Reinforcement of arteriolar myogenic activity by endogenous ANG II: susceptibility to dietary salt.
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The purpose of this study was to determine whether endogenous ANG II augments arteriolar myogenic behavior in striated muscle. Because circulating ANG II is decreased during high salt intake, we also investigated whether dietary salt could alter any influence of ANG II on myogenic behavior. Normotensive rats fed low-salt (0.45%, LS) or high-salt (7%, HS) diets were enclosed in a ventilated box with the spinotrapezius muscle exteriorized for intravital microscopy. Dietary salt did not affect resting arteriolar diameters. Microvascular pressure elevation by box pressurization caused greater arteriolar constriction in LS rats (up to 12 microm) than in HS rats (up to 4 microm). The ANG II-receptor antagonists saralasin and losartan attenuated myogenic responsiveness in LS rats but not HS rats. The bradykinin-receptor antagonist HOE-140 had no effect on myogenic responsiveness in LS rats but augmented myogenic responsiveness in HS rats. HOE-140 with the angiotensin-converting enzyme inhibitor captopril attenuated myogenic responsiveness to a greater extent in LS rats than in HS rats. We conclude that endogenous ANG II normally reinforces arteriolar myogenic behavior in striated muscle and that attenuated myogenic behavior associated with high salt intake is due to decreased circulating ANG II and increased local kinin levels. (+info)
Comparison of enalapril and valsartan in cyclosporine A-induced hypertension and nephrotoxicity in spontaneously hypertensive rats on high-sodium diet.
(42/903)
1. We compared the effects of the angiotensin converting enzyme (ACE) inhibitor enalapril and the angiotensin AT(1) receptor antagonist valsartan in cyclosporine A (CsA)-induced hypertension and nephrotoxicity in spontaneously hypertensive rats (SHR). 2. SHR (8 - 9 weeks old) on high-sodium diet were given CsA (5 mg kg(-1)d (-1) s.c. ) for 6 weeks. The rats were treated concomitantly either with enalapril (30 mg kg(-1)d (-1) p.o.) or valsartan (3 or 30 mg kg(-1) d (-1) p.o.). To evaluate the role of bradykinin in the action of enalapril, some rats received a bradykinin B(2) receptor antagonist icatibant (HOE 140, 500 microg kg(-1) d (-1) s.c.) during the last 2 weeks of enalapril treatment. 3. Blood pressure was recorded every second week by tail cuff method. Renal function was measured by serum creatinine, creatinine clearance and urinary excretion of proteins at the end of the experiment. The activity of the renal kallikrein-kinin system was estimated by urinary kallikrein excretion. 4. CsA caused hypertension, impaired renal function and induced morphological nephrotoxicity with glomerular damage and interstitial fibrosis. Enalapril and the lower dose of valsartan attenuated the CsA-induced hypertension to the same extent, while the higher dose of valsartan totally abolished it. Icatibant did not reduce the antihypertensive effect of enalapril. Urinary kallikrein excretion was similar in all groups. 5. Enalapril and valsartan equally prevented the CsA-induced deterioration of kidney function and morphology. 6. The renin-angiotensin but not the kallikrein-kinin system plays a crucial role in CsA-toxicity during high intake of sodium in SHR. (+info)
Differential subcellular localization of ENaC subunits in mouse kidney in response to high- and low-Na diets.
(43/903)
Previous electrophysiological experiments on renal cortical collecting ducts indicated that dietary sodium intake and variations in aldosterone plasma levels regulate the abundance of functional epithelial Na channels (ENaC) in the apical plasma membrane. In mouse kidney we investigated by immunohistochemistry whether feeding for 3 wk a diet with high (3% Na) and low (0.05% Na) Na content influences the distribution pattern of ENaC. In mice of all experimental groups, ENaC was apparent in cells from the late portion of the distal convoluted tubule (DCT2) down to the medullary collecting duct (CD). In mice on a high-Na diet (plasma aldosterone: 40.8 +/- 2.0 ng/dl), the alpha-subunit was undetectable, and the beta- and gamma-ENaC were detected in the cytoplasm, but not in the apical plasma membrane of the cells. In contrast, in mice on a low-Na diet (plasma aldosterone: 93.6 +/- 9.3 ng/dl) all three ENaC subunits were displayed in the subapical cytoplasm and in the apical membrane of DCT2, connecting tubule (CNT), and, although less prominent, in cortical CD cells. Apical plasma membrane immunostaining progressively decreased along the cortical CD, simultaneously with increasing cytoplasmic staining for beta- and gamma-ENaC. Thus our data on mice adapted to moderately low and high Na intake suggest that regulation of ENaC function in vivo involves shifts of beta- and gamma-subunits from the cytoplasm to the apical plasma membrane and vice versa, respectively. The insertion of these subunits into the apical plasma membrane coincides with upregulation of the alpha-subunit and its insertion into the apical plasma membrane. (+info)
CA-Repeat polymorphism in intron 1 of HSD11B2 : effects on gene expression and salt sensitivity.
(44/903)
Mutations in the HSD11B2 gene encoding the kidney (11-HSD2) isozyme of 11beta-hydroxysteroid dehydrogenase cause apparent mineralocorticoid excess, a form of familial hypertension. Because the hypertension associated with AME is of the salt-sensitive type, it seemed possible that decreases in 11-HSD2 activity might be associated with salt sensitivity. To examine this, Italians with mild hypertension underwent a protocol consisting of a rapid intravenous saline infusion and subsequent furosemide diuresis. To determine whether there were genetic associations between HSD11B2 and salt sensitivity, 198 Italians were genotyped for a CA repeat polymorphism (11 alleles) in the first intron. Increased differences in mean arterial pressure between the sodium loaded and depleted states were correlated with shorter CA repeat length (R=0.214, P=0. 0025). The effect behaved as a recessive trait. This suggested that decreased HSD11B2 expression was associated with shorter CA repeat length. Furthermore, activity of renal 11-HSD2 as measured by an increase in the ratio of urinary-free cortisol/urinary-free cortisone was lower in 33 salt-sensitive subjects (urinary-free cortisol/urinary-free cortisone 0.89+/-0.04 [mean+/-SE]) compared with 34 salt-resistant subjects (0.71+/-0.04, P<0.001). However, when minigenes containing either 14 or 23 CA repeats were transfected into rabbit or human kidney cortical collecting duct cells, the construct with 14 repeats was instead expressed at levels 50% higher than those of the construct with 23 repeats, as determined by reverse transcription-polymerase chain reaction. We conclude that polymorphisms in HSD11B2 and decreased 11-HSD2 activity are associated with sensitivity to sodium loading, but a functional explanation for these associations remains to be elucidated. (+info)
Renal changes induced by a cyclooxygenase-2 inhibitor during normal and low sodium intake.
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Cyclooxygenase-2 (COX-2) has been identified in renal tissues under normal conditions, with its expression enhanced during sodium restriction. To evaluate the role of COX-2-derived metabolites in the regulation of renal function, we infused a selective inhibitor (nimesulide) in anesthetized dogs with normal or low sodium intake. The renal effects elicited by nimesulide and a non-isozyme-specific inhibitor (meclofenamate) were compared during normal sodium intake. In ex vivo assays, meclofenamate, but not nimesulide, prevented the platelet aggregation elicited by arachidonic acid. During normal sodium intake, nimesulide infusion (n=6) had no effects on arterial pressure or renal hemodynamics but did reduce urinary sodium excretion, urine flow rate, and fractional lithium excretion. In contrast, nimesulide administration increased arterial pressure and decreased renal blood flow, urine flow rate, and fractional lithium excretion during low sodium intake (n=6). COX-2 inhibition reduced urinary prostaglandin E(2) excretion in both groups but did not modify plasma renin activity in dogs with low (8.1+/-1.1 ng angiotensin I. mL(-1). h(-1)) or normal (1.8+/-0.4 ng angiotensin I. mL(-1). h(-1)) sodium intake. Meclofenamate infusion in dogs with normal sodium intake (n=8) induced a greater renal hemodynamic effect than nimesulide infusion. These results suggest that COX-2-derived metabolites (1) are involved in the regulation of sodium excretion in dogs with normal sodium intake, (2) play an important role in the regulation of renal hemodynamic and excretory function in dogs with low sodium intake, and (3) are not involved in the maintenance of the high renin levels during a long-term decrease in sodium intake. (+info)
Nitric oxide may be required to prevent hypertension at the onset of diabetes.
(46/903)
Nitric oxide (NO) plays an important role in the regulation of vascular tone, and evidence suggests that endothelial-dependent relaxation, possibly mediated via NO, is impaired in diabetes. However, the role of the endothelium in arterial pressure control early in diabetes, before dysfunction develops, is not known. This was evaluated in the present study by comparing the responses to induction of diabetes in vehicle-treated rats (D, n = 7) vs. rats chronically treated with N(G)-nitro-L-arginine methyl ester (L-NAME; D+L, n = 8). A nondiabetic group also was treated with L-NAME (L, n = 7) to control for L-NAME effects over time, independent of diabetes. After baseline measurements, rats were given either vehicle or L-NAME (10 microg. kg(-1). min(-1) iv) infusion throughout the experiment. Six days later, streptozotocin (60 mg/kg iv) was administered, followed by a 3-wk diabetic study period. Induction of diabetes in the D+L rats caused a marked and progressive increase in mean arterial pressure throughout the diabetic period, averaging approximately 70 mmHg greater than in the D rats and approximately 20 mmHg greater than in the L rats. Glomerular filtration rate and renal plasma flow tended to increase during diabetes, but this trend was reversed in the D+L rats. In addition, plasma renin activity increased in the D and D+L rats during week 1 of diabetes but then returned to control in the D rats, while continuing to increase in the D+L rats. These results suggest that, in the early stages of diabetes, NO synthesis is important to prevent hypertension from developing, possibly through actions to maintain glomerular filtration and suppress renin secretion. (+info)
Postexercise rehydration: effect of Na(+) and volume on restoration of fluid spaces and cardiovascular function.
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Our purpose was to study the interaction between Na(+) content and fluid volume on rehydration (RH) and restoration of fluid spaces and cardiovascular (CV) function. Ten men completed four trials in which they exercised in a 35 degrees C environment until dehydrated by 2. 9% body mass, were rehydrated for 180 min, and exercised for an additional 20 min. Four RH regimens were tested: low volume (100% fluid replacement)-low (25 mM) Na(+) (LL), low volume-high (50 mM) Na(+) (LH), high volume (150% fluid replacement)-low Na(+) (HL), and high volume-high Na(+) (HH). Blood and urine samples were collected and body mass was measured before and after exercise and every hour during RH. Before and after the dehydration exercise and during the 20 min of exercise after RH, cardiac output was measured. Fluid compartment (intracellular and extracellular) restoration and percent change in plasma volume were calculated using the Cl(-) and hematocrit/Hb methods, respectively. RH was greater (P < 0.05) in HL and HH (102.0 +/- 15.2 and 103.7 +/- 14.7%, respectively) than in LL and LH (70.7 +/- 10.5 and 75.9 +/- 6.3%, respectively). Intracellular RH was greater in HL (1.12 +/- 0.4 liters) than in all other conditions (0.83 +/- 0.3, 0.69 +/- 0.2, and 0.73 +/- 0.3 liter for LL, LH, and HH, respectively), whereas extracellular RH (including plasma volume) was greater in HL and HH (1.35 +/- 0.8 and 1.63 +/- 0.4 liters, respectively) than in LL and LH (0.83 +/- 0.3 and 1.05 +/- 0.4 liters, respectively). CV function (based on stroke volume, heart rate, and cardiac output) was restored equally in all conditions. These data indicate that greater RH can be achieved through larger volumes of fluid and is not affected by Na(+) content within the range tested. Higher Na(+) content favors extracellular fluid filling, whereas intracellular fluid benefits from higher volumes of fluid with lower Na(+). Alterations in Na(+) and/or volume within the range tested do not affect the degree of restoration of CV function. (+info)
Hemodynamic, hormone, and urinary effects of adrenomedullin infusion in essential hypertension.
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We examined the effects of the vasodilator peptide adrenomedullin (AM) infused intravenously into subjects with essential hypertension. Eight men 39 to 58 years old with uncomplicated hypertension (147/96+/-5/3 mm Hg at baseline) were studied in a placebo-controlled, crossover design. Each subject received intravenous AM in a low and a high dose (2.9 and 5.8 pmol. kg(-1). min(-1) for 2 hours each) or vehicle-control (Hemaccel) infusion in a random order on day 4 of a controlled metabolic diet (80 mmol/d Na(+), 100 mmol/d K(+)). Plasma AM reached pathophysiological levels during infusion (18+/-4 pmol/L in low dose, 34+/-9 pmol/L in high dose) with a concurrent rise in plasma cAMP (+8.4+/-1.2 pmol/L, P:<0. 05 compared with control). Compared with control, high-dose AM increased peak heart rate (+17.8+/-2.3 bpm, P<0.01), lowered systolic (-24.6+/-0.9 mm Hg; P<0.01) and diastolic (-21.9+/-1.4 mm Hg; P<0.01) blood pressure, and increased cardiac output (+1.0+/-0. 1 L/min in low dose, +2.9+/-0.2 L/min in high dose; P<0.01 for both). Despite a rise in plasma renin activity during high dose (P<0.05), aldosterone levels did not alter. Plasma norepinephrine levels increased 1295+/-222 pmol/L (P<0.001) and epinephrine increased 74+/-15 pmol/L (P<0.05) with high-dose AM compared with control. AM had no significant effect on urine volume and sodium excretion. In subjects with essential hypertension, the intravenous infusion of AM to achieve pathophysiological levels produced significant falls in arterial pressure, increased heart rate and cardiac output, and stimulated the sympathetic system and renin release without concurrent increase in aldosterone. Urinary parameters were unaltered. Although AM has potent hemodynamic and neurohumoral effects in subjects with essential hypertension, the threshold for urinary actions is set higher. (+info)