Effects of renal denervation on the sodium excretory actions of leptin in hypertensive rats. (65/1093)

BACKGROUND: Previous studies from this laboratory have reported a marked attenuation of the renal responses to pharmacologic doses of synthetic murine leptin infused in the spontaneously hypertensive rat (SHR) model compared with normotensive Sprague-Dawley and lean Zucker rat models. METHODS: In the present study, the hemodynamic and renal excretory effects of an intravenous bolus administration of pharmacologic doses of synthetic murine leptin were examined in groups of anesthetized SHR with unilateral nephrectomy and renal denervation or sham-denervation of the remaining kidney. RESULTS: In the SHR with acute renal denervation (N = 8), an intravenous bolus of 1600 microg/kg of leptin produced a significant twofold to fourfold elevation in sodium excretion but did not increase natriuresis in the sham-denervated group (N = 6). Chronic renal denervation of one-week duration (N = 8) was associated with qualitatively and quantitatively similar increases of sodium excretion in response to leptin administration. Mean arterial pressure remained unchanged in all groups after the administration of leptin. CONCLUSIONS: Collectively, these results are interpreted to suggest that the blunted natriuretic and diuretic responses to leptin observed in the SHR with intact renal nerves may be partially explained by the antinatriuretic effect of an enhanced baseline efferent renal sympathetic activity and/or leptin's stimulation of the sympathetic nervous system.  (+info)

Renin inhibition improves pressure natriuresis in essential hypertension. (66/1093)

Pressure natriuresis (PN), i.e., a rise in renal sodium excretion in response to a higher BP, is involved in long-term BP regulation. PN is blunted in essential hypertension, but the mechanism is unknown. This study assessed the role of the renin-angiotensin-aldosterone system (RAAS) in PN in eight essential hypertensive men from the individual correlations between spontaneous fluctuations in BP and time corresponding changes in sodium excretion (collected at 2- and 4-h intervals for 48 h), during strict sodium balance, without treatment, and during renin inhibition (remikiren, 600 mg oral compound). Without treatment, daily values for mean arterial pressure were 109.5 +/- 1.9 and 107 +/- 1.9 mmHg, for urinary sodium excretion were 37.2 +/- 2.8 and 42.0 +/- 2.8 mmol/24 h, and for plasma renin activity were 2.34 +/- 0.48 and 2.23 +/- 0.44 nmol/L per h, respectively, for two consecutive days. During remikiren treatment, mean arterial pressure was 101.9 +/- 1.7 and 100.8 +/- 1. 7 mmHg (P: < 0.05, versus baseline). Urinary sodium excretion was 39. 3 +/- 3.7 and 45.2 +/- 5.3 mmol/24 h (not significant versus baseline), and plasma renin activity was 0.79 +/- 0.11 and 0.82 +/- 0.13 nmol/L per h (P: < 0.05 versus baseline). During remikiren treatment, BP correlated positively with sodium excretion in all patients but in only three of eight patients without treatment. The slope of the regression equation was steeper during remikiren treatment in seven of eight patients. Thus, the relationship between BP and natriuresis was more readily apparent during RAAS blockade, suggesting that RAAS activity blunts PN in hypertensive patients. Improved PN may contribute to the hypotensive effect of RAAS blockade and to maintenance of sodium balance at a lower BP level without volume expansion.  (+info)

Proximal sodium reabsorption: An independent determinant of blood pressure response to salt. (67/1093)

The purpose of this study was to evaluate the contribution of renal sodium handling by the proximal tubule as an independent determinant of blood pressure responsiveness to salt in hypertension. We measured blood pressure (BP), renal hemodynamics, and segmental renal sodium handling (with lithium used as a marker of proximal sodium reabsorption) in 38 hypertensive patients and 27 normotensive subjects (15 young and 12 age-matched) on a high and low sodium diet. In control subjects, changing the diet from a low to a high sodium content resulted in no change in BP and increases in glomerular filtration rate (P<0.05), renal plasma flow (P<0.05), and fractional excretion of lithium (FE(Li), P<0.01). In hypertensive patients, comparable variations of sodium intake induced an increase in BP with no change in renal hemodynamics and proximal sodium reabsorption. When analyzed by tertiles of their BP response to salt, salt-insensitive hypertensive patients of the first tertile disclosed a pattern of adaptation of proximal sodium reabsorption comparable to that of control subjects, whereas the most salt-sensitive patients of the third tertile had an inverse pattern with a high FE(Li) on low salt and a lower FE(Li) on high salt, suggesting an inappropriate modulation of proximal sodium reabsorption. The BP response to salt correlated positively with age (r=0.34, P=0.036) and negatively with the changes in FE(Li) (r=-0.37, P=0.029). In a multivariate analysis, the changes in FE(Li) were significantly and independently associated with the salt-induced changes in BP. These results suggest that proximal sodium reabsorption is an independent determinant of the BP response to salt in hypertension.  (+info)

Renal responsiveness to aldosterone during exposure to simulated microgravity. (68/1093)

We measured renal functions and hormones associated with fluid regulation after a bolus injection of aldosterone (Ald) during head-down tilt (HDT) bed rest to test the hypothesis that exposure to simulated microgravity altered renal responsiveness to Ald. Six male rhesus monkeys underwent two experimental conditions (HDT and control, 72 h each) with each condition separated by 9 days of ambulatory activities to produce a crossover counterbalance design. One test condition was continuous exposure to 10 degrees HDT; the second was a control, defined as 16 h per day of 80 degrees head-up tilt and 8 h prone. After 72 h of exposure to either test condition, monkeys were moved to the prone position, and we measured the following parameters for 4 h after injection of 1-mg dose of Ald: urine volume rate (UVR); renal Na(+)/K(+) excretion ratio; renal clearances of creatinine, Na(+), osmolality, and free water; and circulating hormones [Ald, renin activity (PRA), vasopressin (AVP), and atrial natriuretic peptide (ANP)]. HDT increased Na(+) clearance, total renal Na(+) excretion, urine Na(+) concentration, and fractional Na(+) excretion, compared with the control condition, but did not alter plasma concentrations of Ald, PRA, and AVP. Administration of Ald did not alter UVR, creatinine clearance, Ald, PRA, AVP, or ANP but reduced Na(+) clearance, total renal Na(+) excretion, urinary Na(+)/K(+) ratio, and osmotic clearance. Although reductions in Na(+) clearance and excretion due to Ald were greater during HDT than during control, the differential (i.e., interaction) effect was minimal between experimental conditions. Our data suggest that exposure to microgravity increases renal excretion of Na(+) by a natriuretic mechanism other than a change in renal responsiveness to Ald.  (+info)

Striking increase of natriuresis by low-dose spironolactone in congestive heart failure only in combination with ACE inhibition: mechanistic evidence to support RALES. (69/1093)

BACKGROUND: A marked reduction of overall mortality in patients with severe congestive heart failure (CHF) has been demonstrated by addition of the mineralocorticoid receptor antagonist spironolactone to ACE inhibition. The aim of the present study was to examine a hypothesized interaction of spironolactone and ACE inhibitors in renal electrolyte and volume regulation. METHODS AND RESULTS: Wistar rats with extensive myocardial infarction or sham operation were treated with either placebo, the ACE inhibitor trandolapril, low-dose spironolactone, or a combination of the 2. Twelve weeks after infarction, rats were housed in metabolic cages. Urinary volume and sodium excretion were significantly increased in CHF rats on a combined treatment with spironolactone and trandolapril (21.2+/-2.6 mL/d, 2489+/-320 mmol/d, mean+/-SD; P<0.05 versus other experimental groups) versus placebo-treated rats (16.7+/-5.6 mL/d, 1431+/-458 mmol/d),whereas these parameters were not affected in rats on either spironolactone (16.1+/-6.6 mL/d, 1153+/-273 mmol/d) or trandolapril alone (15.9+/-4.2 mL/d, 1392+/-294 mmol/d). The effects on natriuresis coincided with a significant reduction of left ventricular end-diastolic pressure (LVEDP) in rats on trandolapril and spironolactone (10.8+/-8.2 mm Hg; P:<0.05 versus CHF placebo: 23.3+/-7.2 mm Hg; sham-operated rats: 5.1+/-0.9 mm Hg), whereas LVEDP remained elevated in rats treated with either compound alone. CONCLUSIONS: In the present study, we found an unexpected interaction of low-dose spironolactone and the ACE inhibitor trandolapril in experimental CHF leading to marked effects on renal electrolyte and volume regulation that were not apparent by treatment with either drug alone. These findings may explain the beneficial effects of spironolactone in CHF patients.  (+info)

Involvement of the renal kallikrein-kinin system in furosemide-induced natriuresis in rats. (70/1093)

This study examined whether the renal kallikrein-kinin system (KKS) is involved with furosemide-induced natriuresis in rats. Intravenous administration of furosemide (10 mg/kg) to anesthetized rats infused with physiological saline (saline) increased renal KK excretion as well as urine volume and urinary excretions of sodium, chloride and potassium. The change in the increase of renal KK excretion by furosemide at a dose of 1.0 mg/kg relative to the control was larger than that of urine volume. Pretreatment with a B2-receptor antagonist, 8-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlo robenzyloxy]-2-methylquinoline (FR173657, 100 mg/kg), significantly inhibited the furosemide-induced natriuresis by 58.6%. The effect of FR173657 on the furosemide-induced natriuresis was also examined in hypotonic saline-loading rats. Similar to the saline-loading rats, urinary excretion of sodium collected during the first 8 h in metabolic cages significantly reduced by 22.4% when FR173657 (100 mg/kg) was given concurrently with furosemide (100 mg/kg) and hypotonic saline (5% of body wt.). These results indicate that furosemide increased renal KK excretion through a mechanism different from a washout mechanism and induced natriuresis partly through an augmentation of the renal KKS following the increase in renal KK excretion in both the saline- and hypotonic saline-loading rats.  (+info)

Adenosine activates aromatic L-amino acid decarboxylase activity in the kidney and increases dopamine. (71/1093)

Renal sodium handling is important for regulating BP, and renal dopamine and adenosine play an important role in renal sodium handling, however the interaction of these hormones in the kidney was not clarified. In in vivo experiments, adenosine significantly increased water and sodium excretion by 50% compared with vehicle when infused into the left renal artery, accompanied by an increase in urinary dopamine excretion in the left kidney. Neither water-sodium excretion nor dopamine excretion changed in the vehicle-infused kidney. Aromatic L-amino acid decarboxylase activity in the left kidney was significantly higher than that in the noninfused right kidney. The increase in water-sodium excretion induced by adenosine was significantly inhibited by SCH23390, a selective D1 receptor antagonist. In in vitro experiments, porcine renal proximal tubular cells were incubated with 250 microM L-dopa and N(6)-cyclohexyladenosine, an adenosine type 1 receptor agonist, after treatment with adenosine deaminase. N(6)-cyclohexyladenosine significantly increased dopamine formation at a concentration of 10(-9) to 10(-7) M, and this was completely inhibited by 1,3-dipropyl-8-cyclopentylxanthin, an adenosine A1 antagonist. These results show that renal dopamine synthesis is stimulated by adenosine through the activation of aromatic L-amino acid decarboxylase and suggest that adenosine leads to an increase in renal dopamine and natriuresis.  (+info)

Effects of dehydroepiandrosterone and quinapril on nephropathy in obese Zucker rats. (72/1093)

BACKGROUND: The obese Zucker rat exhibits insulin resistance, develops nephropathy at an early age, and may be a model of diabetic nephropathy. Dehydroepiandrosterone (DHEA) may ameliorate many of the factors that contribute to diabetic nephropathy, while angiotensin-converting enzyme inhibitors are known to be effective. One marker of nephropathy is the expression of alpha-smooth muscle actin. METHODS: We studied the effect of DHEA on the expression of alpha-smooth muscle actin in obese Zucker rats and compared the changes with those in a control group, a group given quinapril, and a group on a low-calorie diet. DHEA (0.6%) added to plain chow, quinapril (0.3 mg/kg) added to drinking water, and a low-calorie diet based on pair-feeding were administered to obese rats from age 4 to 20 weeks. Immunohistochemical expression of alpha-smooth muscle actin, a marker of interstitial and glomerular fibrosis and an early indicator of nephropathy, was measured semiquantitatively in glomeruli, cortical interstitium, and medullary interstitium on a scale of 0 to 4 and was reported as mean +/- SEM. RESULTS: When compared with the obese control group, quinapril exhibited a marked reduction in alpha-smooth muscle actin staining in glomeruli, cortical interstitium, and medullary interstitium (P < 0.0005); DHEA reduced alpha-smooth muscle actin staining in cortical interstitium and medullary interstitium (P < 0. 005), and a low-calorie diet reduced alpha-smooth muscle actin staining in cortical and medullary interstitium (P < 0.005), which was similar to the effects of DHEA. CONCLUSIONS: DHEA was similar to a low-calorie diet in reducing the immunohistochemical staining of alpha-smooth muscle actin in obese Zucker rats. However, quinapril exerted a marked protective effect on the development of fibrosis, as indicated by alpha-smooth muscle actin staining, which was significantly less than that of DHEA at the doses studied.  (+info)