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Biomedical subjects

M E Brier

Publications and source records attributed to M E Brier.

At least 37 records · Page 2Linked to original sources
PubMed1995

Pharmacodynamics of atrial natriuretic peptide in isolated perfused Dahl rat kidneys.

Atrial natriuretic peptide (ANP) has been implicated in the development of hypertension in Dahl R and S rats. To test the responses of DR and DS kidneys in the absence of the influence of neural and humoral mechanisms, we investigated the pharmacokinetics and pharmacodynamics of ANP in isolated perfused DR and DS kidneys, obtained from rats given a high or low sodium diet, after a bolus injection of ANP (1 microgram) or after a bolus injection plus infusion of ANP to maintain the perfusate concentration at 1000 pg/ml. The elimination rate constant was not different between the groups (DR, 0.044 min-1 vs. DS, 0.050 min-1). Clearance of ANP was 4 times greater than the glomerular filtration rate, indicating that a receptor-mediated peritubular clearance is probably the primary route of elimination. DS kidneys excreted 50% less sodium than DR kidneys. However, ANP caused a 5-fold increase in fractional sodium excretion in both DR and DS. ANP also increased sodium excretion, creatinine clearance, and urine flow. No alteration in ANP kinetics occurred to account for the reportedly increased circulating concentrations of ANP seen in DS rats. We conclude that isolated DR and DS kidneys respond differently to ANP after bolus ANP administration to concentrations of 10,000 pg/ml. This difference in response is due to the sodium excretory defect inherent in the DS kidney and not to an alteration in the DS kidney's ANP responsiveness.

Animals↗
PubMed1994

Platelet calcium transport in hypertension.

To determine platelet Ca2+ transport entities involved in increased cytosolic Ca2+ in the platelets of hypertensive individuals, we studied the relations between blood pressure and Ca2+ transporters in platelet membranes from 22 white male volunteers 32 to 68 years old. We used thapsigargin, a specific inhibitor of the internal membrane Ca(2+)-ATPase, to differentiate between plasma membrane and internal membrane Ca(2+)-ATPases. Inositol 1,4,5-trisphosphate-mediated and Ca2+ ionophore (A23187)-induced Ca2+ release was also assayed in membrane preparations using rhod-2, a fluorescent Ca2+ indicator. Levels of glycoprotein IIIa, a possible component of agonist-mediated Ca2+ influx, were measured by immunoblotting. The results show that plasma membrane Ca(2+)-ATPase is decreased as a function of diastolic blood pressure (P < .002), whereas the internal membrane Ca(2+)-ATPase is not (P < .148). Neither activity is correlated with age or systolic blood pressure. However, inositol trisphosphate-mediated Ca2+ release is negatively correlated with age (P < .024) but not blood pressure. Glycoprotein IIIa levels and A23187-induced Ca2+ release were not related to age or blood pressure, demonstrating that inhibition of the plasma membrane Ca(2+)-ATPase was not a result of differences in the proportion of plasma membrane in the preparation or differences in intravesicular Ca2+ concentration. Inhibition of the plasma membrane Ca(2+)-ATPase could directly cause elevation of cytoplasmic Ca2+ and enhancement of platelet sensitivity.

Adult↗
PubMed1994

Initial intraperitoneal therapy for CAPD peritonitis: the Network 9 Peritonitis Study.

The choice of initial antibiotic therapy for continuous ambulatory peritoneal dialysis (CAPD) peritonitis is complex. To test the hypothesis that the initial choice of intraperitoneal antibiotics does not influence the outcome of therapy for CAPD peritonitis, we studied 1930 patients on peritoneal dialysis as of 1 January 1991, and recorded all episodes of peritonitis for one year. There were 1168 episodes of peritonitis for which 64% of the patients received intraperitoneal antibiotics as the first course of treatment. We determined peritonitis resolution, technique failure, hospitalization, and catheter removal rates as measures of successful treatment for peritonitis. Cephalothin, cefazolin, vancomycin, and ceftazidime were used alone or in combination with the aminoglycosides, tobramycin and gentamicin. The mean resolution rate was 65% following the first course of antibiotics and 76% by the third course of antibiotics, if necessary. The antibiotic regimens were not different with respect to resolution rate except when aminoglycosides were used alone. Technique failure was also greater in patients treated with aminoglycosides without other antibiotics. Hospitalizations were increased in patients treated with single drug therapy. If initial intraperitoneal therapy includes treatment for both gram-positive and gram-negative bacteria, the initial choice of intraperitoneal antibiotics does not influence the outcome of therapy for CAPD peritonitis.

Anti-Bacterial Agents↗
PubMed1994

Culture-negative CAPD peritonitis: the Network 9 Study.

A portion of peritonitis episodes are reported as culture-negative or as initial no growth peritonitis (INGP). To determine if demographics, symptoms, signs, treatment, and outcome were different in INGP when compared to culture-positive peritonitis (Pos), we examined data from the Network 9 Peritonitis and Catheter Survival Study. Only peritonitis episodes occurring in adults with peritoneal dialysis (PD) fluid WBC counts greater than 100 were included in the analysis. INGP accounted for 14% of the episodes of peritonitis. Organisms grew out of 13 of the 37 patients in INGP that were recultured: 3 fungal, 5 gram-negative, and 5 gram-positive isolates. A difference in culture methodology for the two groups could not be detected. There was no difference in gender, race, incidence of diabetes, previous peritonitis, or exit-site infections between the two groups. INGP had a greater percentage of patients over age 70 (23.3% vs 14.7%, p < 0.05), and a larger percentage of INGP patients placed additives in their dialysate (55% vs 43.6%, p < 0.05). There was no difference in symptoms or signs between the two groups. The INGP group had half the catheter removal rate (9/103 vs 110/630 for Pos, p < 0.05), otherwise, there was no difference in the rate of hospitalization, death, or switch to hemodialysis. There was no difference in types of drugs used or method of drug administration between the two groups. A lower percentage of INGP patients were treated for 6 days or less and a higher percentage received 7-10 days of intraperitoneal (IP) therapy when compared to Pos.(ABSTRACT TRUNCATED AT 250 WORDS)

Bacteria↗
PubMed1994

Sodium kinetics in white and black normotensive subjects: possible relevance to salt-sensitive hypertension.

The hypothesis that sodium (Na) kinetics are not a first order process was tested. Twelve normotensive white and 12 normotensive black men were given 10, 200, and 400 mmol/d Na as the chloride salt for 7 days in random order. All urine made was collected. No effect of Na intake on blood pressure was identified in either whites or blacks. The half-life (T1/2) with decreasing Na intake to 10 mmol/d was 1.08 days in whites and 1.65 days in blacks (p = not significant [NS]). With increasing Na intake, T1/2 increased in both whites and blacks; at the 400 mmol/d intake, the T1/2 for whites was 2.88 days and for blacks was 5.81 days (p < 0.05). At that intake, whites accumulated 385 +/- 153 mmol compared with 909 +/- 153 mmol for blacks (p < 0.05). The data showed that T1/2 increases with increasing Na intake and is, therefore, dose-dependent or "zero" order. The effect of dose is more prominent in blacks than in whites; blacks accumulate more Na with increasing Na intake than whites. These data may have relevance for the pathogenesis of salt-sensitive hypertension in blacks.

Adult↗
PubMed1993

Erythropoietin-induced antinatriuresis mediated by angiotensin II in perfused kidneys.

Erythropoietin (EPO)-induced hypertension is a common complication of EPO usage. The hypothesis that erythropoietin is antinatriuretic and that the sodium retention is mediated by intrarenal angiotensin II production was tested. Experiments were performed in Wistar rat kidneys perfused for 60 min in an isolated system. A dose-response curve was performed for EPO at 0, 10, 100, 1,000, and 10,000 mU/mL. EPO administration resulted in a dose-dependent decrease in sodium excretion to a maximum of 50% at the 1,000 mU/mL dose. In a second experiment, kidneys from five groups were perfused: controls, EPO (100 mU/mL), captopril (50 ng/mL), captopril (50 ng/mL) plus EPO (100 mU/mL), and the angiotensin receptor antagonist losartan (1 nM) plus EPO (100 mU/mL). The administration of EPO resulted in an immediate decrease in average sodium excretion (30%) with no change in GFR or other renal function parameters. Pretreatment with captopril or losartan blocked the effect of EPO. Captopril alone had no effect on renal function. A final experiment demonstrated the ability of losartan (10 nM) to block the pressor effects of angiotensin II (0.01, 0.1, and 1 nM). It was concluded that EPO acts within the kidney to cause the production of angiotensin II, which mediates the increased reabsorption of sodium.

Angiotensin II↗
PubMed1993

Racial differences in the practice of peritoneal dialysis in Network 9.

In a 1991 prospective evaluation of infections and catheters in Network 9 (Indiana, Kentucky, Ohio), detailed demographic questionnaires on 1930 patients were examined, with special attention to practice management and comparisons between black and white patients. In Network 9, 18.2% of peritoneal dialysis (PD) patients were black compared to 22.6% in the USRDS, and 3.7% of PD patients were black and more than 65 years of age, compared to 3.7% in the USRDS. Statistically significant associations were found in the Network 9 data base. Blacks were less likely than whites to be under 16 years or over 65 years of age, to add insulin to bag, to have nasal cultures performed, to have received previous immunosuppression, to wear exit-site dressings, and to do their own tubing changes. Blacks are more likely than whites to be independent (not age-related), ambulatory (not age-related), to have had previous peritonitis, surgical catheter placement, and to do their own exchanges. There were no differences regarding the number of training days and the use of disconnect or other exchange systems or cyclers.

Adult↗
PubMed1993

Infrequent dosing of subcutaneous erythropoietin for the treatment of anemia in patients on CAPD.

Erythropoietin (EPO) given subcutaneously (SC) once per week has been successful in the treatment of anemia in continuous ambulatory peritoneal dialysis (CAPD) patients. We have identified a population of CAPD patients that requires EPO administration once per week or less often. To determine if specific variables could be identified that would predict which CAPD patients would require infrequent EPO dosing, we reviewed the charts of all our CAPD patients who were receiving EPO as of 1 June 1992. Patients had to have been on CAPD for 3 months and EPO for 3 months to be considered for analysis. We identified 12 patients who required EPO once per week or less frequently (infrequent EPO) and 9 patients who required EPO more than once per week (frequent EPO). Parameters that were analyzed included age, gender, race, time on CAPD, history of gastrointestinal bleeding, exit-site infection or peritonitis in the last 60 days, diabetes, amount of dialysate instilled per day, and the number of exchanges per day. Laboratory data that were analyzed included hemoglobin, hematocrit, serum iron, total iron-binding capacity, ferritin, blood urea nitrogen (BUN), creatinine, BUN/creatinine ratio, albumin, total protein, parathyroid hormone, and aluminum. Categorical data were analyzed via chi-square, and numerical data were analyzed via the t-test. The infrequent EPO group required only 35% as much EPO as the frequent group to maintain hemoglobin and hematocrit, which were significantly greater. The only parameter that was different between the two groups was age (infrequent EPO 42 +/- 13.2 vs frequent EPO 55.8 +/- 11.9 years, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Quantitative and qualitative differences in guanine nucleotide binding protein activation by formyl peptide and leukotriene B4 receptors.

Formyl peptides and leukotriene B4 (LTB4) stimulate disparate neutrophil functional responses and second messenger generation. The hypothesis that differences in receptor-guanine nucleotide-binding proteins (G protein) interaction account for the disparate responses was examined using HL-60 granulocyte plasma membranes. The quantity of receptor-coupled G proteins was determined by guanosine 5'-(gamma-thio)triphosphate (GTP gamma S) equilibrium binding in the presence or absence of f-Met-Leu-Phe and/or LTB4. About one-third of the total GTP gamma S binding sites were coupled to f-Met-Leu-Phe receptors, to LTB4 receptors, and to receptors when both ligands were added simultaneously. The dissociation constant of GTP gamma S-binding sites in the presence of LTB4 was significantly greater than that in the presence of f-Met-Leu-Phe. f-Met-Leu-Phe shifted the GDP dose-inhibition curve for GTP gamma S binding further to the right than did LTB4. The apparent initial rate of GTP hydrolysis and GTP gamma S binding stimulated by f-Met-Leu-Phe was significantly greater than that stimulated by LTB4. There were significantly more formyl peptide receptors than LTB4 receptors, however, formyl peptide and LTB4 receptor density did not differ under GTP gamma S binding assay conditions. The rate of GTP hydrolysis stimulated by LTB4 was not increased in membranes containing twice the LTB4 receptor density. We conclude that formyl peptide receptors stimulate more rapid activation of a common pool of G proteins than LTB4 receptors because of a significantly reduced affinity of formyl peptide receptor-activated G proteins for GDP.

Cell Line↗
PubMed1992

Sodium kinetics in salt-sensitive and salt-resistant normotensive and hypertensive subjects.

OBJECTIVE: To test the hypotheses that sodium kinetics are not affected by blood pressure, salt sensitivity, salt resistance or race, and that the kinetics of sodium balance are not a first-order process. DESIGN, PARTICIPANTS AND INTERVENTIONS: Two studies were conducted. In the first, 18 normotensive and 36 hypertensive men and women were given sodium at 120 mmol/day for 6 days, followed by 10 mmol/day for 8 days, then 400 mmol/day for 8 more days. Salt sensitivity was defined as an increase in diastolic blood pressure from the 10 to the 400 mmol/day intake. Salt resistance was defined as no increase, or a decrease in diastolic blood pressure with the increased sodium intake. In the second study, 12 white and 12 black normotensive men ingested sodium at 10, 200 or 400 mmol/day in random order, each for 7 days. All urine was collected in both protocols. SETTING: Metabolic ward at the University of Greifswald (Greifswald, Germany; study 1), and Clinical Research Center (Indiana University, Indianapolis, Indiana, USA; study 2). MAIN OUTCOME MEASURE: In addition to conventional statistics, a pharmacokinetic analysis was carried out to determine the elimination rate constant and half-life. RESULTS: In the Greifswald study, when the sodium intake was decreased, a longer half-life was determined for the salt-sensitive than the salt-resistant hypertensive subjects. The half-life for the normotensive salt-sensitive and salt-resistant subjects did not differ. When the sodium intake was decreased, a monoexponential equation fitted the data for all subjects; when the sodium intake was increased, only data for half the subjects could be fitted to the same equation. In the Indianapolis study, black race had a significant influence upon urinary sodium excretion. Furthermore, the half-life for sodium elimination was dependent upon sodium intake; namely, the greater the intake, the longer the elimination half-life. CONCLUSIONS: The time required to reach sodium balance may increase following salt-sensitive increases in blood pressure rather than precede them. Race influences the time required to achieve salt balance. Sodium kinetics are not a first-order process.

Adult↗
PubMed1991

Multicenter evaluation of a new fixed-wire coronary angioplasty catheter system: clinical and angiographic characteristics and results.

Coronary angioplasty is increasingly used as an attempt to revascularize patients with severe coronary artery disease. To determine the efficacy of such treatment, a new fixed wire angioplasty catheter was evaluated by a multicenter group in a non-randomized fashion in 50 patients, average 58 +/- 11 years (+/- 1 SD), 58% men. Forty-four percent had a prior revascularization procedure (28% angioplasty, 16% coronary bypass surgery), 38% had a prior Q-wave myocardial infarction, 43% had grade 4 angina, and 60% multiple vessel disease. Angioplasty was attempted in 63 lesions which were located in a mid to distal location in 69%, with a proximal tortuosity score of 1.8 (2 = 45-60 degrees entrance angle), and lesion angulation of 1.4 (1 = 45 degrees lesion bend). In 88%, the device was the primary catheter used and in 6%, it was chosen when another system failed. The balloon was able to successfully cross 94% of all lesions attempted. Six lesions were crossed and dilated but significant residual stenoses remained. There were no significant device malfunctions, or angiographic or clinical complications. This feasibility evaluation of this new fixed wire system yielded excellent angiographic results. Although not a comparative study, this analysis suggests that this new generation of angioplasty catheter may improve the safety and efficacy of complex coronary angioplasty.

Angiography↗
PubMed1991

Conversion of p-tyrosine to p-tyramine in the isolated perfused rat kidney: modulation by perfusate concentrations of p-tyrosine.

We used the isolated perfused rat kidney to evaluate the role of renal decarboxylation of p-tyrosine as the source of urinary p-tyramine. Kidneys were perfused with concentrations of p-tyrosine ranging from 0.02 mM to 2.0 mM. p-Tyramine was measured by a sensitive and specific radioenzymatic assay. An increase in the perfusate concentration of p-tyrosine resulted in a significant increase in p-tyramine production that was blocked by the addition of NSD-1015, an inhibitor of aromatic-1-amino decarboxylase (AADC). We conclude p-tyrosine is the precursor for the renal production of p-tyramine, renal AADC catalyzes the formation of urinary p-tyramine, synthesized p-tyramine is predominantly excreted in the urine, and p-tyramine synthesis is modulated by the arterial delivery of p-tyrosine to the kidney.

Animals↗
PubMed1991

Low-dose recombinant human erythropoietin therapy in chronic hemodialysis patients.

To test the hypothesis that low-dose recombinant human erythropoietin (r-HuEpo) would be effective and safe therapy for the anemia of end-stage renal failure, we studied 37 chronic hemodialysis patients for 3 months before and 6 months after beginning treatment with r-HuEpo, 3,000 U, administered initially intravenously (IV) three times weekly. Hematocrit increased from a mean of 25.2 vol% into the target range (mean, 32.2 vol%, a 28% increase) by 4 months. Transfusion requirements were dramatically reduced. Eight patients (22%) had exacerbated or new development of hypertension, while in trials using higher doses this occurred in 35%. Vascular access thrombosis, dialyzer clotting, and seizures were not seen more frequently during r-HuEpo therapy. Dialyzer reuse was not affected. Low-dose r-HuEpo therapy is effective in most hemodialysis patients and may be associated with less adverse effects because of the slower increase in blood viscosity. As targets are reached, downward dosage adjustments need to be smaller when using an initial low-dose regimen.

Adolescent↗
PubMed1990

Interactions of ceftazidime and tobramycin in patients with normal and impaired renal function.

We studied the in vivo interaction of ceftazidime and tobramycin in normal volunteers and anuric patients given each drug separately or both drugs in combination. Kinetic analysis of plasma concentration data showed minor changes in the disposition of these agents when they were given concurrently. However, the resulting clearance of both tobramycin and ceftazidime was unchanged when these drugs were given concurrently. The volume of distribution of tobramycin at steady state was increased by 20% in normal volunteers when given with ceftazidime. The increase in distribution was accompanied by a slight decrease in ceftazidime elimination rate. No additional alteration in dosing over those necessary to adjust for a decrease in renal function is necessary when giving this combination.

Adult↗
PubMed1990

The treatment of anemia with low-dose recombinant human erythropoietin.

Recombinant human erythropoietin is effective therapy for the anemia of chronic renal failure. Hypertension, seizures, dialysis access thromboses, and clotted dialyzers have been reported as problems associated with the use of this drug. To test the hypothesis that low-dose erythropoietin is effective and safe, we gave 37 chronic hemodialysis patients this compound (3,000 units, i.v.) three times each week for 3 months. Before and for 3 months during therapy, we measured hemoglobin, hematocrit, blood transfusions, blood pressure, access thromboses, seizures, and clotted dialyzers. After 2 months of treatment, mean hemoglobin concentration and mean hematocrit increased significantly. Five patients had no increase in either value. In 4 of these 5 nonresponders, blood loss accounted for treatment failure. Neither blood pressure nor the incidence of access thromboses, seizures, and clotted dialyzers changed during the 3 months of therapy. We conclude that recombinant human erythropoietin is effective as treatment for the anemia of chronic renal failure at much lower doses than have been reported previously. The low incidence of adverse events may be related to the low dose used.

Anemia↗
PubMed1989

Pharmacokinetics and pharmacodynamics of atrial natriuretic peptide after bolus and infusion administration in the isolated perfused rat kidney.

We used the isolated perfused rat kidney to test the hypothesis that the renal pharmacokinetics and pharmacodynamics of atrial natriuretic peptide (ANP) are saturable and dependent on the method of administration. Wistar rat kidneys were perfused for 90 min after a bolus dose or continuous infusion of 45, 180, 450 ng of ANP. ANP clearance ranged from 3.27 to 2.28 ml/min after bolus administration. ANP clearance fell after infusion, resulting in a disproportionate increase in the ANP concentration with increasing infusion rate. The ANP half-life was unaffected by dose in the bolus group averaging 18 min. Increasing the ANP dose also increased the amount of Na excreted into the urine, but there were no differences between experimental groups. However, the area under the curve responsible for the natriuresis was 36 to 41% lower after infusion. Exogenous creatinine clearance, renal perfusion pressure and flow and renal vascular resistance were not affected. We conclude that the renal pharmacokinetics of ANP are saturable and are altered by the method of administration due to a down regulation of the ANP receptor. Furthermore, infusion of ANP should result in a greater net natriuresis due to resulting greater ANP concentrations at steady state and an apparent increased sensitivity of the kidney to ANP after infusion.

Animals↗