Differential effects of T- and L-type calcium antagonists on glomerular dynamics in spontaneously hypertensive rats.
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To determine whether there is a difference in the effects of T- and L-type calcium antagonists on systemic, renal, and glomerular hemodynamics, the pathological changes of N(G)-nitro-L-arginine methyl ester (L-NAME)-exacerbated nephrosclerosis and clinical alterations were investigated in spontaneously hypertensive rats (SHR). Seven groups of 17-week-old male SHRs were studied: Group 1, control; Group 2, mibefradil, 50 mg. kg(-1). d(-1); Group 3, L-NAME in drinking water, 50 mg/L; Group 4, L-NAME (50 mg/L) plus mibefradil (50 mg. kg(-1). d(-1)); Group 5, L-NAME (50 mg/L) plus amlodipine (10 mg. kg(-1). d(-1)); Group 6 and 7, L-NAME (50 mg/L) for 3 weeks followed by mibefradil (50 mg. kg(-1). d(-1)) or amlodipine (10 mg. kg(-1). d(-1)), respectively, for the subsequent 3 weeks. Both the T- and L-channel calcium antagonists similarly reduced mean arterial pressure and total peripheral resistance index. These changes were associated with significant decreases in afferent and efferent glomerular arteriolar resistances and the ultrafiltration coefficient (P<0.01). Furthermore, the histopathological glomerular and arterial injury scores and urinary protein excretion were also significantly improved (P<0.01), and left ventricular and aortic masses were significantly diminished in all treated groups. Both drugs, mibefradil and amlodipine, had effects of increasing the single-nephron glomerular filtration ratio (SNGFR), and single-nephron plasma flow (SNPF), and of reducing glomerular afferent arteriolar resistance and urinary protein excretion. Thus, the T-type (mibefradil) and L-type (amlodipine) calcium antagonists each prevented and reversed the pathophysiological alterations of L-NAME-exacerbated hypertensive nephrosclerosis in SHR. The T-type calcium antagonist (mibefradil) seemed to have been more effective than the L-type amlodipine antagonist and it produced a greater reduction in afferent arteriolar resistance while preserving SNGFR. (+info)
No participation of adenosine A1 receptor in acute nephrotoxicity by 4-pentenoic acid administration in dogs.
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Intrarenal infusion of 4-pentenoic acid is known to lower renal cortical ATP content and cause a reduction in glomerular filtration rate (GFR). The alteration in nucleotide metabolism might augment the production of adenosine, thereby eliciting the fall in GFR. This study was conducted to examine whether 4-pentenoic acid stimulates renal production of adenosine, and if so, to examine the role of adenosine A1 receptor in the reduction of GFR by 4-pentenoic acid. With infusion of 4-pentenoic acid (1 micromol x kg(-1) x min(-1)) into the renal artery of anesthetized dogs, GFR gradually decreased and reached minimum at 60 min with values ranging from 33.9+/-2.2 to 20.2+/-2.8 ml/min. Neither renal blood flow nor mean arterial pressure was affected, but tubular reabsorption of water and sodium was significantly attenuated. Renal venous plasma concentration and urinary excretion of adenosine rose markedly (20-fold) without any change in arterial concentration, suggesting that renal adenosine production was augmented by 4-pentenoic acid. However, KW-3902 (8-(noradamantan-3-yl)-1,3-dipropylxanthine), a selective antagonist of the adenosine A1 receptor, did not affect the action of 4-pentenoic acid on GFR or renal handling of water and sodium. It is concluded that 4-pentenoic acid markedly increases renal adenosine production, but adenosine A1 receptor is not involved in the 4-pentenoic acid-induced nephrotoxicity. (+info)
Rapid and accurate assessment of glomerular filtration rate in patients with renal transplants using serum cystatin C.
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BACKGROUND: Assessment of renal function in patients with renal transplants is of great importance. Various studies have reported cystatin C as an easily and rapidly assessable marker that can be used for accurate information on renal function impairment. To date, no study is available to define the role of cystatin C in patients with renal transplants. METHODS: Thirty steady-state patients (50% male/50% female) with status post-kidney transplantation were studied. To assess renal function, cystatin C, creatinine clearance, serum creatinine, beta2-microglobulin (beta2M), and [125I]iothalamate clearance were determined. Correlations and non-parametric ROC curves for accuracy, using a cut-off glomerular filtration rate (GFR) of 60 ml/min, were obtained for the different markers allowing for calculations of positive predictive values (PPV), positive likelihood ratios (PLR), specificity and sensitivity, respectively. Further, to evaluate the usefulness of these markers for monitoring, intraindividual coefficients of variation (CVs) for cystatin C and creatinine measurements were compared in 85 renal transplant patients. Measurements consisted of at least six pairs of results, which were obtained at different time points during routine follow-up. RESULTS: Cystatin C correlated best with GFR (r=0.83), whereas serum creatinine (r=0.67), creatinine clearance (r=0.57) and beta2M (r=0.58) all had lower correlation coefficients. The diagnostic accuracy of cystatin C was significantly better than serum creatinine (P=0.025), but did not differ significantly from creatinine clearance (P=0.76) and beta2M (P=0.43). At a cut-off of 1.64 mg/l, cystatin C has a PPV of 93%, PLR of 6.4, specificity 89% and sensitivity 70%, respectively. For beta2M, PPV 83%, PLR 1.7, specificity 67% and sensitivity 75% was seen at a cut-off of 3.57 mg/l. Accordingly, at a cut-off of 125 micromol/l for serum creatinine, a PPV 76%, PLR 1.4, specificity 44% and sensitivity 80% was revealed. Finally, at a cut-off of 66 ml/min/1.73 m2 for creatinine clearance, the following characteristics were found: PPV 94%, PLR 7.7, specificity 89% and sensitivity 85%. The intraindividual variation of creatinine was significantly lower than that of cystatin C (P<0.001). With increasing concentrations, their ratios of CV tended towards a value of 1, demonstrating identical variability at low GFR. CONCLUSION: Together, our data show that in patients with renal transplants, cystatin C, in terms of PPV and PLR, has a similar diagnostic value as creatinine clearance. However, it is superior to serum determinations of creatinine and beta2M. The intraindividual variation of cystatin C is greater than that of creatinine. This might be due to the better ability of cystatin C to reflect temporary changes especially in mildly impaired GFR, most critical for early detection of rejection and other function impairment. Thus, cystatin C allows for rapid and accurate assessment of renal function (GFR) in renal transplants and is clearly superior to the commonly used serum creatinine. (+info)
Dietary glycine and renal denervation prevents cyclosporin A-induced hydroxyl radical production in rat kidney.
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Cyclosporin A (CsA) nephrotoxicity is associated with renal hypoxia and increases in free radicals in the urine. This study was designed to elucidate the mechanism of radical production caused by CsA. Pretreatment of rats with CsA (25 mg/kg, i.g.) for 5 days decreased glomerular filtration rates by 65%, an effect largely prevented by both dietary glycine (5%) or renal denervation. CsA dissolved in olive oil produced a 6-line alpha-(4-pyridyl 1-oxide)-N-tert-butylnitrone (4-POBN)/free radical signal in the urine, which partitioned predominantly into the aqueous phase after chloroform extraction (i.e., it is water soluble). Dimethyl sulfoxide (DMSO) is attacked by the hydroxyl radical to produce a methyl radical; administration of CsA with [(12)C]DMSO produced two radical species in urine, one with hyperfine coupling constants similar to the 4-POBN/methyl radical adduct found in aqueous solution. CsA given with [(13)C]DMSO produced a 12-line spectrum, confirming the formation of hydroxyl radicals. The methyl radical produced by the hydroxyl radical represented 62% of radicals detected in urine but only 15% in bile. Therefore, hydroxyl radicals are produced largely in the kidney. Free radicals in urine were increased about 5-fold by CsA, an effect completely blocked by the inhibitory neurotransmitter, glycine, or by renal denervation. CsA infusion for 30 min increased efferent renal nerve activity 2-fold, and dietary glycine (5%) totally blocked this phenomenon. Taken together, these data are consistent with the hypothesis that CsA increases hydroxyl radical formation by increasing renal nerve activity resulting in vasoconstriction and hypoxia-reoxygenation. Glycine blunts the effect of CsA on the renal nerve, which explains, in part, prevention of nephrotoxicity. (+info)
Vasopressin contributes to hyperfiltration, albuminuria, and renal hypertrophy in diabetes mellitus: study in vasopressin-deficient Brattleboro rats.
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Diabetic nephropathy represents a major complication of diabetes mellitus (DM), and the origin of this complication is poorly understood. Vasopressin (VP), which is elevated in type I and type II DM, has been shown to increase glomerular filtration rate in normal rats and to contribute to progression of chronic renal failure in 5/6 nephrectomized rats. The present study was thus designed to evaluate whether VP contributes to the renal disorders of DM. Renal function was compared in Brattleboro rats with diabetes insipidus (DI) lacking VP and in normal Long-Evans (LE) rats, with or without streptozotocin-induced DM. Blood and urine were collected after 2 and 4 weeks of DM, and creatinine clearance, urinary glucose and albumin excretion, and kidney weight were measured. Plasma glucose increased 3-fold in DM rats of both strains, but glucose excretion was approximately 40% lower in DI-DM than in LE-DM, suggesting less intense metabolic disorders. Creatinine clearance increased significantly in LE-DM (P < 0.01) but failed to increase in DI-DM. Urinary albumin excretion more than doubled in LE-DM but rose by only 34% in DI-DM rats (P < 0.05). Kidney hypertrophy was also less intense in DI-DM than in LE-DM (P < 0.001). These results suggest that VP plays a critical role in diabetic hyperfiltration and albuminuria induced by DM. This hormone thus seems to be an additional risk factor for diabetic nephropathy and, thus, a potential target for prevention and/or therapeutic intervention. (+info)
Bone mineral density and biochemical markers of bone turnover in patients with predialysis chronic renal failure.
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BACKGROUND: Metabolic bone disease might commence early in the course of renal failure. This study therefore examined the frequency and severity of the skeletal changes in predialysis chronic renal failure by measurements of bone mineral density (BMD), biochemical markers of bone turnover (osteocalcin, bone-specific alkaline phosphatase, carboxy terminal propeptide of type I collagen, and carboxy-terminal telopeptide of type I collagen), parathyroid hormone (PTH), ionized calcium (Ca++), phosphate (P), and vitamin D metabolites. METHODS: The study was performed in 113 patients (male/female: 82/31) with chronic renal diseases [mean glomerular filtration rate (GFR) of 37 ml/min] and in 89 matched, normal control subjects. RESULTS: The patients had significantly (P<0.05) reduced BMD in the spine (-6.3%), the femur (-12.1%), the forearm (-5.7%), and the total body (-4.2%) as compared with the control subjects. Dividing the patients into quartiles according to GFR revealed that BMD decreased with the gradual decline in renal function at all the measured skeletal sites, but was most pronounced in the femur: 0.63+/-0.03, 0.74+/-0.02, 0.77+/-0.02, and 0.82+/-0.03 g/cm2 in each quartile from lowest to highest GFR compared with 0.82+/-0.02 g/cm2 in the control group (P<0.0001). All of the measured bone markers showed increasing plasma levels with the more advanced stages of renal failure. Serum PTH and serum P levels increased, whereas serum Ca++ and 1,25-dihydroxyvitamin D decreased. BMD Z-scores of the femur and of the forearm correlated to the biochemical markers and to PTH (P<0.05 to P<0.0001). The biochemical markers all showed strong correlations to PTH, also when corrected for the effect of the decline in GFR (r = 0.40 to 0.92, P<0.01 to P< 0.0001). CONCLUSION: Skeletal changes are initiated at an early stage of chronic renal failure, as estimated from reduced BMD and elevated levels of PTH and from the biochemical markers of both bone formation and bone resorption. (+info)
The effect of vasopressin upon the excretion of calcium by the sheep.
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Vasopressin (140 muU/min) was infused intravenously into 12 conscious merino ewes for 2 hr. Urine flow rate and free water clearance were consistently reduced. There was no effect upon renal plasma flow, glomerular filtration rate or the rate of excretion of sodium, potassium, magnesium, chloride or phosphate. Although all animals received 75 mmol calcium chloride into the rumen on the previous day, five commenced the experiment with calcium excretion rates of less than 1 mumol/min. In these, vasopressin further decreased calcium excretion. In seven animals with calcium excretion rates between 2 and 20 mumol/min vasopressin had no effect upon either total calcium or free ionized calcium excretion rate. (+info)
The effect of plasma potassium in determining normal rates of excretion of potassium in dogs.
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Doses of 5-15 mmol KCl or KHCO3 (less than the daily intake in food) given by stomach tube or intravenous infusion, produced increases in plasma K and in K excretion, the time delay between change in plasma K and rate of excretion being minimal. Without doses of K salts in control experiments, plasma K concentration was about 4 mmol/1 and K excretion about 5 mumol/min. After doses of KCl or KHCO3, plasma K and rate of excretion of K both increased, increase of 0-5 mmol/1 in plasma K being associated with an increase of about 35 mumo1/min in K excretion. Increased excretion of K was accompanied by a small increase in Na excretion. Excretion of both C1 and HCO3 increased, C1 more after HCO3 more after KHCO3. The results indicate that within normal ranges, plasma K is an important factor determining the rate of excretion of K. (+info)