Vasopeptidase inhibition has beneficial cardiac effects in spontaneously diabetic Goto-Kakizaki rats

In this study we examined diabetes- and hypertension-induced changes in cardiac structure and function in an animal model of type 2 diabetes, the Goto-Kakizaki (GK) rat. We hypothesized that treatment with omapatrilat, a vasopeptidase inhibitor, which causes simultaneous inhibition of angiotensin converting enzyme and neutral endopeptidase, provides additional cardioprotective effects, during normal- as well as high sodium intake, compared to treatment with enalapril, a selective inhibitor of angiotensin converting enzyme. Fifty-two GK rats were randomized into 6 groups to receive either normal-sodium (NaCl 0.8%) or high-sodium (NaCl 6%) diet and enalapril, omapatrilat or vehicle for 12 weeks. The GK rats developed hypertension, cardiac hypertrophy and overexpression of cardiac natriuretic peptides and profibrotic connective tissue growth factor compared to nondiabetic Wistar rats. The high dietary sodium further increased the systolic blood pressure, and changed the mitral inflow pattern measured by echocardiography towards diastolic dysfunction. Enalapril and omapatrilat equally decreased the systolic blood pressure compared to the control group during normal- as well as high-sodium diet. Both drugs had beneficial cardioprotective effects, which were blunted by the high dietary sodium. Compared to enalapril, omapatrilat reduced the echocardiographically measured left ventricular mass during normal-sodium diet and improved the diastolic function during high-sodium diet in GK rats. Furthermore, omapatrilat reduced relative cardiac weight more effectively than enalapril during high sodium intake. Our results suggest that both the renin-angiotensin and the neutral endopeptidase system are involved in the pathogenesis of diabetic cardiomyopathy since vasopeptidase inhibition was shown to provide additional benefits in comparison with selective angiotensin converting enzyme inhibition alone.     

Effects of enalapril and hydrochlorothiazide on the salt-induced cardiac and renal hypertrophy in normotensive rats

Recent studies have shown that, not only in hypertensive animals but even in normotensive rats, dietary salt (sodium chloride) produces a dose-related increase in the left ventricular and renal mass. In the present study the effects of the angiotensin converting enzyme inhibitor (ACEI) enalapril and the thiazide-type diuretic, hydrochlorothiazide, on the development of the salt-induced left ventricular and kidney hypertrophy were examined in normotensive Wistar-Kyoto and Wistar rats. A high intake of sodium chloride (6% of the dry weight of the chow to mimic the level found in many human food items) during eight weeks produced a marked increase in the mass of the left ventricle and the kidneys in both rat strains with little or no effect on blood pressure. The cardiac hypertrophy correlated strongly with the renal hypertrophy. These salt-induced changes in the heart and in the kidneys were completely blocked by hydrochlorothiazide, while enalapril was devoid of any significant effects during the high-salt diet. However, during a low-salt diet enalapril, but not hydrochlorothiazide, effectively lowered the blood pressure and decreased the left ventricular mass of the normotensive rats. There was a 3- to 4-fold increase in the urinary excretion of calcium during the high intake of sodium chloride. Hydrochlorothiazide decreased the urinary excretion of calcium even during the low salt diet, and it completely blocked the salt-induced hypercalciuria. Enalapril had no significant effect on the urinary calcium excretion. During the low-salt diet hydrochlorothiazide increased the calcium and decreased the potassium concentration in the heart while enalapril increased the phosphorus concentration.In conclusion, a high intake of sodium chloride produced hypertrophy both in the heart and in the kidneys, even in the absence of a rise in blood pressure. Salt also remarkably increased the urinary calcium excretion. These harmful effects of salt were blocked by the thiazide diuretic hydrochlorothiazide but not by the ACEI enalapril. However, this study does not allow to make any direct comparison between the effects of enalapril and hydrochlorothiazide. Correspondence to: E. Mervaala at the above address     

Improvement of cardiovascular effects of metoprolol by replacement of common salt with a potassium- and magnesium-enriched salt alternative.

1. The influence of sodium chloride (NaCl)-enrichment of the diet (6% of the dry weight) and that of a novel sodium-reduced, potassium-, magnesium-, and L-lysine-enriched salt alternative on the cardiovascular effects of the beta 1-adrenoceptor blocking drug, metoprolol, was studied in stroke-prone spontaneously hypertensive rats. 2. Increased dietary sodium chloride intake produced a marked rise in blood pressure and induced left ventricular and renal hypertrophy. By contrast, the salt alternative did not increase blood pressure and caused remarkably less cardiac and renal hypertrophy than did sodium chloride. 3. Metoprolol treatment at a daily dose of 250 mg kg-1 lowered blood pressure and decreased left ventricular hypertrophy index during the control diet. Sodium chloride-enrichment blocked the antihypertensive effect of metoprolol, while a partial protective effect on left ventricular and renal hypertrophy persisted. In the presence of the salt alternative-enrichment both at the level of 6% and 10.5% (corresponding to a NaCl level of 6%), metoprolol was fully able to exert its beneficial cardiovascular and renal effects. 4. Both salt supplementations, irrespective of metoprolol treatment, induced a 3 to 4 fold increase in the urinary excretion of calcium. There was a linear correlation between the urinary excretions of sodium and calcium. The urinary excretion of magnesium rose by 90% and that of potassium by 110% in the salt alternative group. 6. Our findings suggest that replacement of common salt by a potassium-, and magnesium-enriched salt alternative in the diet produces beneficial cardiovascular effects and improves the antihypertensive efficacy of metoprolol in stroke-prone spontaneously hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of salt and water intake on epithelial sodium channel mRNA abundance in the kidney of salt-sensitive Sabra rats

1. The level of mRNA expression of epithelial sodium channel (ENaC) subunits was studied in a salt-dependent hypertensive rat strain (Sabra). These rats exhibit high vasopressin levels compared with their normotensive counterparts. We also investigated whether this expression is influenced by changes in the sodium intake/aldosterone axis or in the fluid intake/vasopressin axis. 2. A higher expression of beta- and gamma-subunit mRNA was found in salt-sensitive compared with salt-resistant rats on a normal salt diet. A high-sodium diet did not alter mRNA abundance in either substrain. In contrast, water supplementation in salt-sensitive rats fed the high-sodium diet induced a marked reduction in mRNA abundance of beta- and gamma-subunits. 3. The present study provides evidence that beta- and gamma-subunits of ENaC are differently expressed in the kidney of salt-sensitive and salt-resistant Sabra rats and that their abundance is regulated by vasopressin, not by sodium intake. These results are consistent with the hypothesis that increased vasopressin-dependent ENaC expression and activity may contribute to the pathogenesis of hypertension in salt-sensitive Sabra rats.     

Prevention of salt induced hypertension and fibrosis by angiotensin converting enzyme inhibitors in Dahl S rats

BACKGROUND AND PURPOSE: In Dahl S rats, high salt increases activity of the tissue renin-angiotensin-aldosterone system (RAAS) in the CNS, heart and kidneys. Here, we assessed the effects of chronic angiotensin converting enzyme (ACE) inhibition on salt-induced hypertension and cardiovascular and renal hypertrophy and fibrosis, relative to the extent of ACE blockade. EXPERIMENTAL APPROACH: From 4.5 weeks of age, Dahl S rats received either the lipophilic ACE inhibitor trandolapril (1 or 5 mg kg(-1) day(-1)) or the hydrophilic ACE inhibitor lisinopril (10 or 50 mg kg(-1) day(-1)) and a high salt diet was started 0.5 week later. Treatments ended at 9 weeks of age. KEY RESULTS: High salt diet markedly increased blood pressure (BP), decreased plasma angiotensin II and increased ACE binding densities in brain, heart, aorta and kidneys. Trandolapril and lisinopril prevented 50% of the increase in BP in light and dark period of the day. After the last doses, trandolapril decreased ACE densities by approximately 80% in brain nuclei and heart and lisinopril by approximately 60% in the brain and by approximately 70% in the heart. The two ACE inhibitors prevented right ventricular hypertrophy and attenuated left ventricular hypertrophy but did not affect renal hypertrophy caused by high salt. Both drugs prevented high salt-induced fibrosis in heart, kidney and aorta. CONCLUSION AND IMPLICATION: As the ACE inhibitors could completely prevent tissue fibrosis and partially prevent tissue hypertrophy and hypertension, the tissue RAAS may play a critical role in salt-induced fibrosis, but a lesser role in the hypertrophy.     

Effect of salt balance on the renal and hemodynamic actions of benazepril in normal men

Renal and hemodynamic effects of diet alone and of single oral doses of the nonsulphydryl angiotensin converting enzyme (ACE) inhibitor, benazepril (10 mg), were investigated in eight healthy volunteers under stable conditions of high salt intake (300 mmol NaCl/day) and low salt intake (10 mmol NaCl/day), in a double blind, placebo controlled study. There were no changes in blood pressure between the two dietary extremes either during the run-in period or once sodium balance had been achieved. Mean renal plasma flow was higher, by approximately 10% and renal vascular resistance lower by 15%, on high salt diet compared to low salt diet. Glomerular filtration rates were found to be similar irrespective of the state of salt balance. Both plasma urate concentration and plasma renin activity were significantly elevated in the low salt compared to high salt state. Benazepril caused a greater fall in blood pressure in the sodium depleted state. Significant increases in the mean renal plasma flow, in the order of 15-20%, were seen over 6 h postbenazepril when compared with placebo response, regardless of the level of salt intake. Glomerular filtration rate over the same period remained unaltered. Benazepril doubled the urinary excretion of sodium over the first 4 hours after dosing whilst on the low salt diet; the equivalent increase during salt loading was approximately 20%. These results suggest that benazepril may exert direct effects on renal tubular function additional to those achieved through ACE blockade.     

D2 -like receptor stimulation decreases effective renal plasma flow and glomerular filtration rate in spontaneously hypertensive rats

In spontaneously hypertensive rats (SHRs) the dopaminergic D1-like renal vasodilator response is impaired. The renal vascular response to D2-like receptor stimulation in vivo is incompletely known. Therefore, renal hemodynamics were studied in conscious SHRs during continuous infusion of D2-like agonist N,N-Di-n-propyldopamine (DPDA) (10 microg/kg/min) with Wistar-Kyoto (WKY) rats as controls. As sodium status may affect dopaminergic responses, rats were studied during both low- and high-sodium diets. D2-like stimulation reduced mean arterial pressure and effective renal plasma flow and glomerular filtration rate (GFR) similarly in SHR and WKY rats. Renal vascular resistance increased significantly in both strains. The response to DPDA is modified by sodium status, with a more pronounced fall in blood pressure (in WKYs and SHRs) and GFR (in WKYs) during high-sodium conditions. The responses were blocked by co-infusion with D2 antagonist domperidone. Thus, D2-like renal vascular responses are normal in SHRs irrespective of sodium intake. The combination of a preserved D2-like renal vasoconstrictive and an impaired D1-like renal vasodilatory response may contribute to maintenance of hypertension in SHRs.     

Renal targeting of captopril using captopril-lysozyme conjugate enhances its antiproteinuric effect in adriamycin-induced nephrosis.

INTRODUCTION: High-sodium intake blunts the renoprotective efficacy of angiotensin-converting enzyme (ACE) inhibitors. We investigated whether targeting the drug to the kidneys may attenuate the inferior response to ACE inhibitor (ACE-I) under high-sodium conditions. The ACE-I, captopril, was coupled to the low molecular weight protein (LMWP) lysozyme, yielding captopril-lysozyme conjugates that accumulate specifically in the proximal tubular cells of the kidneys.We compared the antiproteinuric efficacy of captopril to that of the captopril-lysozyme conjugate in adriamycin-induced proteinuric rats fed with a high-sodium diet. MATERIALS AND METHODS: Rats with adriamycin (single injection 2 mg/kg)- induced proteinuria were put on a high-sodium diet (HS; 3% NaCl). When stable proteinuria developed at 5.5 weeks, animals were assigned to the following subcutaneous treatments: (1) vehicle (n=7); (2) lysozyme (equivalent to the amount in conjugate) (n=7); (3) captopril (5 mg/kg/24 hours) (n=8); (4) captopril-lysozyme conjugate (captopril content equivalent to 1mg captopril/kg/24 hours) (n=7). Blood pressure and proteinuria were monitored. After 10 days of treatment the rats were sacrificed and kidneys and plasma were removed. RESULTS: Results are given as mean + S.E.M. After injection with adriamycin at t=0, stable proteinuria developed, amounting to 547+79 mg/24 hours at week 5.5. Subsequently, after seven and nine days of treatment, no reduction of proteinuria was observed in the captopril-treated group. In contrast, a significant reduction in proteinuria, amounting to 35+4% (day seven) and 25+2% (day nine), was observed in the captopril-lysozyme conjugate group (p<0.05 compared with the captopril group). In contrast, blood pressure was reduced in the captopril-treated group by 13.9+2.9 mmHg, while in the captopril-lysozyme treated group, an increase of 7.9+3.3 mmHg was found. Renal ACE activity was lowered by 30% in the captopril, as well as in the captopril-lysozyme conjugate treated group, compared with control. Furthermore, the ratio of kidney: plasma levels of captopril almost doubled as a consequence of coupling to lysozyme. CONCLUSION: In proteinuric rats fed with a high-sodium diet, captopril induced a reduction in blood pressure without an effect on proteinuria. In contrast, renal targeting of a five times lower dose of the ACE-I with the captopril-lysozyme conjugate reduced proteinuria without reducing blood pressure. Therefore, renal targeting of ACE-I may be a promising strategy to optimise the therapeutic response of ACE-I.     

Sodium balance and blood pressure during high sodium ingestion in spontaneously hypertensive and Wistar Kyoto normotensive rats

Objectives of this study were to compare natriuretic capability and arterial pressure elevation at high Na+ ingestion in male spontaneously hypertensive (SH) and normotensive Wistar Kyoto (WKY) rats at the young adult age of 16-19 weeks. 10 SH and 10 WKY male rats at this age were surgically implanted with arterial catheters. After a period of 10 days on low nutritionally adequate Na+ intake they were fed a high Na+ diet for a period of 1 week. Na+ retention (intake-output) on the high Na+ diet was substantial, but similar in both groups of rats. None of the animals displayed meaningful elevation of arterial pressure. Thus, the functional capacity of the young SH rat to excrete Na+ during excessive ingestion without elevation of blood pressure seems adequate as compared to normotensive rats, at least within the age range of 16-19 weeks.     

Dietary NaCl-induced hypertension in uninephrectomized Wistar-Kyoto rats: role of kidney function

This study tests the hypothesis that combination of unilateral nephrectomy and a high sodium chloride (NaCl) diet causes hypertension in otherwise normotensive Wistar-Kyoto (WKY) rats and that this hypertensive response is due to a deficit in the remaining kidney's function. Four-week-old male WKY rats underwent either a right nephrectomy or a sham operation. Two weeks later, the groups either were switched to a high (8%) NaCl diet or remained on the basal (0.72%) NaCl diet. At ages 3 and 6 months, hemodynamic parameters and renal excretory responses were measured, in the conscious animals, before and after administration of a 30-min isotonic saline challenge (5% of body weight). The high-NaCl diet increased arterial pressure in the uninephrectomized but not in sham-operated rats; the development of hypertension was associated with increases in baseline renal excretion of fluid and sodium and diuretic and natriuretic responses to the isotonic saline challenge. The increased diuresis and natriuresis in the hypertensive WKY rats were related to a significant reduction in renal tubular reabsorption and an associated increase in fractional excretion of fluid and sodium. The high-NaCl diet also increased renal excretion of fluid and sodium in the sham-operated rats; however, the uninephrectomized animals excreted much more fluid and sodium than did sham-operated rats. These data suggest that the combination of unilateral nephrectomy and dietary NaCl excess causes hypertension in the normotensive WKY rats, but the hypertensive response is not likely due to a functional deficit in the remaining kidney.     

Salt and water intake and sodium and potassium excretion in spontaneously hypertensive rats

1. Total fluid and saline intakes were greater in spontaneously hypertensive rats (SHR) than in normotensive rats (NTR). 2. Total fluid and saline intake were significantly elevated in prehypertensive SHR, 5 weeks old, compared with age-matched NTR, and the intakes fell with age in both strains but remained considerably greater in SHR. 3. In SHR, in which the blood pressure was maintained at normotensive levels by treatment with hydralazine, the saline and fluid intakes remained elevated above those of NTR. 4. SHR and NTR fed low sodium diet with water alone to drink have similar excretion rates of sodium, suggesting that their ability to conserve sodium was normal. 5. Measurement of sodium excretion after three different levels of sodium loading, on normal or low sodium diets, also failed to demonstrate an abnormality of renal function in SHR. 6. These results demonstrate that the fluid and saline intakes of SHR are elevated compared with NTR and this difference is independent of the hypertension in SHR and is not secondary to enhanced renal sodium loss.     

Enhanced angiotensin-converting enzyme activity and systemic reactivity to angiotensin II in normotensive rats exposed to a high-sodium diet

A high salt diet is associated with reduced activity of the renin–angiotensin–aldosterone system (RAAS). However, normotensive rats exposed to high sodium do not show changes in systemic arterial pressure. We hypothesized that, despite the reduced circulating amounts of angiotensin II induced by a high salt diet, the cardiovascular system's reactivity to angiotensin II is increased in vivo, contributing to maintain arterial pressure at normal levels. Male Wistar rats received chow containing 0.27% (control), 2%, 4%, or 8% NaCl for six weeks. The high-sodium diet did not lead to changes in arterial pressure, although plasma levels of angiotensin II and aldosterone were reduced in the 4% and 8% NaCl groups. The 4% and 8% NaCl groups showed enhanced pressor responses to angiotensin I and II, accompanied by unchanged and increased angiotensin-converting enzyme activity, respectively. The 4% NaCl group showed increased expression of angiotensin II type 1 receptors and reduced expression of angiotensin II type 2 receptors in the aorta. In addition, the hypotensive effect of losartan was reduced in both 4% and 8% NaCl groups. In conclusion these results explain, at least in part, why the systemic arterial pressure is maintained at normal levels in non-salt sensitive and healthy rats exposed to a high salt diet, when the functionality of RAAS appears to be blunted, as well as suggest that angiotensin II has a crucial role in the vascular dysfunction associated with high salt intake, even in the absence of hypertension.     

SODIUM PREFERENCE AND EXCRETION IN SPONTANEOUSLY HYPERTENSIVE RATS ON VARIOUS DIETS

Stroke-prone spontaneously hypertensive rats (SHRSP) and stroke-resistant SHR (SHRSR) exhibited an increased preference for a 2% NaCl solution, relative to water, in comparison with normotensive Wistar-Kyoto (WKY), but the preference was lost quickly in SHRSP with unbroken exposure. Neither a high protein diet (50% fish protein) nor a low protein diet (5% protein) changed the salt water preference in SHRSR and the former abolished the preference more quickly in SHRSP. The fish protein diet, however, increased the ratio of urinary sodium excretion to dietary sodium intake in the first three days of exposure to a high salt intake in all groups. Results from this experiment suggest that an increased dietary protein intake can facilitate sodium excretion and may possibly ameliorate the adverse effect of a high sodium diet.     

Effect of cross-fostering on blood pressure and renal function in the New Zealand genetically hypertensive rat

1. The severity of hypertension displayed by adult spontaneously hypertensive rats (SHR) and Dahl (SS/Jr) rats can be reduced by 20-30 mmHg if the hypertensive pup is cross-fostered to a normotensive mother within the first 2 weeks of birth. In the SHR, at least, this blood pressure-lowering effect arises through programming of the neonatal kidney to excrete sodium more effectively. Thus, cross-fostering may only be effective in lowering pressure in salt-sensitive hypertensive strains. Accordingly, the aim of the present study was to determine whether cross-fostering is effective in lowering adult blood pressure in the salt-resistant New Zealand genetically hypertensive (GH) rat. 2. Genetically hypertensive and control normotensive (N) rat pups were reared by either their natural mothers or a foster mother of the opposite strain (NX and GHX). Blood pressure was tracked from the age of 6-18 weeks, at which time renal function was assessed using standard clearance techniques in anaesthetized rats. Renal function was also assessed in a separate group of young rats at 5-6 weeks of age. 3. Cross-fostered GHX rats had lower blood pressure than GH rats, but this difference was only apparent until 9 weeks. The NX rats had higher blood pressures than N rats, but again pressure converged at 10 weeks. Basal renal function did not differ between GH and GHX rats or between N and NX rats at either age. However, young GH rats had lower renal blood flow, glomerular filtration rate, urine output and sodium excretion than N rats. 4. These data show that cross-fostering is effective in lowering blood pressure in GH rats, albeit transiently. The kidneys do not appear to play a role, because renal function did not differ under the current experimental conditions between GH and GHX rats. However, the kidney may play a greater role in the onset of hypertension in the GH rat than previously thought.     

Renal catecholamines and alpha 2-adrenergic receptors in salt-related and genetic hypertension

Increased dietary salt intake alters renal function which often leads to deleterious cardiovascular consequences. Studies were carried out to characterize the effects of high-salt diets on renal catecholamines and alpha 2-adrenergic receptors. These parameters were evaluated in both genetic and acquired forms of hypertension and also in normotensive rats on high-salt diets. Renal catecholamine content was determined by high-performance liquid chromatography with electrochemical detection. Renal alpha 2-adrenergic receptor-binding studies were performed on whole kidney homogenates using 3H-p-aminoclonidine to label both high- (0.5 nM) and low-affinity (5.0 nM) renal alpha 2-adrenergic receptors. Increased salt intake elevated blood pressure, decreased renal norepinephrine stores and resulted in renal alpha 2-adrenergic receptor up-regulation in deoxycorticosterone acetate salt hypertensive rats, Dahl-S rats and COX-SHR. The decreased renal stores of norepinephrine (NE) appeared to reflect increased renal NE utilization. In contrast, SHR (Charles River) had elevated NE stores and alpha 2-adrenergic receptors while on normal salt diets. Short-term (10-14 days) exposure to high-salt diets had modest effects in normotensive rats or COX-SHR, although it was sufficient to increase low affinity renal alpha 2-adrenergic receptor number. Renal dopamine metabolism was also altered by high-salt diets. These studies demonstrated a relationship between renal NE content and renal alpha 2-adrenergic receptors. The implications of this relationship and other salt-related changes in renal catecholamine metabolism were discussed as they pertained to hypertension and renal function.     

EFFECT OF SALT LOADING ON BLOOD PRESSURE AND EICOSANOID METABOLISM OF SPONTANEOUSLY HYPERTENSIVE RATS FED A FISH OIL ENRICHED DIET

This study investigated the effects of dietary modification of prostaglandin (PG) synthesis on blood pressure regulation in spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats under conditions of normal and elevated salt intake. After an initial period of 4 weeks on either a 2-series PG 'inhibitory' diet of fish oil (maxEPA) or a control diet of saturated fat, half of each group received 1.5% saline for 1 week. Blood pressures were unaffected by diet during the period of normal salt intake, but following salt loading, the maxEPA-fed SHR showed a blood pressure increase (mean = 21 mmHg) relative to the EPA-fed rats on water. Rats on maxEPA showed impaired ability to generate serum thromboxane and diminished excretion of urinary 6-keto-PGF1 alpha and PGE2. SHR on water showed greater serum TXB2 generating capacity than WKY, but diminished urinary PGE2 excretion. Thus, the increased blood pressure observed in the salt-loaded SHR on the maxEPA diet may be explained by reduced renal PG synthesis resulting in either mild sodium retention and/or increased vascular reactivity.     

ROLE OF PLATELET CYTOSOLIC CALCIUM IN THE RESPONSE TO SALT INTAKE IN NORMOTENSIVE SUBJECTS

1. To investigate the role of cytosolic calcium in salt-induced hypertension, a high salt diet was given to young normotensive subjects with or without a family history of hypertension. 2. A high salt diet raised blood pressure significantly in normotensive subjects with a family history compared with the age and gender matched subjects without a predisposition to hypertension. 3. Platelet cytosolic calcium was increased in predisposed subjects in a control period before salt intake. 4. A positive correlation was observed between the changes in mean blood pressure and cytosolic calcium before high salt intake, although salt loading did not induce any significant change in cytosolic calcium. 5. These results suggest that cytosolic calcium plays a role in elevation of blood pressure induced by salt loading in subjects with a family history of hypertension.     

Early urinary biomarkers of renal tubular damage by a high‐salt intake independent of blood pressure in normotensive rats

Dietary sodium intake has been associated with progression to chronic kidney disease (CKD) as well as hypertension. A high‐salt intake causes renal damage independent of hypertension. Because traditional renal biomarkers are insensitive, it is difficult to detect renal injury induced by a high‐salt intake, especially in normotensive patients. Here, we investigated whether newly developed renal biomarkers could be detected earlier than traditional biomarkers under a high‐salt intake, in normotensive rats. Male Wistar Kyoto rats (WKY) received a regular (0.8% NaCl) or salt‐loaded (2, 4, and 8% NaCl) diet from 9 to 17 weeks of age. A urine sample was obtained once a week and urinary vanin‐1, neutrophil gelatinase‐associated lipocalin (NGAL), and kidney injury molecule‐1 (Kim‐1) were measured. At 17 weeks of age, 8% salt‐loaded WKY showed histopathological renal tubular damage and elevated Rac1 activity in renal tissues. Although there was no significant increase in serum creatinine, urinary albumin, N‐acetyl‐β‐D‐glucosaminidase (NAG), or Kim‐1 during the study period among the groups, urinary vanin‐1 and NGAL significantly increased in 8% salt‐loaded WKY from 10 to 17 weeks of age. These results suggest that urinary vanin‐1 and NGAL, which might be induced by salt per se, are potentially earlier biomarkers for renal tubular damage in normotensive rats under a high‐salt intake.     

Angiotensin and osmoreceptor inputs to the area postrema: role in long-term control of fluid homeostasis and arterial pressure

1. The role of the area postrema (AP) in the long-term control of body fluid homeostasis and arterial pressure under conditions of increased dietary salt intake is reviewed. A model is proposed in which sympathetic nerve activity is suppressed when dietary salt is increased. It is hypothesized that the AP acts as an essential integrative site in the hind-brain for this response. 2. An essential component of the hypothesis is that basal levels of circulating angiotensin II support arterial pressure in animals consuming a normal salt diet by acting on the AP to drive sympathetic nerve activity. This hypothesis is supported by the observation that the long-term hypotensive response to losartan, the AT1 receptor antagonist, is attenuated in AP-lesioned (APx) rats. 3. The role of hepatoportal sodium receptors in signalling the AP about changes in dietary salt intake is discussed. Intragastric hypertonic saline infusion increases portal venous, but not systemic plasma, osmolality and increases Fos-like immunoreactivity in the AP, nucleus tractus solitarius and the supraoptic, paraventricular and lateral parabrachial nuclei. Other studies have shown that stimulation of these receptors decreases renal sympathetic nerve activity. 4. The hypothesis that the AP is critical in long-term control of arterial pressure and body fluid homeostasis under conditions of altered dietary salt intake was studied. The responses of arterial pressure and sodium and water balance to changes in dietary salt intake were measured in intact and APx rats. Contrary to the hypothesis, APx rats did not exhibit impaired regulation of arterial pressure or water balance. However, APx rats did demonstrate an impaired ability to excrete sodium when salt intake was elevated. 5. Based on these observations, it is concluded that the AP is important in the control of sodium balance, but not arterial pressure, when dietary salt intake is altered.     

Celecoxib does not alter cardiovascular and renal function during dietary salt loading

1. Cyclo-oxygenase-2 (COX-2)-derived prostaglandins are important in controlling sodium excretion and renin release. In the present study, we tested the hypothesis that a clinical dose of celecoxib would impair urinary sodium excretion and elevate blood pressure (BP) during dietary salt loading. 2. Twelve normotensive individuals (mean (± SEM) age 35 ± 2 years) completed two separate 17 day dietary perturbations, one taking 200 mg/day celecoxib (CX2) and the other taking placebo (PL), randomized with a 1 month wash out. The controlled 17 day diet consisted of a 3 day run-in diet, 7 days of a low-salt (LS, 20 mmol sodium/day) diet and 7 days of a high-salt diet (HS, 350 mmol sodium/day) diet. The order in which the diets were applied was randomized. Data were collected on the last day of the LS and HS diets. 3. Plasma and urinary prostaglandins were modestly lower during celecoxib (P < 0.05). Urinary sodium excretion was greater (P < 0.01) during the HS diet (253 ± 10 vs 281 ± 27 mmol/24 h for PL vs CX2, respectively) compared with the LS diet (14 ± 3 vs 17 ± 7 mmol/24 h for PL vs CX2, respectively; P(drug) = 0.26). Celecoxib did not alter creatinine clearance (P > 0.50). Twenty-four hour mean arterial BP was similar during PL (87 ± 2 vs 87 ± 2 mmHg for LS and HS, respectively) and CX2 (88 ± 2 vs 87 ± 2 mmHg for LS and HS, respectively; P = 0.85), with no effect of dietary salt (P > 0.80). Plasma renin activity, angiotensin II and aldosterone were all suppressed with dietary salt loading (P < 0.05), with no effect of drug (P > 0.35). 4. In conclusion, blood pressure and renal function were not adversely affected by celecoxib, even during dietary salt loading. These findings support current guidelines suggesting minimal cardiovascular risks associated with short-term, low-dose use of celecoxib in young to middle-aged adults.