Acute Saline Research Articles

Enalapril treatment restores the decreased proximal tubule reabsorption in response to acute volume expansion in diabetic rats

The renin–angiotensin system (RAS) plays an important role in the regulation of blood pressure, fluid and electrolyte homeostasis. The RAS is activated and renal interstitial hydrostatic pressure (RIHP) is decreased in diabetic rats. The objective of this study was to evaluate the roles of proximal tubule reabsorption and RAS in the decreased RIHP and blunted natriuretic and diuretic responses to acute saline volume expansion (VE) in diabetic rats. Enalapril was utilized to inhibit angiotensin II (AII) formation. Diabetes mellitus (DM) was induced by a single intraperitoneal (i.p.) injection of streptozotocin (STZ, 65 mg/kg). RIHP was measured by a polyethylene (PE) matrix that was chronically implanted in the left kidney. Fractional excretion of phosphate (FE Pi) and fractional excretion of lithium (FE Li) were used as indexes for proximal tubule reabsorption. VE significantly increased both FE Li and FE Pi in all groups of rats studied. However, the increase in FE Li (ΔFE Li = 17.26 ± 3.83%) and FE Pi (ΔFE Pi = 7.38 ± 2.37%) in diabetic rats (DC, n = 12) were significantly lower as compared with those in nondiabetic control rats (NC, n = 8; ΔFE Li = 32.15 ± 4.71% and ΔFE Pi = 20.62 ± 3.27%). The blunted increases in FE Li and FE Pi were associated with an attenuated increase in RIHP (ΔRIHP) in DC (1.8 ± 0.4 mm Hg) compared with NC rats (4.3 ± 0.3 mm Hg). Enalapril treatment (25 mg/kg/day in drinking water) had no effect on nondiabetic rats (NE, n = 8) as compared with untreated NC rats, but significantly improved RIHP response (ΔRIHP) to VE in diabetic rats (DE, n = 9; 2.8 ± 0.5 mm Hg). Both ΔFE Li and ΔFE Pi were restored by enalapril treatment in diabetic rats and no significant differences were found in ΔFE Li and ΔFE Pi between DE (ΔFE Li = 26.81 ± 4.94% and ΔFE Pi = 10.45 ± 4.67%) and NC groups of rats in response to VE. These data suggest that the activated RAS and the decrease in RIHP may play an important role in the increased proximal tubule reabsorption, and the attenuated natriuretic and diuretic responses to acute volume expansion in diabetic rats.

Perinatal taurine exposure alters renal potassium excretion in adult conscious rats

Perinatal taurine exposure alters renal hemodynamics and sodium excretion in adult rats. This study further tests the effect of perinatal taurine on renal potassium excretion in adult conscious rats. Female Sprague‐Dawley rats were fed normal rat chow and given water alone (C), 3% beta‐alanine in water (taurine depletion, TD) or 3% taurine in water (taurine supplementation, TS), either from conception until delivery (fetal period; TDF or TSF) or from delivery until weaning (lactation period; TDL or TSL). In Experiment 1, after weaning, male offspring were fed normal rat chow and tap water. In Experiment 2, female pups were treated similarly, but from conception until weaning. At 7–8 weeks of age, renal potassium excretion at rest and after an acute saline load (5% of body weight) was studied in conscious, restrained rats. All male groups displayed similar renal potassium excretion. TSF increased fractional potassium excretion at rest but not in response to saline load, whereas TDF did the opposite. Plasma potassium levels were lower only at rest in TSF but at rest and during the challenge in TDF. Their glomerular filtration rates did not significantly different among groups. In female offspring, perinatal taurine supplementation decreased renal potassium excretion, glomerular filtration rate, and plasma potassium concentration at rest and after the saline load. It is unlikely that increased tubular reabsorption caused these effects, since the fractional potassium excretion significantly increased, especially at rest. Perinatal taurine depletion had no significant effect on renal potassium excretion in the female offspring. The present data suggest that perinatal taurine exposure influences renal potassium excretion in the adult rats.

Effect of acute volume overload on the magnitude of T-wave alternans

LETTERS TO THE EDITOREffect of acute volume overload on the magnitude of T-wave alternansJohn E. MadiasJohn E. MadiasPublished Online:01 Aug 2007https://doi.org/10.1152/japplphysiol.00346.2007MoreSectionsPDF (25 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations To the Editor: I read with great interest the contribution by Narayan et al. (1) on the effect of acute volume loading on the magnitude of the T-wave alternans (TWA) in five dogs without structural heart disease. The authors showed that the acute saline infusion led to a rise of pulmonary capillary wedge pressure and an increase of the magnitude of TWA in comparison with the value of TWA found prior to the acute volume infusion. Importantly, the increased magnitude of the TWA after the volume occurred at a lower atrial paced rate than the one noted at baseline. In addition, there was a linear relationship between the volume loading and the increased magnitude of TWA. Although these findings were noted in normal anesthetized dogs undergoing fluid loading, there may be clinical implications for patients with structural heart disease and associated fluid overload. The findings are also of interest in the light of the current climate that the magnitude of TWA and the heart rate at its onset matter and suggest a higher arrhythmic risk than the one associated with TWA of lower magnitude, elicited at higher heart rates. However, one wonders whether the increase in the TWA magnitude following the fluid overload was of primary nature (indicative of a more advanced electrophysiological destabilization), or secondary, due to changes in the overall T-wave magnitude/morphology/axis consequent to the volume overload and resultant heart enlargement. No data on heart volumes were acquired, but the magnitude of the administered fluid infusions would be expected to produce some heart dilation (indeed the authors refer repeatedly to a plausibly induced “stretch,” and its repolarization and arrhythmic consequences), and such increases in end-diastolic volumes elicit the “Brodie effect” (2), characterized electrocardiographically by an augmentation of the QRS complexes; also changes in the corresponding T-waves (secondary) may be noted. Were changes noted after volume infusion in the ECG QRS and/or T-waves, both before and during atrial pacing? Was the increase in magnitude of TWA after fluid infusion totally or partially secondary to the changes in the amplitude (or other attributes) of the T-waves, and could a “crude” adjustment (notwithstanding the complexity of the spectral TWA method) of the increased TWA magnitude values by possibly increased T-wave amplitude render the magnitude of the TWA after the fluid loading less impressively elevated?REFERENCES1 Narayan SM, Drinan DD, Lackey RP, Edman CF. Acute volume overload elevates T-wave alternans magnitude. J Appl Physiol 102: 1462–1468, 2007.Link | ISI | Google Scholar2 Brody DA. A theoretical analysis of intracavitary blood mass influence on the heart-lead relationship. Circ Res 4: 731–738, 1956.Crossref | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: J. E. Madias, Division of Cardiology, Elmhurst Hospital Center, 79–01 Broadway, Elmhurst, NY 11373 (e-mail:[email protected]) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByReply to MadiasSanjiv M. Narayan, Darrel D. Drinan, Robert P. Lackey, and Carl F. Edman1 August 2007 | Journal of Applied Physiology, Vol. 103, No. 2 More from this issue > Volume 103Issue 2August 2007Pages 728-728 Copyright & PermissionsCopyright © 2007 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.00346.2007PubMed17666734History Published online 1 August 2007 Published in print 1 August 2007 Metrics

Hypoxic preconditioning attenuates lipopolysaccharide-induced oxidative stress in rat kidneys.

Chronic hypoxic (CH) preconditioning reduces superoxide-induced renal dysfunction via the upregulation of superoxide dismutase (SOD) activity and contents. Endotoxaemia reduces renal antioxidant status. We hypothesize that CH preconditioning might protect the kidney from subsequent endotoxaemia-induced oxidative injury. Endotoxaemia was induced by intraperitoneal injection of lipopolysaccharide (LPS; 4 mg kg(-1)) in rats kept at sea level (SL) and rats with CH in an altitude chamber (5500 m for 15 h day(-1)) for 4 weeks. LPS enhanced xanthine oxidase (XO) and gp91phox (catalytic subunit of NADPH oxidase) expression associated with burst amount of superoxide production from the SL kidney surface and renal venous blood detected by lucigenin-enhanced chemiluminescence. LPS induced a morphologic-independent renal dysfunction in baseline and acute saline loading stages and increased renal IL-1beta protein and urinary protein concentration in the SL rats. After 4 weeks of induction, CH significantly increased Cu/ZnSOD, MnSOD and catalase expression (16 +/- 17, 128 +/- 35 and 48 +/- 21, respectively) in renal cortex, and depressed renal cortex XO (44 +/- 16%) and renal cortex (20 +/- 9%) and medulla (28 +/- 11%) gp91phox when compared with SL rats. The combined effect of enhanced antioxidant proteins and depressed oxidative proteins significantly reduced LPS-enhanced superoxide production, renal XO and gp91phox expression, renal IL-1beta production, and urinary protein level. CH also ameliorated LPS-induced renal dysfunction in the baseline and acute saline loading periods. We conclude that CH treatment enhances the intrarenal antioxidant/oxidative protein ratio to overcome endotoxaemia-induced reactive oxygen species formation and inflammatory cytokine release.

Behavioural supersensitivity following neonatal 6-hydroxydopamine: Attenuation by MK-801

Male rat pups were administered 6-hydroxydopamine (6-OHDA, 75 microg, intracisternally, 30 min after desipramine, 25 mg/kg, s.c.) on Days 1 or 2 after birth, or were sham-operated (receiving vehicle). In four experiments, the acute effects of apomorphine, with or without pretreatment with MK-801 (0.03 mg/kg), upon motor activity in test chambers was measured. Acute treatment with apomorphine (0.1 mg/kg) increased locomotor, rearing and total activity markedly compared to both the acute saline administered 6-OHDA rats and the sham-operated rats administered saline. Acute MK-801 (0.03 mg/kg) co-administered shortly before (5 min) apomorphine (0.3 or 1.0 mg/kg) reduced markedly locomotion and total activity in 6-OHDA-treated and sham-operated rats. Rearing behaviour was increased in both the 6-OHDA groups of rats. Acute MK-801 increased activity in the 6-OHDA-treated rats, which was not observed in sham-operated rats. At the 0.3 and 1.0 mg/kg doses of apomorphine, neonatal 6-OHDA treatment increased all three parameters of motor activity. Acute treatment with apomorphine (0.1 mg/kg) induced different effects on the motor activity of 6-OHDA-treated and sham-operated mice. In sham-operated rats apomorphine reduced motor activity during the 1st 30-min period but increased locomotion and total activity, but not rearing, during the 2nd and 3rd periods, whereas in 6-OHDA-treated rats, apomorphine increased locomotor, rearing and total activity markedly. Dopamine loss and serotonin elevation in the striatum and olfactory tubercle were confirmed. The present findings confirm the influence of non-competitive glutamate antagonists in attenuating the behavioural supersensitivity to dopamine antagonists.

Changes in Natriuretic Peptides, Cytokines, Selectins and Adhesion Molecules Plasma Levels in Patients with Heart Failure, After Treatment with High Dose of Furosemide Plus Small Volume Saline Solutions (HSS) and After an Acute Saline Loading

Changes in Natriuretic Peptides, Cytokines, Selectins and Adhesion Molecules Plasma Levels in Patients with Heart Failure, After Treatment with High Dose of Furosemide Plus Small Volume Saline Solutions (HSS) and After an Acute Saline Loading

Accelerated NaCl-induced hypertension in taurine-deficient rat: Role of renal function

Taurine modulates blood pressure and renal function. As the kidney plays a pivotal role in long-term control of arterial pressure, we tested the hypothesis that taurine-deficient rats display maladaptive renal and blood pressure responses to uninephrectomy. Control and taurine-deficient (i.e., beta-alanine-treated) rats with either one or two remaining kidneys were fed diets containing basal or high (8%) NaCl diet. Urine osmolality was greater in the taurine-deficient than controls fed a normal NaCl diet; proteinuria and blood pressure were unaffected by uninephrectomy. Following 6 weeks on an 8% NaCl diet, the uninephrectomized (UNX) animals developed significant hypertension, which was more severe in the taurine-deficient group; baroreflex function was unaffected. However, the UNX taurine-deficient rats displayed impaired ability to dispose of an acute isotonic saline volume load before a switchover to a high NaCl diet. Nonetheless, a more protracted exposure (i.e., 14 weeks) to dietary NaCl excess eliminated the blood pressure differential between the two groups; at this stage, renal excretory responses to an acute saline volume load or to atrial natriuretic peptide were similar in the two groups. Nonetheless, hypertensive taurine-deficient rats displayed greater proteinuria, although both groups excreted proteins of similar molecular weights ( approximately 15-66 kDa). Further, taurine-deficient kidney specimens displayed periarterial mononuclear cell infiltrates with strong immunoreactivity to the histiocyte marker CD68, suggestive of increased phagocytic activity. In conclusion, taurine deficiency modulates renal adaptation to combined uninephrectomy and dietary NaCl excess, resulting in an accelerated development of hypertension.

Effects of group I metabotropic glutamate receptor antagonists on the behavioral sensitization to motor effects of cocaine in rats

Metabotropic glutamate receptors (mGluRs) were reported to regulate various behavioral effects of addictive drugs. The present study evaluated the role of group I mGluRs in the progressive augmentation ("sensitization") of the behavioral effects observed after repeated, intermittent cocaine exposure. After habituation to handling and baseline activity measurement (days 1-2), rats received eight injections of cocaine (10 mg/kg) or saline on days 3-6, 8-11, and then, were tested twice with acute saline and cocaine given in a counterbalanced manner on days 13 and 15. Before the test sessions, subjects were pretreated with mGluR1 antagonist EMQMCM (JNJ16567083, (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate) and mGluR5 antagonist MTEP ([(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine). Pretreatment with EMQMCM (2.5-10 mg/kg) but not MTEP (2.5-10 mg/kg) significantly reduced expression of the sensitized ambulatory motor activity of the cocaine-experienced animals acutely challenged with cocaine. Both EMQMCM and MTEP significantly reduced vertical motor activity across all cocaine/saline treatment conditions. These findings indicate that the expression of behavioral sensitization to cocaine-induced stimulation of locomotor activity may be modulated by group I mGluR antagonists (mGluR1 rather than mGluR5), but these effects occur at the dose levels that attenuate vertical activity.

Enalapril Treatment Restores the Attenuated Proximal Tubule Reabsorption in Response to Acute Volume Expansion (VE) in Diabetic Rats

The natriuretic and diuretic responses to an acutely administered saline load are reduced in diabetes mellitus and these altered responses are associated with sodium retention. Inhibition of the renin-angiotensin-system (RAS) has renoprotective and cardiovascular protective effects. The objective of this study was to determine the roles of proximal tubule reabsorption and the RAS in the attenuated natriuretic and diuretic responses to VE in diabetic rats (DC, n=12). Fractional excretions of phosphate (FEPi) and lithium (FELi) were utilized as indexes for proximal tubule reabsorption. VE significantly increased both FELi and FEPi in all groups of rats. However, the increased FELi and FEPi in DC rats (ΔFELi=17.26±4.69% and ΔFEPi=7.38±2.9%) were significantly lower as compared with those in nondiabetic control rats (NC, n=8; Δ FELi=32.15±5.03% and ΔFEPi=20.62±3.5%). The lower increases in FELi and FEPi are associated with an attenuated increase in renal interstitial hydrostatic pressure (ΔRIHP) in DC (1.8±0.5 mmHg) compared with NC rats (4.3±0.4 mmHg). Enalapril treatment (25 mg/kg/day in drinking water) had no effect on nondiabetic rats (NE, n=8) as compared with untreated NC rats, but significantly improved RIHP response (ΔRIHP) to VE in diabetic rats (DE, 2.8± 0.6 mmHg). Both ΔFELi and FEPi were restored by enalapril treatment in diabetic rats and no significant differences were found in ΔFELi and ΔFEPi between DE (ΔFELi=26.81±5.24% and ΔFEPi=10.45±4.95%) and NC groups of rats in response to VE. These data suggest that RAS and RIHP may play an important role in the attenuated inhibition of proximal tubule reabsorption in response to acute saline volume expansion in diabetic rats.

Acute and chronic tianeptine treatments attenuate ethanol withdrawal syndrome in rats

Effects of acute and chronic tianeptine treatments on ethanol withdrawal syndrome were investigated in rats. Ethanol (7.2% v/v) was given to adult male Wistar rats by a liquid diet for 30 days. Acute or chronic (twice daily) tianeptine (5, 10 and 20 mg/kg) and saline were administered to rats intraperitoneally. Acute and last chronic tianeptine injections and saline were done 30 min before ethanol withdrawal testing. After 2nd, 4th and 6th hours of ethanol withdrawal, rats were observed for 5 min, and withdrawal signs which included locomotor hyperactivity, agitation, tremor, wet dog shakes, stereotyped behavior and audiogenic seizures were recorded or rated. Locomotor activity in naive (no ethanol-dependent rats) was also tested after acute tianeptine treatments. Acute but not chronic tianeptine treatment attenuated locomotor hyperactivity and agitation in ethanol-dependent rats. Both acute and chronic tianeptine treatment produced some significant inhibitory effects on tremor, wet dog shakes, stereotyped behaviors and audiogenic seizures during the ethanol withdrawal. Our results suggest that acute or chronic tianeptine treatment attenuates ethanol withdrawal syndrome in ethanol-dependent rats and this drug may be useful for treatment of ethanol-type dependence.

Natriuretic Response to Direct Renal Interstitial Volume Expansion (DRIVE) in Pregnant Rats

Basal renal interstitial hydrostatic pressure (RIHP) is lower in pregnant rats, suggesting an increase in renal interstitial compliance during pregnancy. The RIHP responses to increases in renal perfusion pressure (RPP) and acute saline volume expansion (VE) are attenuated in pregnant rats. Pressure natriuresis and diuresis responses are significantly attenuated during normal pregnancy, whereas the natriuretic and diuretic responses to VE remain intact. The objectives of this study were to use direct renal interstitial volume expansion (DRIVE) to selectively increase RIHP and determine the renal interstitial compliance and the relationship between RIHP, natriuretic, and diuretic responses in nonpregnant (NP; n = 8), midterm pregnant (MP; n = 8), and late-term pregnant (LP; n = 8) Sprague-Dawley (SD) rats. DRIVE resulted in significant increases in RIHP, fractional excretion of sodium (FE(Na)), and urine flow rate (V) in all groups of rats. The increase in RIHP (DeltaIHP) was greatest for NP (3.3 +/- 0.2 mm Hg) as compared to MP (1.3 +/- 0.1 mm Hg; P < .05 v NP) and LP (1.4 +/- 0.2 mm Hg; P < .05 v NP) in response to DRIVE showing that renal interstitial compliance was greater in MP and LP as compared to the NP group of rats. The increase in fractional excretion of sodium (DeltaFE(Na)) was similar in NP (3.1% +/- 0.3%) and LP (3.6% +/- 0.8%), but was significantly lower in MP (1.5% +/- 0.4%; P < .05 v NP and LP) in response to DRIVE. These data suggest that the blunted increase in RIHP and natriuresis in response to DRIVE in midterm pregnant rats may play an important role in the gradual plasma volume expansion that is occurring during this stage of pregnancy.

Natriuretic and antialdosterone actions of chronic oral NEP inhibition during progressive congestive heart failure

Neutral endopeptidase (NEP) degrades atrial natriuretic peptide (ANP) that via cyclic guanosine monophosphate (cGMP) is natriuretic and aldosterone-inhibiting. We hypothesized that chronic oral NEP inhibition (NEPI), initiated in early experimental congestive heart failure (CHF), would delay onset of decreases in sodium excretion during the progression of CHF and, in the severe phase, suppress aldosterone activation and reduce the magnitude of sodium retention. We also hypothesized that chronic NEPI during progressive CHF (PCHF) would improve the natriuretic response to acute volume expansion. In a novel canine model that progresses over 38 days from early to moderate and finally severe CHF, we defined the actions of chronic NEPI (candoxatril, 10 mg/kg, orally, twice a day) upon cardiorenal and neurohumoral function as well as the clinical well being of treated and untreated dogs in CHF. From baseline through the moderate phase of CHF, NEPI maintained sodium excretion. In contrast, in moderate CHF, sodium excretion was reduced compared to the early phase in the controls. In severe CHF, sodium excretion was higher with NEPI compared to control. Chronic NEPI also resulted in lower plasma aldosterone as compared to controls. In severe CHF, the natriuretic response to acute saline volume expansion was enhanced with oral NEPI as compared to control. This study supports the conclusion that chronic oral NEPI delays the onset of reduction in sodium excretion during the transition from early to severe CHF in this model of PCHF. This therapeutic strategy also improved the natriuretic response to acute volume expansion in severe CHF while enhancing ANP and suppressing aldosterone activation. Thus, these studies demonstrated a selective renal and adrenal action of chronic NEPI in heart failure indicating a therapeutic potential.

Progesterone inhibits behavioral responses and estrogen increases corticosterone levels after acute cocaine administration

Accumulating evidence suggests that estrogen and progesterone contribute to the sexually dimorphic behavioral response to cocaine. In this study, we tested the hypothesis that varying the level of estrogen or progesterone affects cocaine-induced locomotive behavior in female rats. Ovariectomized (OVX) rats received estrogen (0, 5, 10, 20, or 50 μg) 48 h or progesterone (0, 50, 100, 250, or 500 μg) 24 h before acute saline or cocaine (15 mg/kg) administration. Although estrogen did not affect cocaine-induced ambulatory and rearing behaviors, it affected stereotypic behaviors regardless of cocaine administration (animals receiving 50 μg had higher stereotypic counts than did the OVX group). In contrast, progesterone affected rearing activity dose-dependently: 50 and 500 μg of progesterone inhibited, whereas 100 μg and 250 μg stimulated, rearing in response to cocaine. That estrogen and progesterone did not affect overall baseline behavioral activity suggests their effects are mediated in part through interactions with cocaine. Progesterone administration did not affect corticosterone levels in saline- or cocaine-treated rats. Estrogen administration, however, affected levels of corticosterone both at baseline and after cocaine treatment. After accounting for baseline differences, we found that rats receiving 5 or 10 μg of estrogen and cocaine had higher percentage increases in serum corticosterone levels than did the control group that did not receive estrogen. On the basis of these observations, we suggest that progesterone fluctuations during the estrous cycle impact cocaine-induced behavioral responses, whereas estrogen may affect activity in the hypothalamic–pituitary–adrenal axis. Thus, dose-dependent effects of gonadal hormones may underlie some of the reported sex differences and reproductive cycle effects of cocaine.

Piracetam counteracts the effects of amitriptyline on inhibitory avoidance in CD1 mice

The purpose of the present work was to study the effects of amitriptyline on animal cognition in relation to some characteristics of its therapeutic effects. The modulation of acute and chronic effects of amitriptyline on inhibitory avoidance in male and female mice by piracetam was investigated. In Experiment 1, mice were subjected to the training phase of inhibitory avoidance conditioning 60 min after acute piracetam (100 mg/kg) or physiological saline administration. Immediately after the behavioural task, they received a single injection of the tricyclic antidepressant amitriptyline (30 mg/kg) or physiological saline. Twenty-four hours later, subjects were tested for avoidance. In Experiment 2, the same doses of amitriptyline and piracetam were chronically administered. Mice were subjected to the training phase of inhibitory avoidance on the 22nd day, and to the test phase 24 h later. Forty-five minutes after test, subjects explored the elevated plus-maze for 5 min in order to assess whether the effects of amitriptyline on avoidance performance may reflect general behavioural changes. Results obtained were that: (a) acute and chronic amitriptyline impaired inhibitory avoidance of male and female mice, (b) piracetam counteracted the effect of acutely administered amitriptyline on inhibitory avoidance, and (c) piracetam counteracted the effects of chronically administered amitriptyline in males but not females in the same learning task. These effects do not seem to be mediated by non-specific drug effects on spontaneous motor activity or anxiety.

Cardiovascular and renal characteristics, and responses to acute volume expansion of a rat model of diabetic pregnancy

The objective of this study was to characterize the cardiovascular and renal alterations that occur during diabetic pregnancy, and to evaluate the effect of insulin treatment in 12–14 days pregnant diabetic rats. Four groups of female Sprague Dawley rats were studied: virgin control group (NP), pregnant control group (CP), diabetic pregnant group (DP), and diabetic pregnant group with insulin treatment (DPI). Systolic arterial pressure (SAP) was increased on day 12, whereas heart rate (HR) decreased starting with day 3 in DP group of rats. DP rats exhibited marked renal hypertrophy with greater kidney weight (wt) and kidney wt/body wt ratio. Insulin treatment normalized blood glucose (BG) concentration, SAP and HR, and prevented the increase in kidney wt/body wt ratio in DPI rats. At the time of the terminal acute experiment, acute saline volume expansion (VE, 5% body wt/30 min) significantly increased renal interstitial hydrostatic pressure (RIHP), urinary sodium excretion (U NaV) and urine flow rate (V) in all groups, but the increases (Δ) were significantly attenuated in both CP (1.7 ± 0.2mmHg, 12.0 ± 1.5 μEq.min −1.g kidney wt −1 and 76.2 ± 10.9 μl.min −1.g kidney wt −1 for ΔRIHP, ΔU NaV and ΔV respectively) and DP (1.3 ± 0.1 mmHg, 6.8 ± 1.8 μEq.min −1.g kidney wt −1 and 32.3 ± 9.3 μl.min −1.g kidney wt −1 for ΔRIHP, ΔU NaV and ΔV respectively) group of rats as compared to NP (4.0 ± 0.6 mmHg, 21.6 ± 1.4 μEq.min −1.g kidney wt −1and 136.8 ± 10.5 μl.min −1.g kidney wt −1 for ΔRIHP, ΔU NaV and ΔV respectively) group of rats. Although RIHP response to VE was similar in DP and CP group of rats, the natriuretic and diuretic responses to VE were significantly lower in DP as compared to CP group of rats. Insulin treatment had no effect on RIHP response (ΔRIHP = 1.5 ± 0.3 mmHg), but restored most of the natriuretic (ΔU NaV = 15.7 ± 2.9 μEq.min −1.g kidney wt −1) and diuretic (ΔV = 100.2 ± 19.3 μl.min −1.g kidney wt −1) responses to VE in DPI as compared with CP group of rats. These data suggest that with VE, the restoration of the increase in U NaV and V with insulin treatment in diabetic pregnant rats is not mediated by changes in RIHP.

Effects of insulin on renal interstitial hydrostatic pressure and natriuretic response to volume expansion in diabetic rats

Diabetes mellitus (DM) is characterized by alterations in fluid balance and blood volume homeostasis. Renal interstitial hydrostatic pressure (RIHP) has been shown to play a critical role in mediating sodium and water excretion under various conditions. The objective of this study was to determine the effects of immediate and delayed initiation of insulin treatment on the restoration of the relationship between RIHP, natriuretic, and diuretic responses to acute saline volume expansion (VE) in diabetic rats. Diabetes was induced by an intraperitoneal injection of streptozotocin (STZ; 65 mg/kg body wt). Four groups of female Sprague-Dawley rats were studied: normal control group (C), untreated diabetic group (D), immediate insulin-treated diabetic group (DI; treatment with insulin for 2 wk was initiated immediately when diabetes was confirmed, which was 2 days after STZ injection), and delayed insulin-treated diabetic group (DDI; treatment with insulin for 2 wk was initiated 2 wk after STZ injection). RIHP and sodium and water excretions were measured before and during VE (5% body wt/30 min) in the four groups of anesthetized rats. VE significantly increased RIHP, fractional excretion of sodium (FE(Na)), and urine flow rate (V) in all groups of rats. Basal RIHP, RIHP response to VE (Delta RIHP), and FE(Na) and V responses to VE (Delta FE(Na) and Delta V) were significantly lower in the D group compared with the C group of rats. Delta RIHP was significantly higher in both DI and DDI groups compared with D group but was similar to that of the C group of rats. While in the DI group the Delta FE(Na) response to VE was restored, Delta FE(Na) was significantly increased in DDI compared with D group, but it remained lower than that of the C group. In conclusion, insulin treatment initiated immediately after the onset of diabetes restores basal RIHP and RIHP, natriuretic, and diuretic responses to VE; however, delayed insulin treatment restores the basal RIHP and RIHP response to VE but does not fully restore the natriuretic response to VE.

Role of Thyroid Hormones on the Synthesis and Release of Atrial Natriuretic Peptide in Rats with Acute Renal Failure

Background/Aims: High atrial natriuretic peptide (ANP) serum levels are seen in acute renal failure (ARF) due to impaired ANP clearance, but the response of ANP to blood volume expansion is blunted. ARF-associated hypothyroidism influences ANP clearance but it may also play a role in the synthesis and release of ANP because in primary hypothyroidism both mechanisms are disturbed. The aim of this study is to analyze whether thyroxin (T₄) supplementation improves the synthesis and release of ANP in ARF. Methods: Four groups of rats were studied: group C (control); group ARF; Group ARF-T₄ (ARF supplemented with T₄), and group Tx (thyroidectomized). Serum creatinine (SCr), creatinine clearance (CrCl), total T₄, total triiodothyronin (T₃), plasma ANP, ANP response to acute saline load and atrial content of mRNA-ANP were measured 5 days after ARF induction with potassium dichromate. Results: CrCl was 1.8 ± 0.4 ml/min in group C, and it significantly dropped to 0.6 ± 0.5 in ARF (p < 0.01), T₄ improved it (1.7 ± 0.7 in ARF-T₄, p < 0.01) and Tx did not change it. Plasma ANP was higher in ARF as compared with C (152 ± 23 vs. 52 ± 21 fmol/l, p < 0.01). In ARF-T₄, ANP was higher than in C but lower than in ARF (85 ± 28 fmol/l, p < 0.01). No changes were observed in Tx rats (48 ± 17 fmol/l). The atrial content of mRNA-ANP was 0.06 ± 0.025 mRNA-ANP/mRNA-β-actin ratio units in group C, it was higher in ARF (0.13 ± 0.025, p < 0.01) and lower in Tx (0.04 ± 0.01, p < 0.05) as compared to C. Supplementation with T₄ increased the mRNA-ANF content (0.18 ± 0.2 mRNA-ANP/mRNA-β-actin ratio units, p < 0.05) over ARF. Plasma ANP response to saline load was 45 ± 7% in C, but it was reduced in ARF and Tx (20 ± 10 and 26 ± 10%, p < 0.01). In ARF-T₄ the response was restored (36 ± 9%, p < 0.01 vs. ARF). Conclusion: Thyroid hormones modulate the synthesis and release of ANP in ARF. Although the effect is probably direct, T₄-induced amelioration of renal damage may also play a significant role by improving the uremic milieu.

Role of nitric oxide in the natriuretic and diuretic responses in pregnant rats.

Normal pregnancy is characterized by sodium conservation and increase in plasma volume, yet the natriuretic response to acute saline volume expansion (VE) is intact in pregnant rats. Nitric oxide (NO) has been suggested to play a role in renal and cardiovascular adaptations to normal pregnancy. The objective of this study was to determine the role of NO in the natriuretic and diuretic responses to VE during pregnancy. Infusion of NG-monomethyl-l-arginine (l-NMMA) was used to inhibit NO synthesis. Nine groups of Sprague-Dawley (SD) rats were studied: nonpregnant (NP-VE, n = 7), midterm pregnant (MP-VE, n = 8), and late-term pregnant (LP-VE, n = 7) SD groups that underwent VE alone after a control period; NP-l-NMMA (n = 7), MP-l-NMMA (n = 8), and LP-l-NMMA (n = 7) SD groups that were infused with l-NMMA after a control period; and another three groups of SD rats (NP-VE-l-NMMA, n = 8; MP-VE-l-NMMA, n = 7; and LP-VE-l-NMMA, n = 12) that underwent simultaneous VE and l-NMMA infusion after a control period. The change in fractional excretion of sodium was 7.22 +/- 1.03% for NPVE, 9.89 +/- 1.85% for NP-l-NMMA, and 17.66 +/- 1.85% for NP-VE-l-NMMA (P < 0.05 vs. NP-VE and NP-l-NMMA); 6.61 +/- 1.07% for MP-VE, 7.99 +/- 1.92% for MP-l-NMMA, and 10.24 +/- 1.91% for MP-VE-l-NMMA [not significant (NS) vs. MP-VE and MP-l-NMMA]; 8.20 +/- 1.92% for LP-VE, 8.09 +/- 0.70% for LP-l-NMMA, and 7.57 +/- 1.11% for LP-VE-l-NMMA (both NS vs. LP-VE and LP-l-NMMA). The increase in renal interstitial hydrostatic pressure was significantly greater in all NP compared with pregnant groups with similar experimental intervention (i.e., VE, l-NMMA, or VE-l-NMMA). In conclusion, the natriuretic and diuretic responses to VE and l-NMMA infusion were additive in NP but not in pregnant rats, indicating a possible lower ability of pregnant rats to respond to combined significant natriuretic and diuretic stimuli.

Altered renal hemodynamics in mice overexpressing the parathyroid hormone (PTH)/PTH-related peptide type 1 receptor in smooth muscle.

PTH-related protein (PTHrP) is an autocrine/paracrine peptide expressed in renal tubules and vasculature and may play an important role in regulating overall renal function. To evaluate the potential role of endogenous PTHrP in the control of renal hemodynamics, we performed clearance measurements in transgenic (TG) mice in which the SMP8 alpha-actin promoter was used to drive overexpression of the PTH/PTHrP type 1 receptor in smooth muscle. In protocol I, responses to acute saline volume expansion (SVE, 0.75 microl/min.g body weight) were measured in TG and nontransgenic (NTG) mice. Mean arterial pressure was significantly lower in TG mice throughout the experiment, and it decreased comparably in both groups in response to SVE. SVE significantly increased effective renal plasma flow in both groups of mice, but the increase was greater in TG than in NTG. Glomerular filtration rate decreased in response to SVE in NTG but did not change in TG animals. In protocol II, renal responses to angiotensin II (ANG II) infusion were determined (0.5 ng/min.g body weight). Baseline arterial pressure was again significantly lower in TG, compared with NTG mice, and TG mice had a blunted pressor response to ANG II. Also, ANG II decreased effective renal plasma flow and glomerular filtration rate in both groups of animals, but the reductions were less in TG than in NTG mice. Our findings indicate that smooth-muscle-specific overexpression of the PTH/PTHrP type 1 receptor resulted in augmentation of the vasodilatory response to SVE and attenuation of the vasoconstrictor response to ANG II. We conclude that endogenous PTHrP can act as an endogenous vasorelaxant factor to modulate renal responses to vasoactive stimuli.

High prevalence of primary aldosteronism using postcaptopril plasma aldosterone to renin ratio as a screening test among Italian hypertensives

The prevalence of primary aldosteronism (PA) was assessed in a specialized hypertension center. Baseline and postcaptopril (50 mg orally) aldosterone to plasma renin activity ratio (A/R) as a screening tool were preliminarily tested in a sample including 22 patients with histories of PA and 53 patients with low-renin essential hypertension (EH). Sensitivity and specificity of A/R ≥35 were 95.4% and 28.3% at baseline, compared with 100% and 67.9% after captopril. Using postcaptopril A/R ≥35 and confirmation by acute saline loading, a PA prevalence of 6.3% was found among 1046 consecutive hypertensive patients with normal renal function. Of those 66 PA patients, 16 (24.2%) had a unilateral adenoma, whereas 50 (75.8%) had idiopathic hyperaldosteronism. At presentation, 45.4% of the PA and 16.3% of EH patients were treated with two or more antihypertensive drugs (χ 2 = 33.117, P < .0001). However, among untreated patients ( n = 553), the prevalence of mild-to-moderate hypertension (ie, <180/110 mm Hg) was not different between patients with PA and those with EH (70.6% v 76.7%, χ 2 = 0.086, P = .770). Serum potassium ≥3.6 mEq/L was found in 60.6% of PA patients. In conclusion, we observed the following: 1) postcaptopril compared with baseline A/R is a better screening tool for PA; 2) PA is relatively frequent among hypertensive individuals; 3) PA is not necessarily associated with severe hypertension; and 4) hypokalemia is an insensitive screening criterion for PA.