Effects of losartan, a nonpeptide angiotensin II receptor antagonist, on cardiac hypertrophy and the tissue angiotensin II content in spontaneously hypertensive rats.

Losartan, a recently developed nonpeptide angiotensin II (Ang II) receptor antagonist, was administered orally to 10-week-old spontaneously hypertensive rats (SHR) for 2 weeks. Cardiac weight and tissue Ang II, as well as plasma renin activity (PRA) and Ang II, were determined. Treatment with Losartan (10 mg/kg per day) lowered blood pressure markedly. Losartan reduced significantly the left ventricular weight by 11% compared with control rats. The left ventricular Ang II content was lowered by Losartan (18.6 +/- 0.9 pg/tissue; 21.9 +/- 0.9 pg/tissue, control, p less than 0.05), whereas PRA and plasma Ang II concentration were increased by the treatment. With the control and Losartan-treated animals, there was a significant positive correlation between the left ventricular weight and the tissue Ang II content (r = 0.563, p less than 0.05). These results provide evidence that cardiac tissue Ang II, rather than circulating Ang II, plays an important role in the pathophysiology of left ventricular hypertrophy of this animal model of human hypertension.     

Angiotensin II type 1 receptor expression in human pancreatic cancer and growth inhibition by angiotensin II type 1 receptor antagonist

We investigated the expression of angiotensin II type 1 receptor (AT1) in pancreatic cancer. Both AT1 mRNA and protein were expressed in human pancreatic cancer tissues and cell lines. Binding assays showed that pancreatic cancer cells have specific binding sites for angiotensin II and that binding could be eliminated by treatment with a selective AT1 antagonist in a dose-dependent fashion. Surprisingly, the growth of cancer cells was significantly suppressed by treatment with antagonist, also in a dose-dependent manner. These observations suggest AT1 plays an important role in pancreatic cancer growth. Furthermore, ligand-induced inhibition of AT1 may be a useful therapeutic strategy.     

Chronic administration of nitric oxide reduces angiotensin II receptor type 1 expression and aldosterone synthesis in zona glomerulosa cells

Acute nitric oxide (NO) inhibits angiotensin II (ANG II)-stimulated aldosterone synthesis in zona glomerulosa (ZG) cells. In this study, we investigated the effects of chronic administration of NO on the ANG II receptor type 1 (AT1) expression and aldosterone synthesis. ZG cells were treated daily with DETA NONOate (10(-4) M), an NO donor, for 0, 12, 24, 48, 72, and 96 h. Chinese hamster ovary (CHO) cells, stably transfected with the AT1B receptor, were used as a positive control. Western blot analysis indicated that AT1 receptor expression was decreased as a function of time of NO administration in both CHO and ZG cells. ANG II binding to its receptors was determined by radioligand binding. NO treatment of ZG cells for 96 h resulted in a decrease in ANG II binding compared with control. The receptor density was decreased to 1,864 +/- 129 fmol/mg protein from 3,157 +/- 220 fmol/mg protein (P < 0.005), but the affinity was not changed (1.95 +/- 0.22 vs. 1.88 +/- 0.21 nM). Confocal Raman microspectroscopy and immunocytochemistry both confirmed that the expression of AT1 receptors in ZG cells decreased with chronic NO administration. In addition, chronic NO administration also decreased the expression of cholesterol side-chain cleavage enzyme in ZG cells and inhibited ANG II- and 25-hydroxycholesterol-stimulated aldosterone synthesis in ZG cells. This study demonstrates that chronic administration of NO inhibits aldosterone synthesis in ZG cells by downregulation of the expression of both AT1 receptors and cholesterol side-chain cleavage enzyme.     

Effect of angiotensin II non-peptide AT(1) antagonist losartan on phosphatidylethanolamine membranes

Losartan was found to affect both the thermotropic behavior and molecular mobility of dimyristoyl- and dipalmitoyl-phosphatidylcholine membranes (Theodoropoulou and Marsh, Biochim. Biophys. Acta 1461 (1999) 135-146). At low concentrations, the antagonist is located close to the interfacial region of the phosphatidylcholine bilayer while at high mole fractions it inserts deeper in the bilayers. In the present study, we investigated the interactions of losartan with phosphatidylethanolamine membranes using differential scanning calorimetry (DSC), electron spin resonance (ESR) and 31P nuclear magnetic resonance (NMR) spectroscopy. DSC showed that the antagonist affected the thermotropic transitions of dimyristoyl-, dipalmitoyl- and dielaidoyl-phosphatidylethanolamine membranes (DMPE, DPPE and DEPE, respectively). ESR spectroscopy showed that the interaction of losartan with phosphatidylethanolamine membranes is more superficial than in the case of phosphatidylcholine bilayers. Additionally, losartan increased the spin-spin broadening of 12-PESL spin labels in the gel phase of DMPE and DPPE membranes, while in the case of DEPE membranes the opposite effect was observed. (31)P-NMR showed that the antagonist stabilizes the fluid lamellar phase of DEPE membranes relative to the hexagonal H(II) phase. Our results show that losartan affects the thermotropic behavior of phosphatidylethanolamine membranes, while the molecular mobility of the membranes is not affected greatly. Furthermore, its interactions with phosphatidylethanolamine membranes are more superficial than with phosphatidylcholine bilayers.     

Sarcosine1,glycine8 angiotensin II is an AT1 angiotensin II receptor subtype selective antagonist

Studies predating the discovery of the two major subtypes of angiotensin II (Ang II) receptors, AT1 and AT2, revealed anomalous characteristics of sarcosine1,glycine8 Ang II (Sar1,Gly8 Ang II). It competed poorly for 125I-Ang II binding in bovine brain but potently antagonized dipsogenic responses to intracerebroventricularly administered Ang II. Subsequent recognition that bovine brain contains AT(2) receptors, while dipsogenic responses to Ang II are mediated by AT1 receptors, suggests that Sar1,Gly(8) Ang II is AT1 selective. Sar1,Gly8 Ang II competed for 125I-sarcosine1,isoleucine8 Ang II binding to AT1 receptors in pituitary, liver and adrenal (the latter with the AT2 selective antagonist PD 123,319) with Ki's of 0.66, 1.40 and 1.36 nM, respectively. In contrast, the Ki of Sar1,Gly8 Ang II for AT2 receptors in rat adrenal (with the selective AT1 antagonist losartan) was 52 nM. 125I-Sar1,Gly8 Ang II (0.5-3 nM) bound to AT1 receptors in pituitary, liver, heart, adrenal, and hypothalamic membranes with high affinity (Kd=0.43, 1.6, 2.3, 0.96 and 1.8 nM, respectively), but showed no saturable binding to the adrenal AT2 receptor. 125I-Sar1,Gly8 Ang II selectively labeled AT1 receptors in sections of adrenal using receptor autoradiography. Thus, binding studies reveal Sar1,Gly8 Ang II to be the first angiotensin peptide analog to show AT1 receptor selectivity. 125I-Sar1,Gly8 Ang II offers a new means to selectively radiolabel AT1 receptors and may help to characterize ligand docking sites and agonist switches for AT1 versus AT2 receptors.     

Quantitative examination of the cardiac myocytes in hypertensive rats under chronic inhibition of nitric oxide synthesis

This study quantitatively examined myocardial changes during the hypertensive process. Four groups (n=10 for each group) of adultRattus norvegicus (Wistar strain) were studied. Animals were sacrificed at 40 and 80 days of experimentation (control and experimental groups in each age). Although animals in the experimental groups received L-NAME (50 mg/kg/day) for 40 days, one group of animals was without L-NAME for the remaining 40 days. In addition, stereology was performed to determine the volume and numerical densities of myocytes (Vv and Nv, respectively), the mean volume and the total number of myocytes (Vol and N, respectively). According to those results, the blood pressure increased following L-NAME administration and remained high even at 40 days after administering L-NAME. The cardiac weight significantly increased in L-NAME animals and also in control of older animals. Moreover, Vv and the Vol increased in older animals. Notably, inhibition of the NO synthase increased Vol while decreasing Nv and N. These indices remained unchanged even after 40 days of the L-NAME intake interruption. Nv and N also decreased in older animals. Furthermore, hypertrophy and loss of myocytes were not entirely reversible after cessation of the chronic inhibition of the NO synthase in an extended follow-up.     

Reduction of cardiac endothelin-1 by angiotensin II type 1 receptor antagonist in viral myocarditis of mice

Renin angiotensin system contributes to activation of circulating endothelin in congestive heart failure. To investigate the effects of angiotensin II receptor antagonist and angiotensin converting enzyme inhibitors (ACEI) on the levels of endothelin-1 (ET-1), we administered orally angiotensin II type 1 receptor (AT1) antagonist, L-158,809 (ATA) (6, 1.2 and 0.12 mg/kg/day), enalapril (1 mg/kg/day) and captopril (7.5 mg/kg/day) for 14 days to mice with viral myocarditis, beginning 7 days after encephalomyocarditis virus (500 pfu/mouse) inoculation. Plasma ET-1, cardiac ET-1, heart weight (HW) and HW/ body weight (BW) ratio were examined and compared with infected untreated mice. Moreover, the HW (mg) and HW/BW (x 10(-3)) ratio were significantly (P<0.05) reduced in mice treated with ATA and ACEIs in comparison with infected control. ACEIs and higher dosed of ATA reduced myofiber hypertrophy. Both of plasma and cardiac ET-1 proteins were significantly elevated in infected control compared with uninfected normal mice. Plasma ET-1 was significantly (P<0.01) reduced in mice with three different concentrations of ATA but were not decreased in mice with captopril or enalapril compared with infected control. The expression of endothelin-1 mRNA was significantly reduced in mice with ATA in comparison with infected untreated mice by competitive RT-PCR. ATA reduced ET-1 protein and mRNA in the myocardium of mice with myocarditis, improving congestive heart failure and myofiber hypertrophy. We suggest the effect of ATA on the reduction of endothelin has a different pathway from angiotensin converting inhibitor and that ATA seems to be a useful agents for congestive heart failure due to viral myocarditis.     

Beneficial effects of olmesartan,a novel angiotensin II receptor type 1 antagonist,upon acute autoimmune myocarditis

Excess amount of cytokine produced by inflammatory stimuli contributes to the progression of myocardial damage in myocarditis. Some angiotensin II receptor type 1 antagonists are reported to inhibit proinflammatory cytokine production in vitro and in vivo. We tested the hypothesis that olmesartan, a novel angiotensin II receptor type 1 antagonist, ameliorated experimental autoimmune myocarditis (EAM) in rats attributing to the suppression of inflammatory cytokines in the heart. We orally administered olmesartan 1, 3, and 10 mg/kg/day to rats with EAM for 3 weeks. The results showed that olmesartan decreased blood pressure significantly compared with the untreated group, but markedly reduced the severity of myocarditis by comparing the heart weight/body weight ratio, pericardial effusion scores, macroscopic scores and microscopic scores. Myocardial interleukin (IL)- 1beta expression by western blotting and IL-1beta-positive staining cells by immunohistochemistry were significantly lower in rats with EAM given olmesartan treatment compared with those of rats given vehicle. We conclude that Olmesartan ameliorates acute EAM in rats. The cardioprotection of olmesartan may be due to suppression of inflammatory cytokines dependent of the hemodynamic modifications.     

蛋白激酶C在血管紧张素Ⅱ抑制心肌细胞——氧化氮合成中的作用

实验用硝酸还原酶法测定培养新生大鼠内肌细胞亚硝酸盐（ＮＯ２）和硝酸盐（ＮＯ３）总量（ＮＯ２／ＮＯ３）,反映心肌细胞一氧化氮（ＮＯ）生成情况,观察血管紧张素Ⅱ（ＡｎｇⅡ）对凡肌细胞ＮＯ生成的及其蛋白激酶Ｃ（ＰＫＣ）在该效应中的作用。结果显示：ＡｎｇⅡ可减少心肌细胞ＮＯ的含量,并具有明显的剂量－效应关系;ＡｎｇⅡ受体拮抗剂ｓａｒａｌａｓｉｎ可明显抵制ＡｎｇⅡ对ＮＯ生成的影响;Ｌ－精氨酸（Ｌ－Ａｒｇ）明     

Losartan, an antagonist of AT1 receptor for angiotensin II, attenuates lipopolysaccharide-induced acute lung injury in rat

Angiotensin II (Ang II) plays an important role in inflammatory process. Acute lung injury (ALI), an inflammatory disorder of the lung, is commonly associated with endotoxemia; however, the mechanism that endotoxin (lipopolysaccharide, LPS) induces the inflammatory response in ALI is not well defined. Here, we showed, in LPS-induced ALI rat model, that Ang II and Ang II type 1 (AT₁) receptor were significantly increased in lung tissues, compared with those in controls. Meanwhile, nuclear factor (NF)-κB-DNA-binding activity, tumor necrosis factor (TNF)-α mRNA, and pneumocytic apoptosis were significantly increased. Moreover, pretreatment of rats with losartan, an antagonist of AT₁ receptor for Ang II, improved the inflammation, reduced the elevation of Ang II and AT₁ receptor, and inhibited NF-κB-DNA-binding activity, expression of TNF-α mRNA, and pneumocytic apoptosis. The data indicate that Ang II may mediate the inflammatory process in LPS-induced ALI through AT₁ receptor, which can be blocked by losartan.     

The angiotensin II type 1 receptor antagonist Losartan binds and activates bradykinin B2 receptor signaling

The angiotensin II type 1 receptor (AT1R) blocker (ARB) Losartan has cardioprotective effects during ischemia-reperfusion injury and inhibits reperfusion arrhythmias -effects that go beyond the benefits of lowering blood pressure. The renin-angiotensin and kallikrein-kinin systems are intricately connected and some of the cardioprotective effects of Losartan are abolished by blocking the bradykinin B2 receptor (B2R) signaling. In this study, we investigated the ability of six clinically available ARBs to specifically bind and activate the B2R. First, we investigated their ability to activate phosphoinositide (PI) hydrolysis in COS-7 cells transiently expressing the B2R. We found that only Losartan activated the B2R, working as a partial agonist compared to the endogenous ligand bradykinin. This effect was blocked by the B2R antagonist HOE 140. A competitive binding analysis revealed that Losartan does not significantly compete with bradykinin and does not change the binding affinity of bradykinin on the B2R. Furthermore, Losartan but not Candesartan mimicked the ability of bradykinin to increase the recovery of contractile force after metabolic stress in rat atrial tissue strips. In conclusion, Losartan is a partial agonist of the B2R through direct binding and activation, suggesting that B2R agonism could partly explain the beneficial effects of Losartan.     

Effect of an ACE inhibitor and an AT1 receptor antagonist on cardiac hypertrophy

The effect of long-term administration of delapril, an angiotensin converting enzyme inhibitor, and candesartan, an angiotensin II receptor blocker, on cardiac hypertrophy was investigated in spontaneously hypertensive rats (SHR). Delapril (2 mg/kg/day) and candesartan (2 mg/kg/day) were administered for 5 weeks to 15-week-old male SHR. Echocardiographic estimation of cardiac morphology and function revealed cardiac hypertrophy in SHR compared with Wistar-Kyoto rats (WKY) which were used as normal controls. Both treated groups revealed regression of cardiac hypertrophy estimated by echocardiography. Heart to body weight ratio of treated SHR was also smaller than that of untreated SHR. Plasma BNP and ANP concentrations were increased in untreated SHR and decreased in the treated groups. Histological examination was performed using light microscopy and the area of fibrosis was estimated by computer. Reduction of the fibrotic area was observed in SHR treated with delapril and candesartan, although the latter was not statistically significant. Immunohistochemical examination using anti-collagen monoclonal antibody showed a decrease of type I collagen in treated SHR as compared with untreated SHR. It is concluded that both angiotensin converting enzyme inhibitor and angiotensin II receptor blocker sufficiently reduce blood pressure in SHR associated with regression of cardiac remodeling.     

氯沙坦对肾血管性高血压大鼠血清中血管紧张素Ⅱ-1受体自身抗体产生的影响

目的和方法：采用两肾一夹型肾血管性高血压（RVH）模型,以合成的大鼠血管紧张素Ⅱ－1受体（AT1R）细胞外第二环165－191位氨基酸序列作为特异性抗原,用ELISA法检测大鼠血清中血管紧张素Ⅱ－1受体自身抗体,动态观察（13周）氯沙坦（术后第2周开始,5mg/kg dig,连续12周）治疗对模型大鼠AT1R自身抗体产生的影响。结果：RVH组大鼠血清中AT1R自身抗体从术后1周起阳性率、滴度逐渐升高;给予氯沙坦治疗不仅可抑制模型大鼠心脏功能和结构的改变,而且使血清AT1R自身抗体的阳性率和滴度明显低于肾血管性高血压组。结论：氯沙坦有抑制AT1R自身抗体产生而达到降压的作用。     

Effect of angiotensin II type 1 receptor antagonist on tumor growth and angiogenesis in a xenograft model of human bladder cancer

Several authors have investigated the antitumor activity of angiotensin II type 1 receptor (AT1R) antagonists, which are widely used as antihypertensive drugs. In this study, we evaluated the efficacy of the AT1R antagonist candesartan against bladder cancer. For the study in vitro, human bladder cancer cells (KU-19-19) were cultured with and without angiotensin II (A II) and candesartan, and cell viability and vascular endothelial growth factor (VEGF) secretion were analyzed. Also for the study in vivo, a tumor xenograft model was prepared in nude mice using KU-19-19 cells. Mice were administered candesartan daily by oral gavage, and paclitaxel via intravenous infusion. Microvessel density, VEGF expression, and apoptosis were investigated. Candesartan did not induce direct toxicity in KU-19-19 cells, but VEGF was significantly lower in candesartan-treated cells than in the A II-treated control cells. In mice, candesartan, paclitaxel and candesartan-paclitaxel significantly suppressed tumor growth to 46.0%, 35.8% and 17.3%, respectively, of the tumor volume in the control group, showing that combined treatment significantly inhibited tumor growth compared to the candesartan group. Microvessel density and VEGF were significantly decreased in the candesartan and candesartan-paclitaxel groups compared to the control group. The apoptotic index was significantly increased in the paclitaxel and candesartan-paclitaxel groups compared to the control and candesartan groups. In our experimental model, candesartan prevented bladder cancer growth by inhibiting angiogenesis. Furthermore, combined treatment with candesartan and paclitaxel enhanced paclitaxel-induced cytotoxicity. These results suggest that the AT1R antagonist candesartan may be a candidate for innovative therapy for bladder cancer.     

Acute treatment with candesartan cilexetil, an angiotensin II type 1 receptor blocker, improves insulin sensitivity in high-fructose-diet-fed rats

We aimed to determine whether acute treatment with candesartan cilexetil (CV-11974), an angiotensin II type 1 receptor blocker (ARB) can improve insulin sensitivity in high-fructose-diet (HFD)-fed rats. In vivo glucose utilization was measured by applying the euglycemic clamp technique and the expression levels of insulin-signaling molecules in skeletal muscles were examined by western blotting. A bolus injection of CV-11974 improved the glucose infusion rate (GIR) of HFD-fed rats to the level of the control rats. Furthermore, restoration of impaired tyrosine phosphorylation of insulin receptor (IR) β, Akt phosphorylation at Ser??3 and Thr3??, and phosphorylation of the 160-kDa Akt substrate (AS160) in the skeletal muscles of HFD-fed rats were achieved by this treatment. These results suggest that acute administration of candesartan cilexetil can increase insulin sensitivity of HFD-fed rats, which is associated with improved insulin signaling in skeletal muscles.     

Volume expansion during acute angiotensin II receptor (AT(1)) blockade and NOS inhibition in conscious dogs

The responses to AT(1)-receptor blockade (candesartan 1 mg/kg) and to concomitant volume expansion (saline 35 ml/kg for 90 min) with and without nitric oxide synthase (NOS) inhibition (N(G)-nitro-L-arginine methyl ester 30 microg small middle dot kg(-1) small middle dot min(-1)) were investigated in separate experiments in normal dogs. AT(1) blockade decreased arterial pressure (106 +/- 4 to 96 +/- 5 mmHg) and increased glomerular filtration rate (GFR) by 17% and sodium excretion threefold. NOS inhibition increased arterial pressure (103 +/- 3 to 116 +/- 3 mmHg) and decreased GFR by 21% and reduced sodium excretion by some 80%. Volume expansion increased arterial pressure significantly in all series involving this procedure, most pronounced during combined AT(1) blockade and NOS inhibition (21 +/- 4 mmHg). Volume expansion during AT(1) blockade elicited marked natriuresis (26 +/- 11 to 274 +/- 55 micromol/min) that was severely reduced by concomitant NOS inhibition (10 +/- 3 to 45 +/- 11 micromol/min), but still much larger than that seen with volume expansion during NOS inhibition alone (2 +/- 1 to 23 +/- 7 micromol/min). Volume expansion during AT(1) blockade increased GFR (+30%), less so during combined AT(1) blockade and NOS inhibition (+13%), but it did not increase GFR significantly (P = 0.07) during NOS inhibition alone. Plasma ANG II increased greater than sevenfold with AT(1) blockade and doubled with NOS inhibition (paired t-test, P < 0.05), whereas it decreased by 50-80% during volume expansion irrespective of pretreatment, i.e., during NOS inhibition, volume expansion did not generate subnormal plasma ANG II concentrations. In conclusion, 1) acute AT(1) blockade leads to hyperfiltration, natriuresis, and hyperresponsiveness to volume expansion, 2) these responses are >85% inhibitable by unspecific NOS inhibition, and 3) NOS inhibition alone is followed by increases in plasma ANG II, hypofiltration, and severe antinatriuresis that may be counterbalanced but not overwhelmed by volume expansion. Thus NOS inhibition virtually abolishes the volume expansion natriuresis, at least in part, due to the lack of appropriate inhibition of the renin-angiotensin-aldosterone system.     

ANG II type 1 receptor antagonist irbesartan inhibits coronary angiogenesis stimulated by chronic intermittent hypoxia in neonatal rats

Chronic hypoxia has been shown to stimulate myocardial microvascular growth and improve cardiac ischemic tolerance in young and adult rats. The aim of this study was to determine whether the ANG II type 1 receptor (AT(1)) pathway was involved in these processes. Newborn Wistar rats, exposed to chronic intermittent hypoxia (8 h/day) for 10 days, were simultaneously treated with AT(1) receptor blocker irbesartan and compared with untreated animals. The major finding is that chronic hypoxia increased the capillary supply of myocardial tissue, which was even more pronounced in hypertrophied right ventricle, whereas increased arteriolar supply was found only in the left ventricle. This angiogenic response was completely prevented by irbesartan. Moreover, chronic hypoxia improved the postischemic recovery of cardiac contractile function during reperfusion, and this protective effect was also completely abolished by irbesartan. Chronic hypoxia increased the myocardial density of AT(1) but not of ANG II type 2 receptor subtypes, whereas the effect of irbesartan was not significant. The expression of caveolin-1alpha markedly increased in response to chronic hypoxia, and irbesartan prevented this effect. Neither hypoxia nor irbesartan treatment altered the expression of nitric oxide synthase 3, heat shock protein 90, and VEGF. It is concluded that the AT(1) receptor pathway plays an important role in coronary angiogenesis and improved cardiac ischemic tolerance induced in neonatal rats by chronic hypoxia.     

Changes in cardiac structure and function in rats immunized by angiotensin type 1 receptor peptides

Angiotensin II (Ang II) is known to induce cardiomyocyte hypertrophy by activating the Ang II type 1 (AT1) receptor. Some studies have demonstrated that the autoantibodies against angiotensin AT1 receptor (AT1-AAs) cause functional effects, which is similar to those observed for the natural agonist Ang II. In this study, we investigated the effects of AT1-AAs on cardiomyocytes' structure and function. Male Wistar rats were immunized with synthetic peptides corresponding to the second extracellular loop of AT1 receptor and Freund's adjuvant. The titers of AT1-AAs in rat serum were detected by enzyme-linked immunosorbent assay every week. Hemodynamic analysis and heart weight (HW) indices were measured on the 4th and 8th months after initial immunization, respectively. Cultured neonatal rat cardiomyocytes were used to observe the hypertrophic effects of AT1-AAs. Results showed that systolic blood pressure and heart rate were significantly increased, the titers of AT1-AAs were also increased after 4 weeks of initial immunization. Compared with control group, the HW/body weight (BW) and left ventricular weight/BW of immunized rats were increased significantly and cardiac function was enhanced compensatively. The cultured neonatal rat cardiomyocytes respond to AT1-AAs stimulation with increased (3)H-leucine incorporation and cell surface area in a dose-dependent manner. These results suggest that the AT1-AAs have an agonist effect similar to Ang II in hypertrophy of cardiomyocytes in vivo and in vitro. AT1-AAs are involved in the pathogenesis of cardiovascular diseases and hypertension.     

Renal effects of an acute NaCl load in chronic nitric oxide blockade-induced hypertensive rats

Nitric oxide (NO) controls blood pressure and plays a role in the water and sodium handling by the kidneys. Inhibition of NO synthesis with competitive L-arginine analogues leads to increased renal vascular resistance and raised systemic and glomerular blood pressure. The effects of chronic NO-synthesis inhibition by N(G)-nitro L-arginine methyl-esther (L-NAME) in the disposal of an acute NaCl load are studied on fourteen male Munich-Wistar rats. Eight of which were given L-NAME (100 mg/L) in the drinking water for 21 days. Six control rats differed only in not receiving L-NAME. As expected, significant hypertension and a marked renal vasoconstriction were accompanied by a decline in renal plasma flow, without changes in glomerular filtration rate, with filtration fraction thus being increased in the NO-blocked rats. In the basal state there was no significant reduction of sodium urinary excretion in the L-NAME treated rats. Both groups of rats elicited an increase in urinary sodium excretion after the NaCl load which was initially more evident and longer in the L-NAME treated group. The ratio of Na+ excreted to Na+ infused was similar between the groups. This observation suggests that in this model of chronic inhibited NO rats, the disposal of an acute sodium load is reached. The existence of a delayed mechanism in renal excretion of Na+ by the chronic NO-blocked rats could be suggested.