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Biomedical subjects

W F Keane

Publications and source records attributed to W F Keane.

At least 127 records · Page 7Linked to original sources
PubMed1989

Fish oil diet decreases prostacyclin and increases resistance in isolated rat kidneys.

The mechanisms whereby diet-induced alterations in fatty acids may affect renal structure and function are unknown. Kidneys from rats fed chow supplemented with 18% (wt/wt) coconut oil (CO, n = 8), sunflower seed oil (SO, n = 7), or fish oil (FO, n = 8) were isolated from systemic influences of the diets and perfused with a cell-free medium. The FO diet caused a twofold reduction in prostaglandin (PG) I2 (urine excretion of 6-keto-PGF1 alpha) compared with SO and CO. Urine PGE2 and thromboxane (Tx) B2 were similar in the three diet groups. There was a 22% reduction in perfusate flow associated with the decrease in PGI2 in the FO group (42 +/- 6 ml.min-1.g-1) compared with the CO (54 +/- 7 ml.min-1.g-1) and SO (54 +/- 8 ml.min-1.g-1) groups (mean +/- SD, P less than 0.05). The glomerular filtration rate (GFR) was similar in the three groups during the initial base-line determination but subsequently declined to a greater degree in the FO group. Morphologically, tubular injury was most extensive in the FO group, and the distribution of the injury indicated that it was caused, at least in part, by ischemia. The decline in GFR and the degree of histological injury were more closely linked to the diminished PGI2 production. Thus dietary FO supplementation caused decreased renal PGI2, increased renal vascular resistance, and an increased susceptibility to ischemic tubular cell injury in the isolated kidney.

Animals↗
PubMed1989

Therapeutic implications of lipid-lowering agents in the progression of renal disease.

Progressive deterioration in renal function frequently occurs in the absence of the original cause of injury. During the past decade, intense investigations into the factors responsible for progressive nephron destruction have demonstrated that hemodynamic stresses and metabolic and coagulation abnormalities participate in glomerular injury. Hyperlipidemia is a common abnormality in renal disease and is frequently aggravated by protein-uria. Experimentally, therapy with the lipid-lowering agents clofibric acid or lovastatin reduced circulating lipids, particularly cholesterol, decreased proteinuria, and prevented glomerular damage in normotensive and hypertensive models of progressive renal disease. These beneficial effects occurred independently of changes in systemic blood pressure or glomerular injury, supporting the notion that cholesterol or its accompanying changes, or both, were central in lipid modulation of glomerulosclerosis. Clinically, lipid abnormalities are common in patients with renal disease, and atherosclerotic cardiovascular disease is the most frequent cause of death in these patients. Although the role of lipids in atherosclerotic disease has been well established, whether a similar effect of lipids occurs in the microvasculature of the kidney is unknown. Whether therapeutic approaches directed at reducing hyperlipidemia in patients with renal disease will provide a measure of renal protection, as has been seen in experimental models of renal disease, is also unknown.

Animals↗
PubMed1988

Modulatory effects of beta-endorphin on interferon-gamma production by cultured peripheral blood mononuclear cells: heterogeneity among donors and the influence of culture medium.

The stress-responsive neuropeptide beta-endorphin (beta-END) has been shown to either enhance or suppress interferon-gamma (IFN-gamma) production by mitogen stimulated peripheral blood mononuclear cells (PBMNC) in vitro. In this study, we investigated whether donor selection and the medium used for cell culture influenced the modulatory effect of beta-END on the IFN-gamma production by PBMNC. Considerable variation of the effect of beta-END on IFN-gamma production was observed in individuals who underwent multiple testing. Suppression of IFN-gamma was significantly greater in 16 male donors (29 +/- 6.0%) compared to 8 female donors (1.5 +/- 6.4%) when PBMNC were preincubated for 3 h with beta-END followed by concanavalin A stimulation for 72 h in medium containing 20% fetal bovine serum (FBS). Lowering the concentration of FBS resulted in enhanced production of IFN-gamma by PBMNC exposed to beta-END. Arachidonic acid or beta-END added separately to medium containing 3% autologous serum produced no suppression of IFN-gamma, but when added together resulted in significant suppression. This observation provides support for the hypothesis that beta-END achieves its suppressive effect on IFN-gamma via a mechanism involving arachidonic acid metabolism. We conclude that the modulatory effect of beta-END on IFN-gamma production by PBMNC is both donor and medium dependent.

Adult↗
PubMed1988

Treatment of hyperlipidemia reduces glomerular injury in obese Zucker rats.

Hyperlipidemic obese Zucker rats develop albuminuria and spontaneous focal glomerulosclerosis (FGS) at an early age, despite normal glomerular capillary pressures and nephron plasma flows. To investigate the role of abnormal lipid metabolism in the pathogenesis of FGS, pharmacologic agents were used to reduce serum lipids in male, obese Zucker rats. Eight rats were treated from 8 to 40 weeks of age with the cholesterol synthesis inhibitor, mevinolin (group I). A separate group of seven obese rats was treated with the structurally-unrelated lipid lowering agent, clofibric acid (group II). Results from these two groups were compared to controls injected with vehicle only (group III). Body weight and food intake were similar in all three groups. Mevinolin reduced both serum cholesterol and fasting triglyceride levels while clofibric acid lowered only serum cholesterol. Urine albumin excretion was reduced in groups I and II compared to group III. Mesangial matrix expansion and cellularity were both reduced by mevinolin and clofibric acid. In addition, the percent of glomeruli with focal glomerulosclerosis was much less in groups I (0.4 +/- 0.1%) and II (1.3 +/- 0.7%) compared to group III (4.6 +/- 0.7%, P less than 0.05). Micropuncture studies, carried out in separate groups of obese rats, demonstrated that mevinolin and clofibric acid did not affect glomerular hemodynamic function. Although the precise mechanism remains to be defined, these results suggest that abnormal lipid metabolism may be important in the pathogenesis of FGS.

Albuminuria↗
PubMed1988

Hyperlipidemia and the progression of renal disease.

Focal glomerulosclerosis (FGS) is commonly seen in human and in experimental models of chronic renal disease. Although considerable experimental data suggest that hypertension is important in progressive nephron damage, recent studies also have indicated that abnormal lipid metabolism may be an independent risk factor in the pathogenesis of FGS. Indeed, the synergistic impact of hypertension and hyperlipidemia in the pathogenesis of FGS may be analogous to the role of these factors in the pathogenesis of atherosclerosis. This review focuses on some of the recent and pertinent data that support a role of lipid-mediated glomerular injury in the pathogenesis of progressive renal disease.

Animals↗
PubMed1988

Correlation of office and ambulatory blood pressure measurements with urinary albumin and N-acetyl-beta-D-glucosaminidase excretions in essential hypertension.

Ambulatory blood pressure (ABP) correlates better than office blood pressure with hypertensive changes in the heart and vasculature. Using the 24-hour urinary excretions of albumin and N-acetyl-beta-D-glucosaminidase (NAG) as markers, we examined the relationship between office and ABP and target-organ changes in the kidney in 42 untreated patients with essential hypertension. Mean urinary albumin excretion was 23.2 +/- 34.3 mg/day and mean urinary NAG excretion was 45.1 +/- 22.9 nmol/hr/mg creatinine. Urinary albumin excretion was positively correlated with both office and mean 24-hour systolic blood pressure (r = 0.31, P less than 0.05; and r = 0.44, P less than 0.01, respectively). Urinary NAG excretion was positively correlated with 24-hour ambulatory systolic, diastolic, and mean blood pressure (r = 0.32, P less than 0.05; r = 0.32, P less than 0.05; and r = 0.39, P less than 0.05, respectively), but not with office blood pressure. Thus, urinary albumin and NAG excretions are positively correlated with blood pressure and may be useful markers of renal involvement in patients with essential hypertension. Additionally, ABP may be more reliable than office blood pressure in identifying those patients at risk for hypertensive target-organ changes in the kidney.

Acetylglucosaminidase↗
PubMed1988

Glomerular hemodynamic and structural alterations in experimental diabetes mellitus.

Elevated glomerular filtration rate (GFR) is a frequent finding in patients with early insulin-dependent diabetes mellitus (IDDM). The mechanisms responsible for this glomerular hyperfiltration in IDDM are unclear. Rats made diabetic with alloxan or streptozotocin, and treated daily with supplemental insulin, have moderate hyperglycemia and elevated GFR, and thus have been used to study mechanisms of glomerular hyperfiltration in diabetes. Renal micropuncture techniques have shown that single-nephron GFR (SNGFR) is elevated in moderately hyperglycemic diabetic rats. In some cases, this is because of elevated glomerular capillary pressure (Pgc), but in other cases, Pgc is normal despite elevated SNGFR. Several potential mediators of increased SNGFR have been examined, including hyperglycemia, increased glomerular prostaglandin production, and decreased sensitivity of the tubuloglomerular feedback mechanism. Renal failure is a common complication of human IDDM. Diabetic rats with long-term moderate hyperglycemia have been used to study the mechanism by which glomerular injury develops in diabetes mellitus. It has been postulated that glomerular hyperfiltration or some determinant of elevated GFR in early diabetes may ultimately cause glomerular damage, leading to a progressive loss of renal function (diabetic nephropathy). Diabetic rats with long-term moderate hyperglycemia, however, do not develop characteristic glomerular lesions of human diabetic nephropathy and, in fact, develop only minimal glomerular injury even after 1 year of diabetes. Thus, although the diabetic rat with moderate hyperglycemia may be useful to study the mechanisms of glomerular hyperfiltration in early diabetes, it may not be an appropriate model of renal failure in IDDM.

Animals↗
PubMed1988

Suprofen-induced uricosuria. A potential mechanism for acute nephropathy and flank pain.

Suprofen, a nonsteroidal anti-inflammatory drug, has been associated with the onset of acute flank pain, hematuria, and transient renal dysfunction after the ingestion of one or two doses, particularly in young males. Potential mechanisms of this nephropathy were evaluated in normal males following ingestion of suprofen (200 mg) on two occasions: the first with ad libitum fluid intake and the second during forced water diuresis. On the first study occasion, creatinine clearance, the fractional excretions of uric acid (FEUA) and sodium (FENa), the urinary concentration of undissociated uric acid, and the urinary excretions of prostaglandins and glomerular and tubular proteins were assessed. On the second occasion, inulin and PAH clearances and FEUA and FENa were determined. Within 90 min after suprofen administration, the FEUA increased from 8.8 +/- 2.6 to 35.5 +/- 9.6% (p less than 0.05). Urine became supersaturated for uric acid during ad libitum fluid intake. Glomerular filtration rate, renal plasma flow, and FENa decreased significantly, while prostaglandin and protein excretions did not change. The findings are consistent with acute uric acid nephropathy as a mechanism of suprofen-induced renal dysfunction.

Acute Disease↗
PubMed1988

Pharmacologic treatment of hyperlipidemia reduces glomerular injury in rat 5/6 nephrectomy model of chronic renal failure.

The role of lipid abnormalities in the pathogenesis of focal glomerulosclerosis was investigated in the rat remnant kidney model of chronic renal failure. Rats subjected to right nephrectomy and two-thirds segmental infarction of the left kidney (5/6 nephrectomy) were treated for 10 weeks with the lipid-lowering agent clofibric acid. Both serum cholesterol and urine albumin excretion were significantly reduced by clofibric acid. At 10 weeks, the percent of glomeruli with focal glomerulosclerosis was 5 +/- 2% in clofibric acid-treated and 24 +/- 5% in untreated 5/6 nephrectomy rats (p less than 0.01). Inulin clearance was greater in clofibric acid-treated than in untreated 5/6 nephrectomy rats (0.28 +/- 0.02 versus 0.22 +/- 0.02 ml/min 100 g body wt, p less than 0.05). Body weight, kidney weight, and systemic blood pressure were not significantly altered by clofibric acid. Micropuncture studies, performed in separate groups of clofibric acid-treated and untreated 5/6 nephrectomy rats, demonstrated elevated single nephron glomerular filtration rates and glomerular capillary pressures 4 weeks after surgery. However, clofibric acid did not significantly alter single nephron glomerular filtration rates (95 +/- 2.1 nl/min in treated versus 97.0 +/- 6.2 nl/min in untreated, p greater than 0.05) or glomerular capillary pressures (56.6 +/- 1.5 mm Hg in treated versus 57.8 +/- 0.8 mm Hg in untreated, p greater than 0.05) in 5/6 nephrectomy rats. In a separate set of experiments, 5/6 nephrectomy rats were treated with the specific cholesterol synthesis inhibitor, mevinolin. Mevinolin improved serum lipid levels and reduced albuminuria in 5/6 nephrectomy rats without causing significant alterations in blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Efficacy and renal effects of enalapril therapy for hypertensive patients with chronic renal insufficiency.

The antihypertensive efficacy and renal effects of enalapril maleate therapy were evaluated in 13 hypertensive patients with chronic renal failure. Enalapril was administered as follows: alone; added to furosemide, clonidine hydrochloride, or atenolol; or in combination with any of the aforementioned drugs. Three patients did not complete the study; uncontrolled hypertension was the cause in two of these patients. In the remaining ten patients, short-term (mean +/- SD, 63 +/- 9 days) enalapril maleate therapy decreased the patient's seated blood pressure from 161/98 +/- 19/8 to 130/80 +/- 13/7 mm Hg. Furosemide was administered to eight patients; the dose of concomitant sympatholytic therapy was decreased in five of five patients. Serum potassium concentration increased from 4.1 +/- 0.3 to 4.5 +/- 0.3 mmol/L. Levels of urinary total protein excretion decreased from 2.23 +/- 2.05 to 1.08 +/- 1.45 g/d. Renal function (creatinine clearance, 0.58 +/- 0.21 mL/s) did not change from baseline. During long-term therapy, the rate of progression of renal insufficiency seemed to slacken in three of four patients with diabetic nephropathy. Thus enalapril can reduce blood pressure and proteinuria in hypertensive patients with chronic renal insufficiency. The possibility that enalapril can slow the progression of diabetic nephropathy remains to be confirmed by future studies.

Adult↗
PubMed1987

Opioid-mediated suppression of cultured peripheral blood mononuclear cell respiratory burst activity.

Opiate addiction and stress have been associated with altered immune responses. In this study, we evaluated the influence of morphine and the stress responsive opioid peptide beta-endorphin (beta-END) on O-2 and H2O2 production by cultured human peripheral blood mononuclear cells. Exposure of these cells during 48 hr of culture to morphine and beta-END at pharmacologically (10(-8) M) and physiologically (10(-12) M) relevant concentrations, respectively, markedly suppressed peripheral blood mononuclear cell O-2 and H2O2 release in response to the respiratory burst stimuli opsonized zymosan and phorbol myristate acetate. Both opioids also induced a minimal, but statistically significant, increase in resting O-2 and H2O2 generation. The modulatory effects of morphine and beta-END on peripheral blood mononuclear cell oxygen metabolism appeared to involve a classical opioid receptor, because opioid activity was blocked by naloxone and was not observed with N-acetylated-beta-END. Using purified lymphocyte and monocyte preparations, we determined that although opioids directly increase monocyte-resting oxygen metabolism, lymphocytes are the primary target cell in opioid-mediated suppression of monocyte respiratory burst activity. The release of a suppressive product from opioid-triggered lymphocytes was inhibited by cyclosporine. Based on the results of this study, we propose that opioid-mediated suppression of mononuclear phagocyte respiratory burst activity is another factor to be considered in the immunodeficiency of opiate addiction and stress.

Adult↗
PubMed1987

Disposition of famotidine in renal insufficiency.

The disposition of famotidine was evaluated in 18 patients; Group 1, mild renal insufficiency, [creatinine clearance (CLCR): 30-60 mL/min]; Group 2, moderate to severe renal insufficiency (CLCR: 10-30 mL/min); Group 3, end-stage renal disease requiring maintenance hemodialysis (anuric). Blood and urine samples were obtained over a 72-hour period. Plasma concentration-time data demonstrated biexponential decay. The terminal elimination half-life was prolonged in Group 3 (18.6 +/- 5.7 hr) compared with Groups 1 (9.3 +/- 2.3 hr) and 2 (9.7 +/- 1.7 hr), P less than .05. Steady-state volume of distribution ranged from 0.80 to 1.26 L/kg but did not differ among the groups. Total body clearance (CLp) and renal clearance were significantly lower in Groups 2 and 3 patients compared with Group 1 patients. Nonrenal clearance was not related to CLCR. The CLp correlated well with CLCR (CLp = 1.59 CLCR + 33.8, r = 0.830, P less than .05). These data indicate that dosage adjustment may be necessary in patients who have renal insufficiency.

Adult↗
PubMed1987

The role of lipids in progressive glomerular disease.

The role of lipids in the pathogenesis of focal glomerulosclerosis (FGS) was evaluated using two chemically different lipid lowering agents, clofibric acid and mevinolin. Pharmacologically, these two agents have different mechanisms of action. Clofibric acid affects both cholesterol and triglyceride metabolism, while mevinolin inhibits 3-hydroxy-3 methyl-glutaryl coenzyme A reductase, the rate limiting enzyme in cellular cholesterol synthesis. In two different models of FGS in which hyperlipidemia occurs, the obese Zucker rat and the 5/6 nephrectomy model, both agents significantly reduced FGS and albuminuria. Since glomerular hemodynamic function is normal in obese Zucker rats, these results suggested that lipids are an independent factor in the pathogenesis of FGS. Moreover, in the 5/6 nephrectomy model, the beneficial effects on glomerular structure of reducing serum lipids occurred despite persistent systemic and glomerular hypertension. Thus, we postulated that a synergistic interaction between lipids and hypertension might exist in the pathogenesis of FGS.

Animals↗
PubMed1987

Effect of long-term clofibric acid treatment on serum and tissue lipid and cholesterol levels in obese Zucker rats.

The long-term effects of clofibric acid (200 mg/kg body weight) injected subcutaneously from 6-36 weeks of age were assessed in obese, hyperlipemic Zucker rats. At 18 and 36 weeks of age, treated rats had significantly lower fasted serum cholesterol levels but triacylglycerol levels were not affected. Rats were killed at 36 weeks of age at which time there were no differences in body and kidney weights between control and clofibric acid-treated rats. Liver, spleen and heart weights were lowered by clofibric acid treatment. In liver there was an elevation of lipid/g due to treatment but there were no effects on cholesterol/g or on either total liver lipid or cholesterol levels. In the epididymal fat pad of clofibric acid-treated rats, there was a 21% elevation of cholesterol level on a per pad basis. In the other organs, there were no effects of treatment on lipid or cholesterol levels except for lowered total cholesterol in kidney. Several liver lipogenic enzymes were lowered by treatment but malic enzyme was two times higher.

Adipose Tissue↗
PubMed1987

Influence of gender on the disposition of cefotaxime and desacetylcefotaxime.

The pharmacokinetics of cefotaxime and desacetylcefotaxime were evaluated in 11 female and 13 male subjects with end-stage renal disease. Subjects received single 1- or 2-g intravenous doses of cefotaxime sodium. Serum, urine, and dialysate concentrations of cefotaxime and desacetylcefotaxime were determined using high performance liquid chromatography. The results indicate that gender has no clinically significant influence on the disposition of cefotaxime or its active metabolite desacetylcefotaxime.

Cefotaxime↗
PubMed1987

The effect of famotidine on renal function in patients with renal insufficiency.

The effect of famotidine, a new histamine H2-receptor antagonist, on renal tubular creatinine secretion was evaluated in twelve patients with reduced renal function (creatinine clearance 10-60 ml min-1). Creatinine and inulin clearances were determined at baseline and for 4 h after a 10 mg intravenous dose of famotidine. Famotidine renal clearance exceeded inulin clearance by an average of 152%, indicating that renal tubular secretion of famotidine occurred. No significant changes in the clearances of creatinine or inulin, or the fractional clearance of creatinine were observed after famotidine administration. These data suggest that famotidine, unlike cimetidine, does not inhibit renal tubular secretion of creatinine. Thus, famotidine does not affect creatinine-dependent measurements of renal function and is unlikely to alter the renal elimination of basic drugs.

Adult↗