Renal afferent signaling diuretic response is impaired in streptozotocin-induced diabetic rats.
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Renal afferent signaling diuretic response is impaired in streptozotocin-induced diabetic rats. BACKGROUND: Renal insufficiency develops in diabetes and shows structural and functional abnormalities. Renal afferents, including chemoreceptors and mechanoreceptors located in the vascular and ureteropelvic portions of the kidney, may reflect changes in the environment and trigger an afferent nerve-mediated regulatory function that is known as the renorenal reflex. In this study, the involvement of these renal sensory receptors during the early diabetic state is defined. METHODS: Diabetes was induced in rats after a tail vein injection of streptozotocin (STZ; 60 mg/kg intravenously). Four groups of rats, control (C), diabetic (DM), diabetic with acute insulin treatment (DMAI, 9 U/rat, subcutaneously, on the experimental day), and chronic insulin treatment (DMCI, 9 U/rat, subcutaneously, daily) were studied. Spontaneous firing type 2-renal chemoreceptor (CR2), arterial mechanoreceptor (MRa), ureteropelvic mechanoreceptor (MRu), and venous mechanoreceptor (MRv) were identified by single-unit analysis of renal afferent nervous activity. The receptor activities were confirmed by their response patterns to stimuli elicited by renal arterial occlusion (RAO), backflow of urine, increasing arterial pressure, increasing ureteropelvic pressure (UP), or renal venous occlusion (RVO). The response of these afferent receptors to a challenge of volume expansion and their functional activities on renorenal reflexes were also examined. Immunostaining with PGP 9.5 was applied for examination of the nerve distribution in the diabetic kidney. The tissue level of histamine in the renal pelvis was determined. We explored the effect of histamine on renal receptor activity in these animals to address the possible role of histamine in MRu receptor activity. RESULTS: In early diabetics, signaling activities in MRa and MRv were maintained; however, activity in CR2 and MRu was depressed. For CR2, the reduced basal discharge and the repressed responses to RAO, backflow of urine, and volume expansion found in DM rats were recovered by acute insulin treatment to restore glucose levels to near normal. For MRu, the depressed response to increasing UP and volume expansion was not restored by acute correction of hyperglycemia in DMAI rats. However, antihistamine treatment or chronic insulin treatment recovered the MRu response to mechanical stimuli in DM rats. Because of the desensitized CR2 and MRu activity, renorenal reflexes elicited by backflow of urine and increasing UP were depressed in DM rats. CONCLUSION: Despite a lack of structural changes, the operating system, signaling ability, and renorenal reflex regulatory function of two renal afferent nerve receptors, CR2 and MRu, are altered in the early diabetic state. (+info)
Antidiuretic effects of a factor in brain/corpora cardiaca/corpora allata extract on fluid reabsorption across the cryptonephric complex of Manduca sexta.
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Extracts of the brain/corpora cardiaca/corpora allata (Br/CC/CA) complex of Manduca sexta larvae elicit an antidiuretic effect, measured by an increase in fluid reabsorption across the cryptonephric complex of larval M. sexta. Separation of the extract by reversed-phase liquid chromatography gave two fractions with antidiuretic effects. The more potent of these two factors was further characterized for its effects on the cryptonephric complex. Its antidiuretic effect is not inhibited by bumetanide, a drug that inhibits M. sexta diuretic hormone (Mas-DH)-stimulated fluid reabsorption. These data indicate that the mechanism of the antidiuretic effect of the factor is different from that of Mas-DH on the cryptonephric complex. The basal reabsorption of the cryptonephric complex is blocked when treated on the lumen side with bafilomycin A(1), an inhibitor of the H(+)-ATPase, or with amiloride, an inhibitor of the H(+)/K(+) antiporter. However, the antidiuretic-factor-stimulated fluid reabsorption is not affected by either bafilomycin A(1) or amiloride. The increase in reabsorption triggered by the semi-purified factor can be inhibited by Cl(-) channel blockers or by removing Cl(-) from the lumen side of the cryptonephric complex. It appears that this factor activates a Cl(-) pump associated with the cryptonephric complex. Forskolin mimics the effect of this factor on fluid reabsorption, and the effect of forskolin is not inhibited by bumetanide. A selective and potent inhibitor of protein kinase A, H-89, also inhibits antidiuretic-factor-stimulated fluid reabsorption. Addition of the factor to cryptonephric complexes maintained in vitro caused a significant increase in cyclic AMP levels extracted from these tissues compared with values for controls. These data suggest that the antidiuretic effect of the factor in Br/CC/CA extract is mediated by cyclic AMP. (+info)
Diuretic response to adenosine A(1) receptor blockade in normotensive and spontaneously hypertensive rats: role of pertussis toxin-sensitive G-proteins.
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Adenosine A(1) receptor antagonists are being developed for use as diuretics in the treatment of hypertension, however, there is relatively little data in hypertensive animal models regarding the efficacy of these compounds. In addition, some controversy exists surrounding the role of pertussis toxin (PT)-sensitive G-proteins in the signaling pathway for receptors acted on by A(1) antagonists. Our objectives for this study were 1) to compare the diuretic, natriuretic, and cardiovascular effects of acute A(1) receptor blockade in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto rats (WKY); and 2) to determine whether the diuretic effects are mediated through a PT-sensitive mechanism. Acute administration of the selective A(1) antagonist 1, 3-dipropyl-8-cyclopentylxanthine (DPCPX; 10 microgram/kg/min) increased urine output (410 +/- 116 and 317 +/- 86 microliter/30 min/g kidney) and sodium excretion (90.3 +/- 25.6 and 76.8 +/- 18.2 micromol/30 min/g kidney) similarly in WKY and SHR, respectively. DPCPX significantly decreased mean arterial blood pressure in SHR (-11.4 +/- 2.7 mm Hg), but not WKY. Prior treatment with PT (30 microgram/kg i.v.) abolished the diuretic response to DPCPX in both SHR and WKY. In a subsequent experiment in PT-treated Sprague-Dawley rats, DPCPX failed to evoke a diuretic response, whereas coinfusion of furosemide with DPCPX induced marked diuresis. Our results indicate that acute DPCPX administration produces similar natriuretic/diuretic effects in SHR and WKY, with beneficial effects on blood pressure in SHR. PT abolishes the response to DPCPX, indicating that the natriuretic/diuretic response to DPCPX is mediated via blockade of A(1) receptors linked to tubular sodium transport through PT-sensitive G-proteins. (+info)
Diuretic effect of hypoxia, hypocapnia, and hyperpnea in humans: relation to hormones and O(2) chemosensitivity.
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We studied the contributions of hypoxemia, hypocapnia, and hyperpnea to the acute hypoxic diuretic response (HDR) in humans and evaluated the role of peripheral O(2) chemosensitivity and renal hormones in HDR. Thirteen healthy male subjects (age 19-38 yr) were examined after sodium equilibration (intake: 120 mmol/day) during 90 min of normoxia (NO), poikilocapnic hypoxia (PH), and isocapnic hypoxia (IH) (days 1-3, random order, double blind), as well as normoxic voluntary hyperpnea (HP; day 4), matching ventilation during IH. O(2) saturation during PH and IH was kept equal to a mean level measured between 30 and 90 min of breathing 12% O(2) in a pretest. Urine flow during PH and IH (1.81 +/- 0.92 and 1.94 +/- 1.03 ml/min, respectively) but not during HP (1.64 +/- 0.96 ml/min) significantly exceeded that during NO (control, 1.38 +/- 0.71 ml/min). Urine flow increases vs. each test day's baseline were significant with PH, IH, and HP. Differences in glomerular filtration rate, fractional sodium clearance, urodilatin, systemic blood pressure, or leg venous compliance were excluded as factors of HDR. However, slight increases in plasma and urinary endothelin-1 and epinephrine with PH and IH could play a role. In conclusion, the early HDR in humans is mainly due to hypoxia and hypocapnia. It occurs without natriuresis and is unrelated to O(2) chemosensitivity (hypoxic ventilatory response). (+info)
Analysis of the vasopressin system and water regulation in genetically polydipsic mice.
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Polydipsic mice, STR/N, which show extreme polydipsia and polyuria, were discovered in 1958. In the STR/N, urine outputs are much higher than in control mice. The possibility of an abnormal regulation of the arginine vasopressin (AVP) system, or an abnormality in the renal susceptibility to AVP, should be considered. In this study we investigated the AVP system and water regulation in STR/N. We sequenced the AVP and the AVP V(2)-receptor genes of the STR/N by direct sequencing. No mutation was found in either of them. AVP gene expression examined by in situ hybridization and plasma sodium in 8-wk-old STR/N was significantly lower than in control mice, whereas it was significantly higher at 20 wk. Renal sensitivity to injected AVP was attenuated in 20-wk-old STR/N. The suppression of AVP synthesis due to excessive water retention in 8-wk-old STR/N suggests that polydipsia may be the primary cause in this strain. The 20-wk-old STR/N became dehydrated with the acceleration of AVP synthesis, which might have resulted from secondary desensitization to AVP. (+info)
Blood pressure-independent effects in rats with human renin and angiotensinogen genes.
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The blood pressure-independent effects of angiotensin II (Ang II) were examined in double transgenic rats (dTGR) harboring human renin and human angiotensinogen genes, in which the end-organ damage is due to the human components of the renin angiotensin system. Triple-drug therapy (hydralazine 80 mg/L, reserpine 5 mg/L, and hydrochlorothiazide 25 mg/L in drinking water) was started immediately after weaning. Triple-drug therapy normalized blood pressure and coronary resistance, only partially prevented cardiac hypertrophy, and had no effect on ratio of renal weight to body weight. Although triple-drug therapy delayed the onset of renal damage, severe albuminuria nevertheless occurred. Semiquantitative scoring of ED-1-positive and MIB-5-positive (nuclear cell proliferation-associated antigen Ki-67) cells showed profound perivascular monocyte/macrophage infiltration and cell proliferation in kidneys and hearts of untreated dTGR. Triple-drug therapy had only a minimal effect on local inflammatory response or vascular cell proliferation. In contrast, a novel orally active human renin inhibitor (HRI), 30 mg/kg by gavage for 4 weeks, normalized blood pressure and coronary resistance and also prevented cardiac hypertrophy and albuminuria. ED-1-positive cells and MIB-5-positive cells were decreased by HRI in hearts and kidneys almost to levels observed in normotensive Sprague-Dawley rats. The renoprotective effects of HRI were at least in part due to improved renal hemodynamics and distal tubular function, since HRI shifted renal pressure-diuresis/natriuresis curves leftward by approximately 35 mm Hg, increased glomerular filtration rate and renal blood flow, and shifted the fractional water and sodium excretion curves leftward. In untreated dTGR, plasma Ang II was increased by 400% and renal Ang II level was increased by 300% compared with Sprague-Dawley rats. HRI decreased plasma human renin activity by 95% and normalized Ang II levels in both plasma and kidney compared with triple-drug therapy. Our findings indicate that in dTGR harboring human renin and angiotensinogen genes, Ang II causes end-organ damage and promotes inflammatory response and cellular growth largely independent of blood pressure. (+info)
Input rate as a major determinant of furosemide pharmacodynamics: influence of fluid replacement and hypoalbuminemia.
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To investigate how the response to a bolus and an infusion of furosemide is modulated by the rate of fluid replacement and by hypoalbuminemia, rabbits received 5 mg/kg of furosemide as a bolus or infused over 60 min, whereas diuresis was replaced with 13, 121, or 238 ml/h NaCl 0.9%/glucose 5% (50:50). Natriuretic and diuretic efficiencies were greater with the infusion than with the bolus of furosemide. Fluid replacement increased natriuretic and diuretic efficiency of furosemide bolus but only diuretic efficiency of furosemide infusion. Furosemide net fluid depletion reached a plateau when fluid replacement increased beyond 121 ml/h. Repeated plasmapheresis decreased plasma albumin by 30% (P <.05) and increased furosemide unbound fraction (P <.05). Compared with control rabbits, hypoalbuminemia decreased the natriuresis of the bolus (22.7 +/- 1.5-16.6 +/- 1.3 mmol, P <.05) but not that elicited by furosemide infusion (26.2 +/- 1.8 mmol). Given as a bolus, furosemide natriuretic and diuretic response as a function of its urinary rate of excretion exhibited an hyperbolic relationship, and after its infusion a clockwise hysteresis, denoting tolerance. Plasma renin activity was increased by the bolus and the infusion of furosemide, even in the presence of 121 ml/h of fluid replacement. It is concluded that: 1) the increase in natriuretic/diuretic efficiency of the bolus induced by fluid replacement is greater than when furosemide is infused, 2) furosemide net effect does not increase proportionally to fluid replacement, and 3) the infusion of furosemide prevents the hypoalbuminemia-induced decrease in response of furosemide given as a bolus. (+info)
The contribution of residual renal function to overall nutritional status in chronic haemodialysis patients.
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BACKGROUND: The benefits of residual renal function (RRF) in peritoneal dialysis patients have been described frequently. However, previous reports have shown that RRF diminished faster in haemodialysis (HD) patients than in peritoneal dialysis patients, and in most of the studies in HD patients, RRF was ignored. In this study, the RRF in chronic HD patients was studied to assess its impact on patients' nutritional status. METHODS: In 41 chronic HD patients with at least a 2-year history of HD treatment, RRF was determined by a urine collection for 7 consecutive days. Nutritional parameters, such as percentage body fat, fat-free mass index, serum albumin concentration and normalized protein catabolic rate, were also measured. RESULTS: In all 41 patients, mean weekly total Kt/V urea was 4.88 and renal Kt/V urea was 0.65. RRF was well correlated with serum albumin concentration, but dialysis Kt/V urea was not. One year after the start of this study, RRF and nutritional indices were re-examined and patients were classified into two groups: with RRF, preserved residual renal diuresis over 200 ml/day (mean, 720 ml; range, 230-1640 ml), N=23; and without RRF, persistent anuria (mean, 51 ml; range, 0-190 ml), N=18. At the start of this study, the mean serum albumin concentration and mean normalized protein catabolic rate in patients with RRF were 3.84 g/dl and 1.16 g/kg/day, respectively, which were significantly higher than those in patients without RRF (P=0.02 and P=0.0002, respectively), despite total (renal+dialysis) Kt/V urea being equal in both groups. During the 1-year study period, there was no significant change in total Kt/V urea in either group. Mean serum albumin concentration increased to 4.05 g/dl in patients with RRF, but did not change significantly (from 3.66 to 3.62 g/dl) in patients without RRF. The same trend was observed in all other parameters. CONCLUSION: Over half of our HD patients had sufficient RRF. RRF itself may have a beneficial effect on nutritional parameters, and it is important to determine RRF over time, even in chronic HD patients. (+info)