arterial pressure (MAP) measured by direct recording in conscious rats. Rats became hypertensive in response to L-NAME administration; tail SBP significantly increased (P < 0.05) as early as 3 d after the start of treatment. Figure 1 also shows that the DOCA treatment aggravated the L-NAME hypertension: the tail SBP was higher in NAME+DOCA rats throughout the 4 wk of the study. The administration of DOCA alone maintained BP at normal values. The simultaneous administration of losartan markedly attenuated but did not normalize BP in L-NAME—treated rats. However, losartan was ineffective in NAME+DOCA—treated rats. These findings were confirmed by direct measurement from the arterial catheter in conscious rats at the end of the experiment.

View larger version (20K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 1. Time course of systolic BP (SBP) measured by the tail-cuff method (A) and final mean arterial pressure (MAP) measured by direct recording (femoral artery) in conscious rats (B). CONT, control; DOCA, rats treated with DOCA; NAME, rats treated with L-NAME; NAME+DOCA, rats treated with DOCA plus L-NAME; NAME+LOS, rats treated with L-NAME plus losartan; NAME+DOCA +LOS, rats treated with DOCA, L-NAME and losartan. * P < 0.01 versus control, +P < 0.01 versus NAME.

Morphologic Variables
Final body weight was similar in all of the experimental groups. No significant differences were found in ventricular weight, kidney weight, or relative kidney weight. Relative ventricular weight was significantly reduced in the NAME+LOS group, whereas this variable was similar to controls in the rest of the groups (Table 1).

Table 2 lists the results of the morphologic evaluation. The lesions were mild, with the exception of hyaline arteriopathy and glomerulosclerosis. The NO-blocked rat groups (NAME, NAME+DOCA, and NAME+DOCA+LOS) exhibited greater injury in comparison with the control and NAME+LOS rat groups (Table 2). Hyaline arteriopathy was observed in 35.7% of the rats in the NAME+LOS group, although with mild intensity and only in afferent glomerular arterioles (Figure 2). In contrast, the hyaline deposits were more intense in the NAME, NAME+DOCA, and NAME+DOCA+LOS groups and involved afferent glomerular arterioles and interlobular and interlobulillar arteries. Losartan did not protect against renal injury when the rats were treated with L-NAME plus DOCA.

View larger version (40K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 2. Microalbuminuria in the experimental groups. * P < 0.01 versus control, +P < 0.01 versus NAME.

Plasma and Urine Variables
Sodium and urea in plasma were similar in all groups, whereas potassium was significantly reduced in the plasma of all DOCA-treated groups. A tendency to increased plasma levels of creatinine with a concomitant reduction in the GFR was observed in all of the L-NAME—treated groups; in the NAME+DOCA group, this increase was significant. Plasma protein concentrations were significantly reduced in the NAME+DOCA group when compared with control and NAME groups, whereas no significant differences were observed among the other groups. PRA was significantly reduced in the group that was treated with L-NAME alone and suppressed in the DOCA and NAME+DOCA groups. The administration of losartan markedly increased PRA in the NAME+LOS group and inhibited the suppressive effect of DOCA in the NAME+DOCA+LOS group (Table 3).

No significant differences were observed in food and fluid intake between any experimental group and the control group. Diuresis, natriuresis, and kaliuresis were also similar between the control and experimental groups (Table 4). Microalbuminuria was significantly increased in L-NAME rats and further increased in the NAME+DOCA group. Losartan suppressed microalbuminuria in L-NAME rats but was ineffective in NAME+DOCA rats (Figure 3).

View larger version (92K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 3. Hyaline arteriopathy. (A) Interlobular artery with severe hyaline arteriopathy in L-NAME—treated rats (periodic acid-Schiff [PAS] x200). (B) hyaline deposits in the artery wall persist and increase in NAME+ DOCA+LOS-treated rats (PAS x200). (C) Mild hyaline arteriopathy only in afferent glomerular arteriole in NAME+LOS-treated rats (PAS x 200).

	Discussion

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One of the main findings of this study is that the administration of DOCA interferes with the preventive effects of losartan against the elevated BP and increased microalbuminuria, hyaline arteriopathy, and glomerulosclerosis of L-NAME hypertension. That DOCA suppresses PRA, whereas the renal content of renin (11) and Ang II (10) is almost normal, seems to indicate that losartan prevents L-NAME hypertension by blocking the activity of systemic Ang II. Moreover, the significant decrease in plasma protein and the suppressed PRA of the rats treated in the present study with L-NAME and DOCA suggest that DOCA transforms L-NAME hypertension into a volume-dependent type of hypertension.

The chronic administration of losartan had no effects on the BP of the DOCA-treated rats, in line with previous reports on DOCA+salt hypertensive rats treated with losartan (14,16) or other AT₁ receptor blockers (11,14,15).

Increased BP is associated with renal damage and proteinuria in L-NAME and DOCA+salt hypertension. AT₁ blockade reduces BP and ameliorates renal injury and proteinuria in L-NAME hypertension (2,4,5,6,7), whereas in a DOCA+salt model it improves renal damage and proteinuria but does not reduce the elevated BP (11,15). In the present study, renal injury and microalbuminuria were related to the level of BP. Thus, our data on the NAME+DOCA+LOS group contrast with the aforementioned findings in a DOCA+salt model; the cause of these discrepancies is unclear. Nevertheless, we can speculate that the AT₁ blockade produced unsuppressed PRA (Table 3) (11) and hence Ang II in both situations. The unsuppressed circulating and tissular Ang II may act through AT₂ receptors or may produce the fragment angiotensin 1-7, whose activation produces antiproliferative effects via NO (18,19). These protective effects against renal injury may therefore be active in DOCA+salt but not in NAME+DOCA rats.

The treatment of DOCA without salt supplementation did not produce an elevation in BP, consistent with data from Selye et al. (8) on DOCA+salt-induced hypertension that were later confirmed in other reports (12,13). However, when we added DOCA to L-NAME, there was a greater increase in BP and an aggravation of the microalbuminuria and renal parenchymal injury, in comparison with rats that were treated with L-NAME alone. These outcomes may result from the combined impact on renal function of the antinatriuretic effects of DOCA and of the NO inhibition, as seems to be borne out by the reduced PRA and plasma protein levels in the present experimental group. These BP results agree with previous observations of our group (13).

The reduced PRA of L-NAME rats in the present study, when compared with studies using a similar dose (30 mg/100 ml) and time (28 d), agrees with the data of Arnal et al. (1) and Navarro et al. (20) but contrasts with the normal values reported by Jover et al. (4). As expected, the blockade of Ang II with losartan and the consequent removal of negative feedback on renin release resulted in an elevation in PRA, and the administration of DOCA produced a suppression of PRA with and without L-NAME administration. However, when DOCA was administered to rats that were treated simultaneously with L-NAME and losartan, PRA was not suppressed. As reported above, this last observation is consistent with the unsuppressed plasma renin concentration in DOCA+salt hypertensive rats that were treated with enalapril or TCV-116 (an AT₁ receptor blocker) reported by Kim et al. (11). To explain this surprising phenomenon, these authors suggested that the kidney releases differently glycosylated forms of renin that are cleared from the circulation by the liver at a different half-life (21) and that the treatment of rats with RAS inhibitors causes the preferential renal release of the renin form with the longest plasma half-life (22). Thus, the increased plasma renin in DOCA+salt hypertensive rats after inhibition of the RAS may be partially due to the modification of the glycosylation of renin.

The presence of cardiac hypertrophy in the L-NAME model is controversial. Neither group of our L-NAME—treated animals showed an increased heart and left ventricle weight, either absolute or relative to body weight, in agreement with data reported by Arnal et al. (23) but different from previous findings by our group when a higher dose of L-NAME was used (24,25). In these earlier studies, we explained our discrepancies by suggesting that the different doses of L-NAME used could have inhibited the NO synthase isoforms to different degrees in the heart and in other organs involved in the regulation of arterial pressure. This explanation is the same as that given for the different pattern of salt sensitivity in L-NAME hypertension (3). Only the NAME+DOCA group showed a significant reduction in GFR when compared with the control group. The normal plasma levels of creatinine and GFR in the NAME group agree with the results of Pollock et al. (5) but contrast with findings in L-NAME hypertensive rats that were treated for a longer period and with greater doses of L-NAME (24,25).

In conclusion, the results of the present work show that the administration of DOCA blocks the preventive effect of losartan on the increased BP and renal injury of L-NAME hypertension, suggesting that DOCA transforms L-NAME hypertension, an Ang II—dependent model, into a volume-dependent type of hypertension. Our data also suggest that losartan prevents L-NAME hypertension by blocking the activity of systemic Ang II.

	Acknowledgments

 
This study was supported by a grant (SAF97-0194) from the Dirección General de Investigación Científica y Técnica de España. We thank R. Arcas, M. Quintana, and Dr. Rodrí gues for expert technical assistance. We thank R. Davies for revising the English style of the manuscript.

	References

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