Effect of parathyroid hormone activity on gentamicin nephrotoxicity

Dietary calcium (CA++) supplementation attenuates gentamicin nephrotoxicity in rats. It has been proposed that this protective effect results from the ability of Ca++ to interfere with gentamicin binding to renal cell membranes. However, calcium supplementation also suppresses parathyroid hormone (PTH) activity, which may affect gentamicin nephrotoxicity by altering renal brush border phospholipid composition or renal calcium handling. We therefore compared gentamicin nephrotoxicity in PTH-stimulated control rats and parathyroidectomized (PTX) rats. Although their pretreatment serum ionized calcium concentration was significantly higher (1.27 +/- 0.01 vs. 0.88 +/- 0.06 mmol/L; P less than 0.001), PTH-stimulated rats had higher peak renal cortical gentamicin concentrations (543 +/- 20 vs. 395 +/- 49 micrograms/gm; P less than 0.025) and serum creatinine concentrations (3.0 +/- 0.8 vs. 0.9 +/- 0.3 mg/dl; P less than 0.05). Structural injury and depression of renal cortical slice uptake of p-aminohippurate were also less severe in PTX rats. Gentamicin treatment also caused increased urinary Ca++ excretion in control rats (from 2.12 +/- 0.64 mumol/mg creatinine per day [pretreatment] to 16.86 +/- 2.07 mumol/mg creatinine per day; P less than 0.001) but not in PTX rats. Control rats ingesting chow containing a standard Ca++ content (1.2%) resembled PTX rats. These results indicate that PTH stimulation exacerbates gentamicin nephrotoxicity. Increased peak renal cortical gentamicin concentrations in PTH-stimulated rats may be caused by increased gentamicin transport across the brush border as a consequence of PTH-mediated alteration of plasma membrane phospholipid composition, turnover, or both.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of angiotensin-converting enzyme inhibition in diabetic rats with reduced renal function.

To test the effect of converting enzyme inhibition (CEI) on diabetes, with or without renal insufficiency, we studied streptozotocin-induced diabetic rats, with or without reduced renal mass, which were treated with insulin in sufficient amounts to maintain glucose values in the mild to moderately hyperglycemic range. We found that diabetes increased glomerular filtration rate (GFR) (inulin clearance, 2.3 +/- 0.5 ml/min vs 1.9 +/- 0.1 ml/min; p < 0.05) and blood pressure (137 +/- 15 mm Hg vs 116 +/- 6 mm Hg; p < 0.05) but did not increase plasma atrial natriuretic peptide (ANP) values, when compared with control rats (72 +/- 38 vs 68 +/- 24 pg/ml). CEI decreased GFR and blood pressure to control values. In rats with diabetes and concomitantly reduced renal mass, hypertension, elevated ANP values, proteinuria, and glomerulosclerosis were prominent features. CEI was associated with reduced blood pressure (172 +/- 17 mm Hg vs 138 +/- 15 mm Hg; p < 0.05), without a concomitant decrease in GFR (1.1 +/- 0.1 ml/min vs 1.1 +/- 0.1 ml/min). Further, CEI reduced the elevated ANP values (140 +/- 34 pg/ml vs 66 +/- 19 pg/ml; p < 0.05) to those of control rats. CEI reduced proteinuria by 50% and ameliorated the histopathologic changes. In separate experiments, rats with 5/6th nephrectomy and hypertension but without diabetes were also found to have elevated ANP levels that decreased to control values with CEI. The data speak for a renal protective effect of angiotensin I-converting enzyme inhibition in this model but do not support a specific role for ANP in the model of diabetes with concomitantly reduced renal mass.     

Different behaviour of the N-terminal and C-terminal fragment of proatrial natriuretic factor in plasma of healthy subjects as well as of patients with cirrhosis

N-terminal (atrial natriuretic factor (ANF) 1-98) and C-terminal (ANF 99-126) fragments of proatrial natriuretic factor (NTA and CTA, respectively) were determined in plasma of healthy subjects adopting different postures and in patients with cirrhosis. Seven healthy subjects were investigated while seated and 30 min after assuming a horizontal position. NTA plasma concentrations increased in subjects in the horizontal position (from 734 +/- 250 (SE) fmol/ml to 902 +/- 227 fmol/ml; p less than 0.05). In contrast, CTA plasma concentrations remained unchanged (9.2 +/- 1.3 fmol/ml vs 8.9 +/- 1.6 fmol/ml). In 10 patients with cirrhosis of the liver, NTA concentrations were markedly (p less than 0.001) elevated compared to 11 healthy subjects (2334 +/- 291 fmol/ml vs 743 +/- 155 fmol/ml). However, there was no difference of CTA plasma levels between cirrhotic patients and healthy subjects (8.7 +/- 1.3 fmol/ml vs 8.2 +/- 0.9 fmol/ml). These data demonstrate changes of the plasma concentration of the N-terminal fragment of proatrial natriuretic factor by posture and in liver disease, in contrast to unchanged levels of the C-terminal fragment.     

Effects of probucol in renal function and structure in rats with subtotal kidney ablation.

Probucol is a bisphenolic compound that lowers serum cholesterol and also has potent antioxidant properties. The present studies examined the effects of probucol administration on renal function and structure in a rat model of subtotal renal ablation. After subtotal nephrectomy, rats were fed an isocaloric rat chow diet containing 22.8% protein with or without the addition of 1% probucol. After 4 weeks, clearance studies were performed for determination of glomerular filtration rate (inulin clearance) and effective renal plasma flow (paraaminohippurate clearance). After completion of clearance studies and measurements of arterial blood pressure, the animals were exsanguinated and renal tissue was obtained for histologic evaluation. There were no differences in body weight, hematocrit, and blood pressure between the two groups of rats 4 weeks after subtotal nephrectomy. Rats with a remnant kidney given probucol had a significantly lower serum cholesterol level (47.4 +/- 5.3 mg/dl vs 87.2 +/- 10.4 mg/dl) and urea nitrogen level (40.7 +/- 3.2 mg/dl vs 63.6 +/- 8.1 mg/dl) than the control group. Rats given probucol also had significantly greater values for inulin clearance and clearance of paraaminohippurate and significantly less proteinuria than control rats. Also, rats with a remnant kidney given probucol had a significantly greater number of normal glomeruli (6.2% +/- 2.1% vs 1.1% +/- 0.9%) and a lesser number of severely affected glomeruli, grades III and IV (26.0% +/- 5.9% vs 50.9% +/- 9.1%) than rats with a remnant kidney not given probucol. Tubulointerstitial changes also were significantly less in rats with a remnant kidney given probucol.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of atrial natriuretic peptide versus mannitol on renal blood flow during radiocontrast infusion in chronic renal failure

This study was performed to investigate the effects of atrial natriuretic peptide (ANP) and mannitol on renal blood flow (RBF) and radiocontrast-induced nephropathy (RCIN) in human subjects with chronic renal failure. ANP preserves glomerular filtration rate or RBF (or both) in severe animal models of acute renal failure. Radiocontrast is known to substantially decrease RBF and can induce acute renal failure. Twenty consecutive patients with chronic renal failure (60% with diabetes) were randomized in a prospective, double-blind fashion to receive either ANP (50 micrograms bolus, then 1 microgram/min infusion) or mannitol (15% at 100 ml/hr) for 2 hours before and during cardiac catheterization with diatrizoate. Baseline serum creatinine level (ANP 2.4 +/- 0.7 mg/dl, mannitol 2.5 +/- 0.8 mg/dl), medications, and quantity of radiocontrast were similar in both groups. Direct measurements of RBF were made with thermodilution catheters placed in the left renal vein. RBF rose significantly (p less than 0.05), to 198% of baseline at 15 minutes and 166% of baseline at 65 minutes in the group receiving ANP and remained stable in the group receiving mannitol. ANP levels rose significantly from baseline at 5, 15, 65 and 120 minutes in both groups (p less than 0.05). Acute renal failure defined as a 0.5 mg/dl rise of creatinine within 24 hours of cardiac catheterization, developed only in patients with diabetes mellitus and was similar in both experimental groups (ANP, 50%; mannitol, 30%). Only patients with diabetes mellitus responded with an increase in RBF after a 5-minute infusion of either ANP or mannitol (diabetes, 165% +/- 28% baseline; no diabetes, 96% +/- 8% baseline) (p less than 0.05). In conclusion, RBF was maintained or increased despite administration of radiocontrast, a documented renal vasoconstrictor. Patients with diabetes mellitus had a renal vasodilatory response to drug infusion. Acute renal failure occurred to a similar extent in both groups. Plasma ANP levels rose significantly in both groups. Mannitol may induce ANP release, thus contributing to mannitol's renal effects.     

Elevated plasma atrial natriuretic peptide levels in diabetic rats. Potential mediator of hyperfiltration.

Infusion of atrial natriuretic peptide (ANP) increases the glomerular filtration rate (GFR), and ANP is released from cardiac myocytes in response to extracellular fluid volume expansion. Since diabetes mellitus is associated with glomerular hyperfiltration and volume expansion, we investigated the relationship between ANP and GFR in diabetic rats given insulin to achieve stable moderate hyperglycemia or normoglycemia. At 2 wk after induction of diabetes, moderately hyperglycemic diabetic rats exhibited elevations of plasma ANP levels averaging 281 +/- 28 pg/ml vs. 158 +/- 15 pg/ml in normoglycemic diabetic rats. In hyperglycemic rats, the GFR was also elevated on average to 2.24 +/- 0.28 ml/min as compared with 1.71 +/- 0.13 ml/min in normoglycemic diabetic rats. To test further the relationship between ANP and GFR in diabetes, moderately hyperglycemic diabetic rats were infused either with a specific ANP antiserum or with nonimmune serum. The infusion of specific ANP antiserum uniformly reduced the GFR on average from 2.38 +/- 0.1 ml/min to 1.60 +/- 0.1 ml/min, whereas the infusion of nonimmune serum was without effect. It is concluded that elevated endogenous ANP levels contribute to the hyperfiltration observed in early diabetes in the rat.     

In-vivo and in-vitro studies on the effect of amphotericin B on endothelin release.

Since amphotericin B nephrotoxicity is mediated, in part by hypoxic tubular injury, the role of endothelin in the renal vasoconstriction, characteristic of amphotericin toxicity has been studied. Intact and salt depleted rats were infused with amphotericin B (20 micrograms/kg per min) or 5% dextrose over 20 min. Plasma endothelin levels determined at the conclusion of the infusion period, did not differ between the experimental groups, despite a marked reduction in renal blood flow noted in rats infused with amphotericin B. Amphotericin B (10(-5)-10(-7) M) did not stimulate endothelin release from cultured bovine aortic endothelial cells. However, in a model of chronic amphotericin nephrotoxicity produced by repeated daily intraperitoneal injections of amphotericin B (5 mg/kg) to salt depleted rats, renal failure was associated with elevated plasma endothelin levels (29.3 +/- 4.4 fmol/mL, vs 10.8 +/- 1.2 fmol/mL in salt depleted controls, P less than 0.01). We conclude that while plasma endothelin may be increased in chronic amphotericin B nephropathy, this peptide does not mediate the acute renal vasoconstriction associated with the infusion of this drug.     

Effects of diphenyl-phenylenediamine on gentamicin-induced lipid peroxidation and toxicity in rat renal cortex

The hypothesis that lipid peroxidation is linked causally to the pathogenesis of aminoglycoside nephrotoxicity was tested by determining whether administration of the antioxidant, diphenyl-phenylenediamine (DPPD) would inhibit lipid peroxidation and ameliorate gentamicin-induced proximal tubular cell injury. Rats were injected with saline, gentamicin or gentamicin plus DPPD for 4 days and were sacrificed 48 hr later. Gentamicin increased malondialdehyde in renal cortex from a control level of 0.65 +/- 0.04 to 1.01 +/- 0.03 nmol/mg of protein, P less than .01; it was reduced to 0.20 +/- 0.03 by DPPD, P less than .01 compared to control. Arachidonic acid comprised 27.6 +/- 0.5% of the fatty acid in renal cortical phospholipid of control rats. Gentamicin lowered arachidonic acid to 16.7 +/- 0.9%, P less than .01, and promoted a shift toward saturated fatty acids. DPPD reversed these changes. Gentamicin depressed catalase activity from a control value of 0.211 k/min to 0.154 +/- 0.008 k/min, P less than .01. DPPD depressed catalase further to 0.095 +/- 0.066 k/min, P less than .01. Total glutathione and reduced glutathione were depressed whereas the fraction of total glutathione in the oxidized state was augmented by gentamicin. These changes were prevented by DPPD. The renal cortical phospholipidosis induced by gentamicin was not altered by DPPD. The increased urinary excretions of alanine aminopeptidase and N-acetyl-beta-glucosaminidase induced by gentamicin were augmented further by DPPD. In DPPD rats serum creatinine (0.45 +/- 0.04 mg/dl) was higher (P less than .01) than that of gentamicin rats (0.35 +/- 0.01 mg/dl), which was higher (P less than .01) than that of control rats (0.26 +/- 0.01 gm/dl).(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term effects of acetazolamide and sodium chloride loading on cisplatin nephrotoxicity in the rat

The protective effect of acetazolamide or sodium chloride loading on cisplatin nephrotoxicity was investigated in rats. After a single dose of cisplatin (5 mg kg-1 i.p.) kidney function was studied after 5, 28 and 84 days. Acetazolamide (75 mg kg-1 i.p.) was administered as a single dose prior (30 min) to the cisplatin injection. By the time of cisplatin administration, the rats were sodium depleted except the sodium-loaded group. Five days after the cisplatin administration all rats received a regular rat chow for the rest of the experiment. Cisplatin alone caused renal failure that could be observed for up to 12 weeks (ClCr 0.32 +/- 0.13 vs. 0.62 +/- 0.06 ml min-1 x 100 g BW-1) with polyuria (UVol 41.2 +/- 4.5 vs. 18.4 +/- 4.6 ml 24 h-1). Pretreatment with acetazolamide was the most protective manoeuvre tested. Five days after cisplatin, kidney function was significantly better than in rats treated with cisplatin alone (ClCr 0.21 +/- 0.06 vs. 0.03 +/- 0.01 ml min-1 x 100 g BW-1), after 28 days the only sign of nephrotoxicity was polyuria (UVol 28.9 +/- 3.7 vs. 19.0 +/- 2.6 ml 24 h-1) after 84 days no differences could be observed at all. Sodium chloride loading was less protective on cisplatin nephrotoxicity. Impaired renal function could still be observed after 12 weeks (ClCr 0.41 +/- 0.05 vs. 0.62 +/- 0.06 ml min-1 x 100 g BW-1) with no difference in comparison with the rats treated with cisplatin alone. However, since 12 rats died in the group having received cisplatin alone and only one rat in the high-salt group, sodium chloride loading is regarded as being advantageous over sodium depletion on cisplatin nephrotoxicity.     

Acute and chronic effects of flucytosine on amphotericin B nephrotoxicity in rats.

The combination of intravenous flucytosine (FC) in 0.9% saline (NaCl) and amphotericin B (AmB) provides synergistic antifungal activity and is associated with a lower incidence of nephrotoxicity than with AmB treatment alone. This study was conducted to examine whether flucytosine can influence renal function and whether it can modify the acute and chronic renal responses to AmB in the rat. In the in situ perfused rat kidney, FC at a concentration of 10 mg/kg/min for 15 min had a vasodilator effect, increasing renal blood flow by 2.5 +/- 0.7 ml/min, an effect not observed with vehicle. After the infusion of FC was stopped for 15 min, AmB induced a decrease in renal blood flow similar to that with both FC and vehicle. In a second series of studies, AmB (5 mg/kg/day intraperitoneally) was administered to four groups of rats for 7 days. In addition, the following groups received the intravenous daily interventions indicated: group 1, 5% dextrose in water (15 ml/kg/12 h); group 2, FC (150 mg/kg/12 h) in 0.9% saline (15 ml/kg/12 h); group 3, 0.9% saline (15 ml/kg/12 h); and group 4, FC (150 mg/kg/12 h) in 5% dextrose in water. Group 1 sustained a 77% decrease in creatinine clearance over the 7 days and a threefold increase in serum creatinine concentration (P of < 0.05). Groups 2, 3, and 4 sustained significantly less nephrotoxicity, with no change in serum creatinine concentration and only 38, 41, and 53% decreases in creatinine clearance, respectively (P of < 0.05), compared with that for group 1. AmB levels in renal tissue varied inversely to creatinine clearance (r of 0.57, P of < or = 0.005). However, no significant differences were found in levels in tissue between groups (P of 0.06). The results of this study suggest that FC has a small but significant effect in reducing chronic AmB-induced nephrotoxicity. This amelioration of renal injury is independent of saline administration. There was evidence that the extent of renal uptake of AmB related to the efficiency of renal function at the end of the experiment.     

Reduced incidence of radiocontrast-induced nephropathy in ICU patients under theophylline prophylaxis: a prospective comparison to series of patients at similar risk

OBJECTIVE: To investigate whether the adenosine-antagonist theophylline reduces the incidence of contrast-induced nephropathy (CIN). DESIGN AND SETTING: Prospective, comparison to series of patients at similar risk of CIN in a university hospital medical ICU. PATIENTS: 78 ICU patients with at least one risk factor for CIN undergoing 150 consecutive contrast examinations. INTERVENTIONS: Administration of 200 mg theophylline/70 kg BW intravenously 30 min before that of 100 ml or more low-osmolarity contrast medium (CM). MEASUREMENTS AND RESULTS: Concentrations of serum creatinine and blood urea nitrogen (BUN), urine volume, fluid balance, and the incidence of CIN [increase in creatinine > or =20.5 mg/dl (= 44.2 micromol/l) within 48 h] were monitored for 48 h. Despite the large number of risk factors (6.8 per patient) including a high dose of CM (169.4 ml), impaired renal function (51%), diabetes (38%), aminoglycosides (61%), vancomycin (53%), catecholamines (52%), creatinine concentrations were not increased 24 h (1.40+/-0.92 mg/dl) or 48 h (1.38+/-0.88 mg/dl) after CM [1.47+/-1.0 mg/dl (= 130+/-88 micromol/l)] vs. baseline. The fluid balance was not different before (+3 ml/h) and after CM (-9 ml/h). The urine volume slightly increased after CM and theophylline (184 ml/h vs. 164 ml/h). Only three patients (2%) developed CIN. The incidence was significantly lower than that of 14% (78/565) in the control series with patients at comparable risk of CIN (p < 0.0001). CONCLUSIONS: Using a theophylline prophylaxis the incidence of CIN in patients with increased risk of CIN is as low as 2%.     

Effects of physiological increments in renal arterial plasma osmolality on renin secretion rate

The present study was performed in anesthetized dogs to examine the effects of physiological increments in renal arterial plasma osmolality on basal renin secretion rate and on the response of renin secretion rate to RNS. Three concentrations of hypertonic NaCl were infused into the renal artery (i.r.a.) at 0.38 ml/min for 3 min; i.r.a. Hypertonic NaCl at 0.45M, 0.9M, and 1.8M increased the renal arterial plasma osmolality by 6 +/- 2, 8 +/- 2, and 28 +/- 9 mOsm/kg H2O, respectively. NaCl, 0.45M, did not affect renal function, whereas both 0.9M and 1.8M NaCl increased renal blood flow and urinary sodium excretion; neither 0.45M, 0.9M, nor 1.8M NaCl affected renin secretion rate. RNS was applied at two different frequencies: LFRNS and HFRNS. LFRNS did not affect renal blood flow, whereas HFRNS reduced renal blood flow by 50%. Both LFRNS and HFRNS increased renin secretion rate significantly. An i.r.a. infusion of 0.9M NaCl increased urinary sodium excretion and reduced the renin secretion rate response to LFRNS (-52% +/- 15, p less than 0.02) and HFRNS (-25% +/- 8, p less than 0.01). These findings demonstrate that increases in renal arterial plasma osmolality within the physiological range increase renal blood flow but do not affect renal secretion rate. The renal secretion rate response to RNS is attenuated by increased renal arterial plasma osmolality, an effect consistent with increased sodium chloride delivery to the distal tubular macula densa receptor.     

Vasodilator agents protect against indinavir nephrotoxicity

Indinavir (IDV) is a protease inhibitor widely used in AIDS treatment. A sustained elevation of creatinine was identified in IDV-treated patients. We have previously demonstrated that IDV causes renal vasoconstriction in rats. The objective of this study was to investigate the mechanism of IDV-induced vasoconstriction and the effect that the vasodilator agents L-arginine (LA), nifedipine (NF), as well as magnesium supplementation (Mg), have on IDV-induced nephrotoxicity. Male Wistar rats were kept on fast overnight and given free access to water. IDV (80 mg/kg BW) and NF (3 mg/kg BW) were given by gavage for 15 days. LA (1.5%) and MgCl2 x 6H2O (1%) were added to drinking water. Six groups were studied: Control (n=6): normal rats treated with vehicle, a 0.05 M citric acid solution; IDV (n=7): IDV-treated rats; IDV+LA (n=6): IDV- and LA-treated rats; IDV+NF (n=7): IDV- and NF-treated rats; IDV+Mg (n=7): IDV- and MgCl2-treated rats; IDV+Mg+L-NAME (n=9): IDV- and MgCl2-treated rats, supplemented with L-NAME (2.5 mg/l in drinking water). Clearance studies and evaluations of urinary nitrite (NO2) excretion were performed on day 16. No changes in blood pressure were observed. NO2 excretion decreased in IDV-treated rats. LA and NF protected against IDV effects, improving GFR (IDV+LA, 1.95 +/- 0.10; IDV+NF, 1.94 +/- 0.07 vs IDV, 1.15 +/- 0.07 ml/min, P<0.001) and RBF (IDV+LA, 7.83 +/- 0.09; IDV+NF, 7.63 +/- 0.14 vs IDV, 6.17 +/- 0.25 ml/min, P<0.001). These results suggest that IDV-induced vasoconstriction is mediated by NO and Ca2+ channels. Magnesium also ameliorated GFR and RBF in IDV-treated rats (GFR IDV+Mg, 1.77 +/- 0.08 ml/min, P<0.001; RBF IDV+Mg, 7.35 +/- 0.158 ml/min, P<0.001). Magnesium protection is not NO-mediated since it was not blocked by L-NAME. In conclusion, LA, NF and Mg protect against IDV-induced nephrotoxicity in rats. This study may have potential clinical implications for prevention of IDV-induced nephrotoxicity.     

Pharmacokinetics of zidovudine (AZT) and its metabolite (G-AZT) in healthy subjects and in patients with kidney failure

Pharmacokinetics of zidovudine was investigated after oral administration (200 mg) in 25 HIV seronegative subjects: 14 patients with severe renal impairment (creatinine clearance 6 to 31 ml/min), 5 hemodialyzed anuric patients, and 6 healthy subjects. In healthy subjects, G. AZT concentrations are higher than those of AZT; AUC were 23.7 +/- 1.9 and 5.2 +/- 0.6 mumol.h/l respectively. Formation of G. AZT rate-limits its elimination: G. AZT half-life parallels that of AZT which is around 1 hour. In uremic patients AZT concentrations are moderately increased (AUC = 11.7 +/- 1.1 mumol.h/l), whereas half-life and MRT remains unchanged, despite the decreased renal clearance (16 +/- 2 vs 220 +/- 58 ml/min). In contrast G. AZT concentrations are markedly increased (AUC = 403 +/- 89 mumol.h/l). As a consequence of the decreased renal clearance (27 +/- 3 vs 331 +/- 42 ml/min), elimination is the rate limiting step and half-life is increased (8 +/- 2 vs 0.9 +/- 0.1 h). Contribution of a 4-hour hemodialysis session to AZT elimination appears negligible whereas elimination of G. AZT is enhanced.     

Is skeletal response to parathyroid hormone abnormal in experimental renal failure?

It is widely believed that skeletal resistance is the mechanism of impaired calcemic response to parathyroid hormone (PTH) in renal failure. The action of PTH not only involves skeletal mobilization of Ca, it may also stimulate intestinal absorption of Ca and renal conservation of Ca. We have examined each of these factors and studied the calcemic response to PTH in renal failure. PTH, 3 U/hr/100 gm, was infused for 5 hours in rats with renal failure 3 weeks after a five-sixths nephrectomy. In nonfasted animals, the post-PTH increments of total plasma Ca (0.71 +/- 0.06 mg/dl) and ionized Ca (0.37 +/- 0.06 mg/dl) of control sham-operated rats were significantly greater than those of rats with renal failure (plasma Ca 0.37 +/- 0.02 mg/dl and plasma ionized Ca 0.17 +/- 0.01 mg/dl both p less than 0.001). Urinary Ca excretion rate remained unchanged during PTH infusion despite the increase in plasma Ca. Plasma levels of calcitriol after PTH injection were higher in control rats (257 +/- 18 pg/ml) than in rats with renal failure (162 +/- 5 pg/ml, p less than 0.001). Pretreatment of rats with renal failure with 50 ng calcitriol intravenously corrected the abnormal calcemic response to PTH. To exclude the PTH effect on intestinal Ca absorption, PTH infusion was carried out in animals fasted for 18 hours. The post-PTH increments of Ca were no longer different between rats with renal failure (plasma Ca 0.37 +/- 0.04 mg/dl, plasma ionized Ca 0.20 +/- 0.01 mg/dl) and control rats (plasma Ca 0.37 +/- 0.03 mg/dl, plasma ionized Ca 0.19 +/- 0.01), suggesting that skeletal mobilization of Ca was similar between the two groups of animals. We conclude that lack of intestinal response to PTH rather than skeletal resistance was the mechanism of impaired calcemic response to PTH in this model of renal failure.     

Effects of angiotensin-converting enzyme inhibition on altered renal hemodynamics induced by low protein diet in the rat.

We assessed the role of angiotensin II in mediating the alterations in renal hemodynamics known to result from low protein feeding to normal rats by examining the effect of the angiotensin-converting enzyme (ACE) inhibitor captopril. 2 wk of low protein (6% casein) diet resulted in decreased glomerular filtration rate (normal protein [NP], 1.82 +/- 0.17 vs. low protein [LP], 0.76 +/- 0.01 ml/min; P less than 0.05) and renal plasma flow (NP, 6.7 +/- 0.2 vs. LP, 3.3 +/- 0.3 ml/min; P less than 0.05); renal vascular resistance rose (NP, 8.7 +/- 0.4 vs. LP, 19.8 +/- 1.4 dyn . s per cm5; P less than 0.05). These changes were accompanied by a significant decrease in plasma renin activity (NP, 7.0 +/- 0.7 vs. LP, 4.4 +/- 0.8 ng A I/ml per h; P less than 0.05), plasma aldosterone concentration (NP, 7.0 +/- 0.6 vs. LP, 4.1 +/- 0.7 ng/dl; P less than 0.05), and urinary PGE2 excretion (NP, 3,120 +/- 511 vs. LP, 648 +/- 95 pg/mgCr; P less than 0.05); by contrast renal renin content was significantly increased (NP, 2,587 +/- 273 vs. LP, 7,032 +/- 654 ng A I/mg protein; P less than 0.05). Treatment with captopril (30 mg/kg per d) raised glomerular filtration rate (GFR; LP + capt, 1.6 +/- 0.2 ml/min) and renal plasma flow (RPF; LP + capt, 6.7 +/- 0.7 ml/min), and reduced renal vascular resistance (LP + capt, 9.2 +/- 0.5 dyn/s per cm5) in low protein-fed animals. These values were not different from those measured in untreated and captopril-treated rats fed a normal (23%) protein diet. There were no changes in systemic mean arterial pressure in any group of rats. These data provide evidence that intrarenal angiotensin II mediates the changes in intrarenal hemodynamics induced by protein deprivation. The effects of low protein feeding may be partly potentiated by the reduction in PGE2 synthesis. However, the normalization of GFR and RPF in view of only modest increases in PGE2 excretion after captopril (LP, 648 +/- 95 vs. LP + capt, 1,131 +/- 82 pg/mgCr; P less than 0.05) suggests that if PGE2 is involved in these changes, it plays a permissive but not essential role in the increased renovascular resistance.     

An investigation of the acute effect of gentamicin on the renal handling of electrolytes in the rat.

Standard renal clearance techniques were used to investigate the acute effects of gentamicin on renal electrolyte handling in anesthetized rats. Data were obtained before substantial changes in tubular integrity would be expected to occur, thus permitting a distinction between the actions of the drug per se and renal changes resulting from underlying tubular damage. Infusion of gentamicin over a 3-hr period resulted in an immediate and sustained calciuresis and magnesiuresis, with no significant change in the renal clearance of sodium or potassium. Within 60 min of the onset of drug infusion at 0.28 mg/kg/min, renal calcium clearance (ml/min) increased from 0.095 +/- 0.013 to 0.210 +/- 0.016 (P less than .001) and renal magnesium clearance (ml/min) increased from 0.538 +/- 0.059 to 0.662 +/- 0.053 (P less than .01). Because it was subsequently shown that infusion of gentamicin did not alter glomerular filtration rate, it is clear that both responses resulted from a reduced tubular reabsorption of the respective ions; they were rapidly reversible when gentamicin infusion ceased. A higher dose of gentamicin (0.56 mg/kg/min for 3 hr) also significantly decreased plasma magnesium concentrations (0.40 +/- 0.01 vs. 0.49 +/- 0.02 mmol/l, treated vs. control; P less than .01). Gentamicin-induced changes in the renal handling of calcium and magnesium, therefore, occur independently of and before the development of nephrotoxicity. They may be at least partially responsible for the alteration in electrolyte homeostasis seen in humans during aminoglycoside treatment (e.g., hypomagnesemia). It is interesting to speculate on the possibility that they may also in some way contribute to the subsequent cellular injury that is known to occur with prolonged use of gentamicin.     

Elevated remnant-like particle cholesterol and triglyceride levels in diabetic men and women in the Framingham Offspring Study

OBJECTIVE: Remnants of triglyceride-rich lipoproteins are thought to be atherogenic. A new antibody-based assay allows for the isolation of remnant-like particles (RLPs) from plasma or serum, and the subsequent measurement of RLP cholesterol (RLPC) and triglycerides (RLPTGs). We hypothesized that diabetic patients would have higher remnant levels than nondiabetic patients. DESIGN AND METHODS: We compared RLPC and RLPTG levels of diabetic subjects (68 women, 121 men) participating in the Framingham Heart Study with those of nondiabetic subjects (1,499 women, 1,357 men). RESULTS: Mean RLPC values for diabetic women were 106% higher than those for nondiabetic women (0.367 +/- 0.546 mmol/l [14.2 +/- 21.1 mg/dl] vs. 0.179 +/- 0.109 mmol/l [6.9 +/- 4.2 mg/dl]; P < 0.0001), and RLPTG values for diabetic women were 385% higher than those for nondiabetic women (1.089 +/- 2.775 mmol/l [93.1 +/- 245.6 mg/dl] vs. 0.217 +/- 0.235 mmol/l [19.2 +/- 20.8 mg/dl]; P < 0.0001). Similar but less striking differences were observed in diabetic men, who had mean RLPC values 28% higher than those seen in nondiabetic men (0.285 +/- 0.261 mmol/l [11.0 +/- 10.1 mg/dl] vs. 0.223 +/- 0.163 mmol/l [8.6 +/- 6.3 mg/dl]; P < 0.001) and mean RLPTG values 70% higher than those seen in nondiabetic men (0.606 +/- 1.019 mmol/l [53.6 +/- 90.2 mg/dl] vs. 0.357 +/- 0.546 mmol/l [31.6 +/- 48.3 mg/dl]; P < 0.001). Moreover, diabetic men and women had significantly higher total triglycerides and lower HDL cholesterol levels than nondiabetic subjects. CONCLUSIONS: The data indicate that RLP particles are elevated in diabetic subjects. To achieve optimal reduction of risk for cardiovascular disease, treatment of elevated RLP values, along with the control of LDL cholesterol levels, should be considered.     

A functional role for endogenous atrial natriuretic peptide in a canine model of early left ventricular dysfunction.

Asymptomatic or early left ventricular dysfunction in humans is characterized by increases in circulating atrial natriuretic peptide (ANP) without activation of the renin-angiotensin-aldosterone system (RAAS). We previously reported a canine model of early left ventricular dysfunction (ELVD) produced by rapid ventricular pacing and characterized by an identical neurohumoral profile and maintenance of the natriuretic response to volume expansion (VE). To test the hypothesis that elevated endogenous ANP suppresses the RAAS and maintains sodium excretion in ELVD, we assessed the effects of antagonism of ANP on cardiorenal and neurohumoral function in ELVD. Chronic ANP suppression was produced by bilateral atrial appendectomies before the production of ELVD by rapid ventricular pacing (ELVD-APPX, n = 5). This group was compared with a separate group with ELVD and intact atrial appendages (ELVD-INTACT, n = 8). ELVD-APPX was characterized by lower circulating ANP (50 +/- 11 vs. 158 +/- 37 pg/ml, P < 0.05), activation of plasma renin activity (PRA) (9.4 +/- 2.4 vs. 0.6 +/- 0.4 ng/ml per h, P < 0.05) and aldosterone (36.4 +/- 12.5 vs. 2.5 +/- 0.0 ng/dl, P < 0.05) when compared to ELVD-INTACT. In comparison to the ELVD-INTACT group, sodium excretion was decreased before and during VE in the ELVD-APPX group. Acute ANP antagonism was produced by administration of the particulate guanylate cyclase coupled natriuretic peptide receptor antagonist, HS-142-1, to seven conscious dogs with ELVD and intact atrial appendages (ELVD-INTACT). HS-142-1 decreased plasma concentrations and renal generation of the ANP second messenger, cGMP, and was associated with activation of PRA and sodium retention with enhanced tubular sodium reabsorption. These data support a significant role for elevated endogenous ANP in the maintenance of sodium excretion and regulation of the RAAS in experimental ELVD.     

Dietary intake of sodium chloride in the rat influences [3H]nitrendipine binding to adrenal glomerulosa cell membranes but does not alter binding to vascular smooth muscle membranes.

Angiotensin II-stimulated secretion by adrenal glomerulosa cells and contraction by vascular smooth muscle (VSM) are dependent on calcium influx through membrane calcium channels. We have examined the hypothesis that the altered responsiveness of adrenal glomerulosa cells and VSM to angiotensin II during NaCl restriction may be associated with a change in membrane calcium channel number. To test this hypothesis, female rats were placed on a high or low NaCl diet. On the 14th day, membranes were prepared from the zona glomerulosa, aorta, mesenteric artery, and uterus. [3H]Nitrendipine binding was used to monitor calcium channel number. The [3H]nitrendipine binding capacity was observed to be higher in the zona glomerulosa during NaCl restriction than during high NaCl intake (83 +/- 18 vs. 49 +/- 9 fmol/mg protein, P less than 0.025, n = 6 paired experiments). The binding capacities of [3H]nitrendipine on the low and high NaCl diet were similar in the mesenteric artery (10 +/- 1 vs. 9 +/- 1 fmol/mg protein, n = 8), aorta (33 +/- 5 vs. 35 +/- 8 fmol/mg protein, n = 5), or uterus (87 +/- 15 vs. 85 +/- 16 fmol/mg protein, n = 4), respectively. The dissociation constants of [3H]nitrendipine binding did not differ on a low or high NaCl intake in the zona glomerulosa (0.84 +/- .12 vs. 0.79 +/- .10 nM), mesenteric artery (0.82 +/- .06 vs. 83 +/- .05 nM), aorta (0.90 +/- .11 vs. 0.92 +/- .12 nM), or uterus (0.55 +/- .12 vs. 0.56 +/- .10 nM), respectively. We conclude that the blunted response of VSM to angiotensin II during NaCl restriction is best explained by the previously reported lower number of angiotensin II receptors since calcium channel number does not change. In the adrenal glomerulosa cell, NaCl restriction is associated with a higher number of membrane calcium channels and angiotensin II receptors. The increase in calcium channel number may reflect the influence of an unknown factor(s) believed to be necessary for the full expression of the adrenal glomerulosa cell response to NaCl restriction.