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This corrects the article DOI: 10.1038/jhh.2017.41.

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The renin-angiotensin system in the kidney plays a critical role in the regulation of renal hemodynamics and sodium handling through the activation of vascular, glomerular and tubular angiotensin II type 1 (AT1) receptor-mediated signaling. We previously cloned a molecule that specifically bound to the AT1 receptor and modulated AT1 receptor signaling in vitro, which we named ATRAP (for AT1 receptor-associated protein). The purpose of this study is to analyze the renal distribution of ATRAP and to examine whether ATRAP is co-expressed with the AT1 receptor in the mouse kidney. We performed in situ hybridization, Western blot analysis, and immunohistochemistry to investigate the expression of ATRAP mRNA and protein in the mouse kidney. The results of Western blot analysis revealed the ATRAP protein to be abundantly expressed in the kidney. Employing in situ hybridization and immunohistochemistry, we found that both ATRAP mRNA and the protein were widely distributed along the renal tubules from Bowman's capsules to the inner medullary collecting ducts. ATRAP mRNA was also detected in the glomeruli, vasculature, and interstitial cells. In all tubular cells, the ATRAP protein colocalized with the AT1 receptor. Finally, we found that the dietary salt depletion significantly decreased the renal expression of ATRAP as well as AT1 receptor. These findings show ATRAP to be abundantly and broadly distributed in nephron segments where the AT1 receptor is expressed. Furthermore, this is the first report demonstrating a substantial colocalization of ATRAP and AT1 receptor in vivo.

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OBJECTIVE: Circulating levels of lipocalin-type prostaglandin D synthase (L-PGDS)/beta-trace reportedly increase in renal failure as well as in cardiovascular injuries. We investigated the alterations of L-PGDS in urine and plasma in the early stage of type-2 diabetic patients. METHOD: Thirty-six type-2 diabetic patients and 29 normal subjects were studied. Overnight spot urine and plasma samples were obtained in the morning. L-PGDS was measured by ELISA method using anti-L-PGDS antibody. Variables indicating renal function were determined. RESULTS: Plasma L-PGDS concentration was slightly higher in the patients with diabetes mellitus than in the control subjects, whereas the urinary L-PGDS excretion almost doubled in the diabetic patients as compared with that in the control subjects. Plasma L-PGDS was determined by plasma creatinine (Cr) concentration while urinary L-PGDS excretion was correlated solely with urinary protein excretion. There was no relationship between plasma L-PGDS concentration and urinary L-PGDS excretion. The averaged plasma concentration of L-PGDS in the diabetics with a normal Cr level in plasma, corresponding to that in the controls, was determined by the plasma Cr concentration. On the other hand, the urinary L-PGDS excretion was determined by the amount of proteinuria and greater in the diabetics with a normal Cr level in plasma than in the controls even when the patients exhibited urinary protein excretion equal to that in the control subjects. CONCLUSIONS: Urinary L-PGDS excretion increased in the early stage of kidney injury in patients with type-2 diabetes mellitus. The urinary excretion was correlated independently with urinary protein excretion even when there was no difference in urinary protein or albumin excretions, thereby suggesting that urinary L-PGDS excretion is possibly a more sensitive indicator of renal injuries than proteinuria. Urinary L-PGDS may thus predict the progression of renal injuries in diabetic patients.

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The Dahl salt-sensitive (DS) rat, a genetic model of salt-induced hypertension in humans, is more likely to develop severe vascular injuries than a rat with spontaneous hypertension. We designed an experiment to scrutinize the effects of renin-angiotensin inhibition on cognitive dysfunction in the aged, normotensive DS with a passive avoidance test. Eighteen months of treatment with a very low dose of the angiotensin-converting enzyme (ACE) inhibitor cilazapril (2.5 microg/mL in drinking water) or the angiotensin II type 1 receptor antagonist E4177 did not reduce blood pressure throughout the experiment, although in the low dose cilazapril group (12.5 microg/mL in drinking water), blood pressure dropped within 6 months after treatment began. The cilazapril treatments dose-dependently improved memory function in the aged, normotensive DS fed a low-salt diet compared with the untreated, control rats. This improvement was associated with significant increases in hippocampal CA1 cells and capillary densities in the CA1 regions compared with those in the untreated DS. Similarly, E4177 slightly improved the memory dysfunction observed in the aged DS. The cells in the hippocampal CA1 region were restored slightly, but the capillary densities were not influenced by the receptor antagonist. On the other hand, the ACE inhibitor and receptor antagonist both attenuated urinary protein excretions with an improvement of glomerular sclerosis. These data suggest that long-term treatment with an ACE inhibitor improves memory dysfunction probably through restoration of capillary and hippocampal cells. The effects are due to the inhibition of the angiotensin II type 1 receptor and probably to the enhancement of the kallikrein-kinin system.

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OBJECTIVE: We recently reported that the renin-angiotensin system plays an important role in the progression of vascular and kidney injuries, even in Dahl salt-sensitive rats with volume-dependent hypertension. In this study, we investigated whether a high-salt diet increases susceptibility to kidney injury induced by angiotensin II in normotensive, uni-nephrectomized Sprague-Dawley rats, which mimics the condition of salt-volume repletion and blunted renin-angiotensin system. METHODS: The rats were fed either a low-salt (0.3% NaCl) or a high-salt (4% NaCl) diet and divided into five groups: two control groups with a low-salt or a high-salt diet without angiotensin II infusion (saline infusion), and three angiotensin II groups (angiotensin II infusion, 10 or 50 ng/kg per min with high-salt diet, 50 ng/kg per min with low-salt diet, subcutaneously). The rats were kept on these regimes for 8 weeks. The blood pressure was measured every week. Functional and morphological alterations in the kidney were assessed at the end of the experiment RESULTS: There were no differences in the arterial blood pressures of the five experimental groups. However, angiotensin II infusion increased the weights of the heart and aortic walls in a dose-dependent manner in the high-salt groups. There was also a dose-dependent increase in proteinuria, N-acetyl-beta-D-glucosaminidase activity (NAG) excretion, and additional glomerular and arterial injuries in the kidney, associated with angiotensin II infusion in the high-salt groups. In the rats given a higher dose of angiotensin II, the high-salt diet significantly increased the weights of the heart and aortic walls and exacerbated the renal function and morphological injuries, compared to the low-salt group. High-salt diet alone increased the kidney and heart weights. However, it did not significantly influence the results of the morphological and functional study. On the other hand, angiotensin II infusion on a low-salt diet showed a trend towards glomerular damage; however, the effects were small and not significant. Similarly, there were few effects of angiotensin II infusion on morphology and functional study on a low-salt diet CONCLUSION: These data clearly show that a high-salt intake increases susceptibility of the kidney to injuries induced by low doses of angiotensin II in normotensive, uni-nephrectomized rats.

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The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is a new genetic model of non-insulin-dependent diabetes mellitus (NIDDM). We investigated whether treatment with an angiotensin II (ANGII) subtype-1 receptor antagonist delays the onset of NIDDM and attenuates diabetic nephropathy in the OLETF rat. OLETF rats fed a regular chow were treated with ANGII subtype-1 receptor antagonists (E4177 or TA606) for 22 weeks. Hemodynamic changes, glucose metabolism, and the effects on diabetic nephropathy were examined. Systolic blood pressure increased in OLETF rats in an age-dependent manner. OLETF rats exhibited increases in plasma concentrations of glucose and insulin and developed glucosuria at the age of 28 weeks. The changes in glucose metabolism were associated with proteinuria and an increase in urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG). Morphologic investigation revealed nodular lesions in glomeruli in the OLETF rats. The ANGII receptor antagonist treatment abolished the blood pressure elevation. However, the treatment did not affect plasma glucose and insulin levels and did not significantly reduce glucosuria. Nodular lesions in glomeruli were not improved by the treatment. However, the receptor antagonists significantly reduced proteinuria and urinary NAG excretion. Multivariate analyses revealed that proteinuria was determined by systolic blood pressure, lipid metabolism, and glucose levels in plasma. ANGII subtype-1 antagonism does not improve glucose metabolism in the OLETF rat model of NIDDM, which has abnormalities in the glucose-uptake system. Blood pressure elevation and part of the proteinuria associated with NIDDM depends on the renin-angiotensin system rather than glucose metabolisms per se.

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AIMS: We investigated whether kallikrein infusion attenuates renal injury in Dahl salt-sensitive rats with hypertension and assessed the role of bradykinin-nitric oxide axis in the renal protection using HOE-140, the bradykinin type-2 (B2) receptor specific antagonist. METHODS: Subdepressor dose of purified rat urinary kallikrein (RUK) (400 ng/day) was continuously infused through the jugular vein by an osmotic mini-pump for 4 weeks in Dahl salt-sensitive (Dahl S) rats fed a high-salt (2% NaCl) diet. RESULTS: Blood pressure increased in a time-dependent manner in Dahl S rats fed a high-salt diet. The RUK infusion did not influence the elevation of blood pressure in Dahl S rats. However, the RUK infusion significantly decreased urinary protein excretion, and increased glomerular filtration rate, as compared with untreated high-salt Dahl S rats. Morphological investigation disclosed that the RUK infusion significantly attenuated glomerulosclerosis and arterial and tubular injuries in the kidney of hypertensive Dahl S rats. The RUK infusion produced an increase in urinary excretions of nitric oxide and cyclic guanosine monophosphate. In addition, the RUK infusion enhanced the generation of nitric oxide from the kidney slices. The functional and morphological effects of the RUK infusion on the kidney were completely lessened by co-administration of the bradykinin B2-receptor antagonist, HOE-140. CONCLUSION: Long-term infusion of subdepressor dose of rat urinary kallikrein attenuates functionally and morphologically the progression of renal injury in Dahl rats susceptible to salt-induced hypertension, and that the protection is mediated by stimulation of bradykinin B2 receptor.

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To assess the effects of sodium reduction on insulin sensitivity in hypertension, we examined the change of insulin sensitivity after two degrees of dietary sodium restriction by the euglycemic hyperinsulinemic glucose clamp method in 12 subjects with primary hypertension. A controlled period of 1 week, when the subjects were taking a normal sodium diet, was followed by a randomized crossover study in which the subjects were placed on either moderate or strict reduced sodium diets for 1 week. The result of the 1-week moderate dietary sodium reduction from 200 to 100 mmol/day showed significant decreases in systolic and diastolic blood pressure by 6.5 and 5.0 mm Hg, respectively. Strict dietary sodium reduction to 30 mmol/day for 1 week resulted in no further decrease in blood pressure, but it increased plasma insulin by 40.6% without changing plasma glucose. There were no changes in glucose infusion rate (GIR) or insulin sensitivity index (ISI), which is a measure of GIR divided by plasma insulin, after moderate dietary sodium reduction. However, strict dietary sodium reduction induced decreases in GIR by 19.8% (from 1318+/-189 to 1057+/-173 micromol/m2/ min; P < .01), and ISI by 20.5% (from 16.6+/-2.1 to 13.2+/-1.9 micromol/m2/min/microU/mL; P < .01) with a paralleled increase of plasma norepinephrine by 90.0% (from 150.5+/-61.6 to 287.3+/-114.9 pg/mL; P < .01). These results indicate that dietary sodium restriction leads to a deterioration of insulin sensitivity when plasma norepinephrine levels increase, and suggest that moderate dietary sodium reduction may lower blood pressure without a distinct adverse effect on glucose metabolism in subjects with primary hypertension.

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This study compared renal and intestinal handling of sodium in Dahl-Iwai salt-sensitive (S) and salt-resistant (R) rats given a normal-salt diet (0.3% NaCl) and a high-salt diet (4.0% NaCl). Six-week-old female S and R rats (n = 7 each) were given a normal-salt diet for 14 days followed by a high-salt diet for 3 weeks. Systolic blood pressure was significantly higher in the S rats than in the R rats only at the end of the high-salt diet period (170 +/- 5, mean +/- SEM, vs 152 +/- 1 mmHg, p < 0.01). Daily sodium intake, water intake, urine volume, and urinary and fecal excretions did not significantly differ between the R and the S rats during the normal- and high-salt diets, except for a slight, although significant, decrease in fecal sodium excretion in the S rats as compared with the R rats in the 2nd week of the high-salt diet period. After switching from the normal-salt diet to the high-salt diet, urinary sodium excretion increased by 17- to 18-fold and fecal sodium excretion increased by about 5-fold in the 1st week of salt loading. The changes in urinary and fecal sodium excretions did not differ significantly between the groups. Cumulative sodium retention was similar in the two groups. The aldosterone/creatinine ratio in 24-hr urine, which was significantly lower in the S than in the R rats during the normal-salt diet, decreased to similar levels in both groups after salt loading, indicating a blunted response of aldosterone in the S rats. Thus, there were no discernible differences in renal and intestinal handling of sodium between the S and the R rats, except for a slight, but significant, difference in fecal sodium excretion in the 2nd week of the high-salt period. The results indicate that inappropriate suppression of aldosterone or some other mechanism induced by salt loading may be involved in blood pressure elevation in Dahl-Iwai S rats.

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BACKGROUND: The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is a new genetic model of non-insulin-dependent diabetes mellitus (NIDDM). We investigated whether angiotensin inhibition influences the onset of NIDDM and brings about a regression of renal injury in diabetes mellitus. METHODS AND RESULTS: Six-week-old OLETF rats were treated with the angiotensin-converting enzyme (ACE) inhibitors imidapril or enalapril for 16 weeks. Systolic blood pressure is increased in an age-dependent manner in OLETF rats. In this study, the elevation in systolic blood pressure was dose-dependently reduced by ACE inhibitor treatment. In OLETF rats, plasma concentrations of insulin and glucose increased and the glucosuria occurred at the age of 22 weeks. Simultaneously, OLETF rats exhibited proteinuria and nodular lesions in glomeruli. The ACE inhibitor treatment almost completely reduced glucosuria, and also decreased plasma concentrations of insulin and glucose in OLETF rats. ACE inhibitor treatment lessened the proteinuria and attenuated morphologically the severity of nodular lesions in OLETF rats. Moreover, increases in plasminogen activator inhibitor 1 (PAI-1) in OLETF rats were reduced by the ACE inhibitor treatment, and the improvement of glomerular lesions was related to decreases of PAI-1 and angiotensin II levels in plasma but not to improvement of glucose metabolism. CONCLUSIONS: ACE inhibitors delay onset of NIDDM with attenuation of kidney injury. The regression of kidney lesions is probably due to angiotensin reductions but not to glucose metabolism per se. ACE inhibitor drug therapy may be useful in preventing NIDDM and the subsequent renal injury in patients with NIDDM.

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Serum N-acetyl-beta-D-glucosaminidase activity (NAG) is a possible predictor of vascular injury in hypertension. We assessed whether the activity of this enzyme reflects vascular damage in a genetic rat model of non-insulin-dependent diabetes mellitus (NIDDM) in humans. Otsuka Long-Evans Tokushima Fatty (OLETF) rats fed a regular chow were treated with the angiotensin converting enzyme (ACE) inhibitor imidapril for 16 wk. Systolic blood pressure increased in a time-dependent manner in the untreated OLETF rats as compared with that in the control Long-Evans Tokushima (LET) rats. The blood pressure elevation was associated with increases in cardiac and aortic weight. Imidapril treatment significantly attenuated the blood pressure elevation and reduced the increases in cardiac and aortic weight. The untreated OLETF rats had higher plasma glucose and insulin concentrations than did the LET rats and presented with glucosuria at the age of 22 wk. Imidapril treatment strikingly decreased plasma glucose levels and the glucosuria. Plasma insulin concentrations decreased, approaching those of the non-diabetic control LET rats. ACE inhibitor treatment attenuated the nodular lesions in the glomeruli of OLETF rats and improved the kidney function. Serum NAG activity increased significantly by 35% in the untreated rats; this increase was attenuated significantly by imidapril treatment. The reduction in serum NAG activity correlated with improvement in cardiovascular injury. In contrast, there were no changes in urinary NAG excretion in the three OLETF rat groups. In addition, NAG excretion did not correlate with indices of cardiovascular injury. These data suggest that serum NAG activity is useful in predicting injury in the cardiovascular system in rats with diabetes mellitus.

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We investigated the effects of the immunosuppressant HR-325 on arterial lesions in Dahl rats with salt-induced hypertension. Forty-eight 6-wk-old Dahl salt-sensitive (DS) rats were divided into 1) a low-salt (0.3% NaCl) group, 2) a high-salt (4% NaCl) group, 3) a high-salt and low-dose (1 mg/kg) HR-325 group, and 4) a high-salt and high-dose (30 mg/kg) HR-325 group. The rats were treated for 8 wk. Various variables of renal function and morphological alterations in the kidney were assessed. Blood pressure was measured by the tail-cuff method. HR-325 significantly decreased systolic blood pressure in a dose-dependent manner throughout the study. HR-325 tended to decrease plasma creatinine level and increase creatinine clearance rate. Morphological studies revealed that HR-325 treatment strikingly resolved infiltration of immune-related cells in perivascular and intraluminal lesions, thereby decreasing the total arterial injury score by 32%. High-dose HR-325 also attenuated glomerulosclerosis and tubular injury by 35% and 34%, respectively, as compared with untreated high-salt Dahl S rats. Reduced levels of immune-related cells resulted in a decrease in urinary nitrite excretion. These data indicate that long-term treatment with the immunosuppressant HR-325 decreases systolic blood pressure in Dahl salt-sensitive rats, and that this decrease is associated particularly with resolution of infiltration of immune-related cells in arterial lesions. Hyperimmune state is responsible in part for the susceptibility of Dahl S rats to hypertensive organ damage.

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We investigated the role of lipid metabolism in renal protection by chronic cicletanine treatment in Dahl salt-sensitive (Dahl S) rats with salt-induced hypertension. Forty-four 6-week old Dahl S rats were divided into four groups: (1) low-salt (0.3% NaCl) control group: (2) high-salt (4% NaCl) control group; (3) low-dose (10 mg/kg/day) cicletanine (CICL)-treated group given a high-salt diet; and (4) high-dose (30 mg/kg/day) cicletanine-treated group given a high-salt diet. The rats were treated for 6 weeks; blood pressure was measured by the tail-cuff method. Cicletanine significantly reduced the systolic blood pressure in a dose-dependent manner (223 mmHg in the high-salt controls vs 195 mmHg in the high-dose, high-salt group, p < 0.01). Cicletanine treatment did not affect plasma concentration of total cholesterol or triglyceride or free fatty acid; in contrast, it significantly decreased low-density lipoprotein (LDL) cholesterol and increased high-density lipoprotein (HDL) cholesterol. Morphological examination demonstrated that glomerulosclerosis in the kidney was significantly improved by 15% with high-dose cicletanine (p < 0.01). Multivariate analysis revealed that glomerular sclerosis was determined independently by LDL cholesterol levels and arterial injury score, but not by total cholesterol or HDL cholesterol levels or blood pressures. LDL cholesterol was also an independent predictor of urinary excretion of protein. Thus, it is suggested that cicletanine treatment lowers the levels of LDL cholesterol in Dahl salt-sensitive rats, and that besides blood pressure reduction, this decrease in LDL cholesterol level contributes, in part, to regression of glomerular injury in salt-induced hypertension.

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We investigated whether long-term infusion of kallikrein would attenuate renal injury in salt-induced hypertension in Dahl salt-sensitive (Dahl S) rats. A subdepressor dose of purified rat urinary kallikrein (RUK) (700 ng/day) was infused intravenously by an osmotic minipump for 4 weeks in male Dahl S rats fed a high-salt (2% NaCl) diet. This dose did not affect the time-dependent elevation of blood pressure. However, urinary protein excretion was significantly decreased, and the glomerular filtration rate was increased. These beneficial effects were reflected morphologically by an attenuation of the glomerulosclerotic lesions and tubular injury seen in the hypertensive Dahl S rats. The kallikrein infusion increased the urinary excretion of bradykinin and stimulated the excretion of cyclic GMP, suggesting that the kallikrein-kinin-prostaglandin and nitric oxide axes were enhanced by the RUK infusion. The alterations induced by such infusion were potentiated by the concomitant administration of the angiotensin converting enzyme inhibitor alacepril. These studies indicated that long-term replacement with rat tissue kallikrein attenuates renal injury in hypertensive Dahl S rats, and this is probably mediated by an enhanced function of the kallikrein-kinin-prostaglandin and nitric oxide systems.

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Angiotensin II (Ang II) progresses to remodeling of the cardiovascular system through nonhemodynamic as well as hemodynamic effects. There have been few data in vivo on whether subpressor concentration of Ang II is exerted to injure directly the cardiovascular system in hypertension. To test this hypothesis, we investigated, using Dahl salt-sensitive (Dahl S) rats, whether subpressor dose of Ang II progresses to cardiovascular injury observed in salt-induced hypertension. Recent studies have provided evidence that renin-angiotensin inhibition protects against renovascular injury in human hypertension as well as in experimental animals. Particularly in the case of Dahl salt-sensitive rats, a genetic model of volume-dependent hypertension in humans, they are likely to develop more severe arterial and renal injuries than those seen in spontaneously hypertensive rats with similar blood pressure levels. The mechanism of the susceptibility to hypertensive injuries is uncertain; however, renin-angiotensin inhibition significantly improved morphologic and functional injuries in the kidney of Dahl S rats. Conversely, subpressor dose of Ang II infusion exacerbated renal function and progressed to glomerulosclerotic lesions. Alterations of Ang II concentration in physiologic range influenced morphologic and functional injuries in Dahl S rats. Multivariate analysis revealed that activity of the renin-angiotensin system is an independent risk factor to glomerular injury in salt-induced hypertension. These data are in favor of the therapeutic strategy in human hypertension that inhibition of renin-angiotensin system is of value to produce beneficial effects of blood pressure reduction on organ injuries.

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We investigated the influence of the vascular and renal thromboxane system on the antihypertensive effects of the alpha 1 adrenoceptor antagonist (alpha 1 blocker) bunazosin in spontaneously hypertensive rats (SHR). SHR were treated for 2 weeks with the alpha 1, blocker bunazosin (0.5 mg/kg body weight/day). The systolic blood pressure immediately declined with bunazosin treatment, and then rose toward the level observed in untreated SHR. This antihypertensive effect was accompanied by a decrease in the ratio of prostacyclin to thromboxane A2 in the vascular wall and the kidney. A subdepressor dose of the thromboxane synthase inhibitor OKY-046 lessened the thromboxane generation during bunazosin treatment, and synergistically potentiated the antihypertensive action of the alpha 1 blocker. Such synergy was also observed between OKY-046 and prazosin, an alternative alpha 1 blocker, but not with amosulalol, an alpha 1 blocker having no quinazoline moiety. alpha 1 blockers with a quinazoline moiety dose-dependently stimulate thromboxane generation in cultured smooth muscle cells from SHR. These data indicate that alpha 1 blockers enhance thromboxane generation in the arterial wall and kidney, thereby contributing to the lessening of the antihypertensive effects observed during alpha 1 blocker treatment.

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The effects of chronic cicletanine (CICL) treatment on endothelial cell function were investigated in Dahl salt-sensitive (Dahl S) rats. Forty-four six-week-old Dahl S rats were divided into four groups: i) 10 Dahl S rats fed a low-salt (0.3% NaCl) diet and given vehicle, ii) 12 Dahl S rats fed a high-salt (4% NaCl) diet and given vehicle, iii) 11 low-dose (10 mg/kg body weight/d) CICL-treated Dahl S rats fed a high-salt diet, and iv) 11 high-dose (30 mg/kg body weight/d) CICL-treated Dahl S rats fed a high-salt diet. The rats were maintained on the respective salt regimen for 12 wk and treated with cicletanine for the last 6 wk, after which various parameters of endothelial cell function were determined. Systolic blood pressure, measured by the tail-cuff method, was reduced significantly by high-dose cicletanine (223 vs. 195 mmHg, p < 0.01). Scanning electron microscopy revealed that high-dose CICL attenuated endothelial injury in the aorta of Dahl S rats. Arterial lesions in the heart and glomerulosclerosis in the kidney were significantly reduced by treatment with high-dose CICL. Moreover, prostacyclin (PGI2) and prostaglandin E2 (PGE2) generation in the aortic wall was significantly increased by 28% (p < 0.005) and by 149% (p < 0.001), respectively, by high-dose CICL. Nitric oxide (NO) generation in the aortic walls was significantly increased by high-dose CICL (0.38 vs. 15.4 pmol/cm2/30 min, p < 0.001). This effect was accompanied by a 47% increase in cGMP synthesis in the vascular walls. In contrast, the synthesis of PGI2, PGE2, and NO in the kidney slices did not differ significantly among the four experimental groups. In addition, the generation of vasodilatory substances inversely correlated with the score of vascular lesions in the heart and kidney. The results suggested that the blood pressure reduction by chronic cicletanine treatment in Dahl S rats is associated with an improvement in endothelial cell function. The increased release of vasodilatory substances from endothelial cells may contribute to the blood pressure reduction and attenuation of vascular injury observed with cicletanine treatment.

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We characterized the adenosine A1 receptor and the levels of its mRNA expression in the ventricles of 6- and 13-wk-old Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). The binding of 2-chloro-[3H]cyclopentyladenosine ([3H]CCPA), an A1 agonist ligand, to ventricular membranes was saturable and reversible. The receptor density was significantly lower in SHR than in WKY at 13 wk. The dissociation constant values were not different among these groups. In Northern blot analysis using rat A1 receptor cDNA, levels of mRNA did not differ significantly in the two groups at 13 wk, but the level in SHR significantly exceeded that in WKY at 6 wk. Because plasma adenosine levels were reported to be increased at 13 wk in SHR and we found mRNA levels were similar at this age, the discrepancy between A1 receptor density and its mRNA levels might be related to the desensitization of A1 receptors. Although the implication of this decreased density of A1 receptors is not known, it may involve an increased susceptibility to ischemia.

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