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Biomedical subjects

P A Abraham

Publications and source records attributed to P A Abraham.

At least 19 recordsLinked to original sources
PubMed1994

Urinary albumin and N-acetyl-beta-D-glucosaminidase excretions in mild hypertension.

Renal effects of mild hypertension and therapy have not been established. Since urinary albumin and N-acetyl-beta-D-glucosaminidase excretions reflect renal effects of hypertension, they were related to blood pressure, other cardiovascular risk factors, cardiac target organ effects, and response to therapy in mild hypertension (diastolic blood pressure 85-99 mm Hg). Participants were from two clinics of the Treatment of Mild Hypertension Study (TOMHS), a multicenter randomized, double-blind, controlled trial. Participants received nutritional-hygienic therapy and one of five active drugs or placebo. Urinary albumin and N-acetyl-beta-D-glucosaminidase excretions were assessed prospectively using office "spot" collections from one clinic (n = 213) and retrospectively using overnight collections from the other clinic (n = 210). Relationships were determined between protein excretions and blood pressure, age, gender, race, blood glucose, cholesterol concentrations, and indices of body mass and left ventricular mass and function at baseline. Treatment effects were assessed after 3 to 12 months. Spot and overnight albumin excretions related positively to baseline systolic blood pressure by univariate analyses. Spot albumin excretion related positively to systolic blood pressure, age, creatinine clearance, and left ventricular function while overnight albumin excretion related positively to left ventricular mass and female gender by multiple regression analyses. Spot, but not overnight, albumin excretion declined significantly with active drug therapy. N-acetyl-beta-D-glucosaminidase excretion did not relate to blood pressure or decline with therapy. The combined results suggest albumin excretion correlates with blood pressure, decreases with antihypertensive drug therapy, and is associated with greater left ventricular function and mass, as well as glomerular filtration rate, even at mild levels of hypertension.

Acetylglucosaminidase↗
PubMed1994

The relationship between renin isoelectric forms and renin glycoforms.

Active renin can be separated into multiple isoelectric forms using shallow gradient isoelectric focusing and into multiple glycoforms using concanavalin A (Con A) affinity chromatography. The relationship between renin isoelectric forms and glycoforms has not been previously determined. In this study, each of three renin Con A glycoforms from rat kidney was composed of significantly different proportions of six renin isoelectric forms; glycoforms with the greatest affinity for Con A contained proportionally less of the acidic isoelectric forms than those with the least affinity for Con A. A set of compartmental models accurately predicted previously measured differential plasma clearance rates of the three renin glycoforms based on their corresponding isoelectric form proportions. We conclude that 1) each Con A renin glycoform is composed of significantly different proportions of isoelectric forms, and 2) the different proportions of isoelectric forms found in Con A glycoforms are sufficient to account for the differential renin plasma clearance rates demonstrated previously for renin glycoforms in the rat. These data suggest that the isoelectric and glycoform heterogeneity of active renin are, in fact, closely related and may result from variable and interrelated mannose (Con A affinity) and sialic acid (charge) attachments to renin.

Animals↗
PubMed1993

Role of renin isoelectric heterogeneity in renal storage and secretion of renin.

Renin is a glycoprotein that is heterogeneous with respect to carbohydrate content and net charge. In an attempt to clarify the role of renin isoelectric heterogeneity in renal renin storage and secretion, the isoelectric profile of renal renin, secreted renin, and circulating renin were directly assessed and compared under basal and stimulated conditions by the use of an in vivo blood perfused rabbit kidney preparation. Under basal conditions, the kidney preferentially stored and secreted the relatively basic isoelectric forms of renin. Acute stimulation of renin secretion (reduced renal perfusion pressure and angiotensin-converting enzyme inhibition) significantly increased the secretion of the relatively basic isoelectric forms but had very little effect on the secretion of the relatively acidic renin forms. Circulating renin was composed primarily of relatively basic forms, which increased disproportionately after stimulation of renin secretion. These findings suggest that the isoelectric heterogeneity of renin is important in the cellular processing of renin and can be explained by a two-pool model in which the relatively acidic isoelectric forms of renin are constitutively secreted (and not stored) and the relatively basic isoelectric forms represent a regulated pathway in which they are stored and rapidly released in response to acute secretory stimuli. Preferential hepatic extraction of the more basic isoelectric forms has previously been described. Data from this study suggest that the disproportionate increase in circulating basic forms of renin observed after acute stimulation reflects the net effect of preferential renal the more basic renin isoelectric forms. The disproportionate increase in relatively basic circulating renin forms after acute secretory stimulation results in an overall circulating renin activity with a shorter half-life.

Animals↗
PubMed1993

Renin and renin inhibition in anephric man.

Renin activity appears to be present in low concentrations in the plasma of anephric humans but could be artifactual secondary to inadvertent activation of prorenin during specimen collection and handling or from a renin-like enzyme. We studied the effects of specimen collection, storage, different assay conditions, trypsin activation, and the renin inhibitor EMD 56133 (E Merck, Darmstadt) on plasma renin activity (PRA) in anephric man. PRA was detectable in all seven bilaterally nephrectomized (BNX) patients (0.2 +/- 0.1 ng AI/ml/hr, range 0.1-0.7) but was significantly lower than normals (2.4 +/- 0.3 ng AI/ml/hr, range 1.5-3.1, p = 0.001). PRA was not different in BNX whether blood samples were collected on ice or at room temperature and assayed immediately or whether samples were frozen and assayed several days later. Prolonged cold storage of samples and five freeze-thaw cycles over six to seven months did not significantly increase PRA in normals or anephrics. However, deliberate repeated freezing and thawing over the period of a single day increased PRA 4.1-fold in BNX and 1.6-fold in normals. Renin-like activity was also detected in BNX individuals using renin concentration determinations with either excess human or sheep angiotensinogen. The inhibition of renin activity (IC-50% = 3.16 x 10(-9) molar) by EMD 56133 was not different between BNX and normals. Thus, active renin is present in the plasma of anephric humans and does not result from the inadvertent activation of prorenin due to sample handling. Although the source of PRA in BNX is unknown, the enzyme appears functionally normal as evidenced by the dose-response to a single renin inhibitor.

Adult↗
PubMed1992

The pharmacokinetics of quinapril and its active metabolite, quinaprilat, in patients with various degrees of renal function.

Single- and multiple-dose pharmacokinetics of quinapril and its active metabolite, quinaprilat, were determined after oral administration of 20 mg quinapril HCl on day 1 and days 4 through 10 in 17 normotensive subjects with various degrees of renal function. Blood and urine samples were collected over 72- and 24-hour periods, respectively, after the first single dose and last multiple dose for measurement of quinapril and quinaprilat concentrations. The renal clearance of quinapril and quinaprilat decreased with increasing renal insufficiency but did not result in significant changes in quinapril pharmacokinetics in patients with renal impairment. In contrast, quinaprilat maximum plasma concentration, trough and peak steady-state plasma concentrations, area under the plasma concentration-time curve, and half-life increased significantly with increasing renal insufficiency. The disposition of quinapril and quinaprilat was unchanged from single to multiple doses. Small changes in the pharmacokinetic disposition of quinapril, together with a decreased rate of quinaprilat elimination, resulted in increased quinaprilat plasma concentrations following administration of both single and multiple quinapril doses to normotensive patients with renal impairment. Thus, quinapril dosage adjustment may be required in some patients with renal impairment.

Administration, Oral↗
PubMed1992

Epoetin enhances erythropoiesis in normal men undergoing repeated phlebotomies.

Epoetin may enhance autologous blood donation, but efficacy and dose response have not been established. This multicenter, double-blind trial compared intravenous placebo (n = 23) with epoetin beta, 250 U/kg (n = 23), 500 U/kg (n = 19), and 1000 U/kg (n = 22), administered three times weekly for 26 days. Normal men (age, 28 +/- 7 years; mean +/- SD) received phlebotomies up to three times weekly as long as the hemoglobin remained greater than or equal to 12 gm/dl. Subjects treated with epoetin donated 32% more units of blood (p less than 0.05) compared with placebo. A dose response was not observed. Platelet counts increased with epoetin compared with placebo, but platelet function and bleeding time did not change. Prothrombin times increased and partial thromboplastin times decreased with both epoetin and placebo. The supernatant of packed red blood cells collected after multiple phlebotomies and stored 42 days had slightly lower glucose concentrations and pH after therapy with epoetin. Blood pressure did not change with epoetin or placebo. These findings support the efficacy and safety of epoetin for enhancing the erythropoietic response of normal subjects during intensive phlebotomy.

Adolescent↗
PubMed1991

Comparative pharmacokinetics and pharmacodynamics of epoetin alfa and epoetin beta.

Different recombinant human erythropoietin products have been developed. Although they appear to have similar pharmacokinetics and function, these have not been directly compared. This randomized, double-blind, four-period crossover study compared the pharmacokinetics and pharmacodynamics of intravenous and subcutaneous epoetin alfa and epoetin beta in 18 normal male volunteers. As a control, three subjects received placebo treatment. After intravenous administration, the steady-state volume of distribution and beta-phase volume of distribution of epoetin beta were 7.7% and 16.9% larger than for epoetin alfa (p less than 0.05). The terminal elimination half-life after intravenous administration of epoetin beta was 20% longer than the terminal elimination half-life of epoetin alfa. After subcutaneous administration there was a delayed drug absorption with epoetin beta compared with epoetin alfa (p less than 0.05). There was a small but significantly greater absolute reticulocyte response after subcutaneous epoetin beta compared with subcutaneous epoetin alfa. The findings support differences in the pharmacokinetics and function of epoetin alfa and beta that are possibly caused by differences in their glycosylation.

Adolescent↗
PubMed1991

The effects of benazepril, a new angiotensin-converting enzyme inhibitor, in mild to moderate essential hypertension: a multicenter study.

Benazepril hydrochloride is a new angiotensin-converting enzyme inhibitor. In a multicenter study, 206 patients with mild to moderate hypertension were randomized to receive benazepril at a dose of 2, 5, 10, or 20 mg, hydrochlorothiazide, 25 mg, or placebo once daily for 4 weeks. The 20 mg dosage of benazepril lowered blood pressure to a degree equal to that of 25 mg hydrochlorothiazide: -12.2/7.7 mm Hg and -13.4/-7.5 mm Hg, respectively. Hydrochlorothiazide proved to be more effective in black subjects. At lower dosage levels of benazepril (2, 5, and 10 mg), blood pressure reduction was not significantly different from that with placebo. In those patients who failed to achieve goal diastolic blood pressure of less than 90 mm Hg with monotherapy after 4 weeks, the addition of open-label hydrochlorothiazide (25 mg/day) to benazepril, hydrochlorothiazide, or placebo produced a substantial additional decrease in blood pressure over a 2-week period. No definite adverse effects on hematologic measurements, serum biochemistry test results, or urinalyses were noted. Subjective adverse experiences were common in all groups but except in three or possibly four instances were not considered causally related to the study drug.

Adult↗
PubMed1991

Acute stimulation of renin secretion changes the multiple form profile of active plasma renin.

Active renin is composed of multiple forms with variable isoelectric points. In this study, the relative proportions of five major active renin forms in human peripheral venous plasma were compared before and 2 h after stimulation of renin secretion with both converting enzyme inhibition (quinapril) and upright posture in five patients with essential hypertension. The five major active renin forms were separated by shallow gradient isoelectric focusing and quantitated by radioimmunoassay of generated angiotensin I. Plasma renin activity increased from 1.2 to 5.1 ng AI/mL/h (P less than .05). This was accompanied by a significant increase in the proportions of the two most basic renin forms and a significant decrease in the proportion of the most acidic form in venous plasma. Although the mechanism cannot be determined from this study, the altered renin form profile observed could have resulted from preferential renal secretion and/or altered hepatic extraction of the more basic forms. An altered renin form profile in response to acute stimulation has important physiologic implications. Since the relatively basic renin forms are preferentially degraded they possess shorter half-lives. Additionally, the multiple forms of active renin may be functionally heterogenous. Thus, acute stimulation of renin secretion may result in circulating renin with a shorter duration of action and different functional effects than renin released under steady state conditions.

Antihypertensive Agents↗
PubMed1991

Blood pressure in hemodialysis patients during amelioration of anemia with erythropoietin.

This study analyzed blood pressure in hemodialysis patients treated with epoetin beta in multicenter trials. Antihypertensive drugs were prescribed as usual. Placebo-controlled trials compared epoetin (100 to 150 U/kg; N = 151) with placebo (N = 78) for 82 days. Hemoglobin (108 +/- 18 versus 75 +/- 14 g/L) (mean +/- SD) and diastolic blood pressure (84 +/- 14 versus 78 +/- 15 mm Hg) were greater (P less than 0.05) after epoetin. Clinically important increases in blood pressure (increases in diastolic blood pressure greater than or equal to 10 mm Hg and/or drug therapy) were more frequent with epoetin (58 versus 37%; P = 0.005). A dose-response trial compared epoetin, 25 U/kg (N = 42), 100 U/kg (N = 40), and 200 U/kg (N = 39) for 138 days. Increases in hemoglobin were dose dependent, but clinically important increases in blood pressure were not. In analyses of all patients treated with epoetin (N = 272), no baseline or final level of hemoglobin, or rate of hemoglobin rise, was a threshold for a rise in blood pressure. Patients requiring antihypertensive drugs or having uncontrolled hypertension (diastolic blood pressure greater than 90 mm Hg) at baseline had decreases in blood pressure (P less than 0.05) with antihypertensive therapy. Thus, compared with placebo, 21% of patients had clinically important increases in blood pressure during amelioration of anemia. The baseline or final levels of hemoglobin, the extent or rate of hemoglobin rise, or uncontrolled hypertension or antihypertensive drug use at baseline were not confirmed as risks. Antihypertensive drug therapy was important for blood pressure control.

Adult↗
PubMed1991

Analysis of active renin heterogeneity.

Active renin is a heterogeneous enzyme that can be separated into multiple forms with high-resolution isoelectric focusing. The isoelectric heterogeneity may result from differences in glycosylation between the different forms. In order to determine the relationship between active renin heterogeneity and differences in composition or attachment of oligosaccharides, two separate experiments were performed: (i) Tunicamycin, which interferes with normal glycosylation processing, increased the proportion of relatively basic renin forms secreted into the incubation media by rat renal cortical slices. (ii) Endoglycosidase F, which enzymatically removes carbohydrate from some classes of glycoprotein, similarly increased the proportion of relatively basic forms when incubated with active human recombinant renin. In addition, further studies with inhibitors of human renin activity revealed that the heterogeneous renin forms were similarly inhibited by two separate renin inhibitors. These results are consistent with the hypothesis that renin isoelectric heterogeneity is due in part to differences in carbohydrate moiety attachment and that the heterogeneity of renin does not influence access of direct renin inhibitors to the active site of renin.

Animals↗
PubMed1990

Renal effects of angiotensin converting enzyme inhibitors: nondiabetic chronic renal disease.

Based on studies in the rat remnant kidney model, it has been proposed that glomerular hypertension is responsible for the progressive nature of chronic renal disease. In that model, therapy with angiotensin converting enzyme (ACE) inhibitors reduced glomerular pressures. As a result, glomerular injury was reduced and the rate of progression of renal disease was slowed. Thus, alterations in hemodynamics may play an important role in glomerular injury. However, it is now evident that a variety of metabolic and other factors affect the progression of renal disease. Moreover, recent studies suggest that ACE inhibitors may also have beneficial effects that are independent of alterations in glomerular pressure. In humans, the glomerular hemodynamic response to renal disease cannot be measured, and it is not known whether or under which conditions glomerular capillary pressure might be elevated. Treatment with ACE inhibitors safely lowers blood pressure without adversely affecting renal function in most patients with nondiabetic chronic renal failure. Although proteinuria and the rate of progression of renal disease may decrease in some patients, these effects are inconsistently seen. Identification of the factors that modulate this variability in response to ACE inhibition may provide new insight into the pathogenesis and treatment of progressive renal disease in humans.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1990

Body fluid spaces and blood pressure in hemodialysis patients during amelioration of anemia with erythropoietin.

Blood pressure (BP) may increase in hemodialysis patients during treatment of anemia with recombinant human erythropoietin (r-HuEPO). Since fluid volume is a determinant of BP in dialysis patients, changes in body fluid spaces during r-HuEPO therapy could affect BP. Thus, 51Cr-labeled red blood cell (RBC) volume, inulin extracellular fluid (ECF) volume, and urea total body water (TBW), as well as cardiac output, plasma renin activity (PRA), and plasma aldosterone concentration were determined postdialysis before and after r-HuEPO therapy in patients in whom changes in BP could be managed by ultrafiltration alone. Eleven patients entered the study: one had a renal transplant and two required addition of antihypertensive drug therapy and were excluded; eight, of whom two required antihypertensive drug therapy following the study, were included in the analyses. Results revealed an increase in predialysis hemoglobin from 67 to 113 g/L (6.7 to 11.3 g/dL) (P = 0.001) during 18 +/- 6 weeks of therapy. Predialysis diastolic BP increased from 80 to 85 mm Hg (P = 0.07), while postdialysis diastolic BP was unchanged at 73 mm Hg. 51Cr-RBC volume increased, from 0.7 to 1.3 L (P = 0.004). ECF tended to decrease, from 13.7 to 10.8 L (P = 0.064), while TBW decreased to a similar extent, but not significantly, 34.3 to 31.2 L (P = 0.16). Postdialysis ECF volume was positively correlated with mean arterial BP at baseline (r = 0.89, P = 0.007) and after therapy (r = 0.74, P = 0.035). However, the regression lines for this relationship were different (P = 0.022) before and after therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Effect of acute stimulation of renin secretion on renal renin content in vivo.

Acute stimulation of renal renin secretion has been reported to increase, not change, or decrease intra-renal renin (IRR) content. However, these effects and the potential mechanisms for acute changes in IRR content have not been studied directly. In this study, the effect of acute stimulation of renin secretion on IRR content was studied directly using a new in vivo blood perfused rabbit kidney preparation. Following removal of the right kidney for determination of IRR content (N = 7) the left kidney was cannulated and perfused for an average of 55 minutes (baseline) at mean arterial blood pressure. Renin secretion by the left kidney was subsequently stimulated by reducing renal perfusion pressure to 60 mm Hg and administering enalapril, 1 mg/kg intravenously. After 38 to 140 minutes (mean 90 min) of stimulation, the left kidney was also removed and IRR content assessed. Renal blood flow and renin secretory rate (RSR) were determined frequently at baseline and following stimulation of renin secretion. The total amount of renin secreted in response to acute stimulation was calculated by integrating the RSR response over time. RSR from the left kidney increased by 515% during acute stimulation. IRR content in the left kidney also increased and averaged 16% greater than the right kidney from the same animal. In order to account for all of the renin secreted as well as the increase in IRR content following acute stimulation, it was calculated that the renin synthesis rate would have been required to increase over 26-fold.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Effect of concomitant administration of piperacillin on the dispositions of netilmicin and tobramycin in patients with end-stage renal disease.

The effect of piperacillin administration on the dispositions of netilmicin and tobramycin was assessed in 12 chronic hemodialysis patients. Six subjects each received netilmicin (2 mg/kg) or tobramycin (2 mg/kg) alone and in combination with piperacillin (4 g every 12 h for four doses). Subjects also received a single dose of piperacillin (4 g) on a separate occasion. The serum concentration-versus-time profiles of netilmicin and tobramycin were biexponential. The terminal elimination half-life (t1/2 beta) of tobramycin was markedly reduced (59.62 +/- 25.18 [mean +/- standard deviation] versus 24.71 +/- 5.41 h) and total body clearance (CLP) was significantly increased in the presence of piperacillin (3.45 +/- 1.61 versus 7.16 +/- 1.64 ml/min). In contrast, the t1/2 beta (41.80 +/- 13.24 versus 40.07 +/- 10.37 h) and CLP (5.11 +/- 2.15 versus 5.55 +/- 2.32 ml/min) of netilmicin were not significantly altered when netilmicin was administered in combination with piperacillin. No change in the central or steady-state volume of distribution of netilmicin or tobramycin was observed. The disposition of piperacillin in hemodialysis patients was not altered in the presence of either aminoglycoside antibiotic. Although no adjustment in netilmicin dosing is required, tobramycin should be administered more frequently when given concomitantly with piperacillin to hemodialysis patients to avoid prolonged periods of subtherapeutic concentrations.

Adult↗
PubMed1990

Renal function during erythropoietin therapy for anemia in predialysis chronic renal failure patients.

Recombinant human erythropoietin (r-HuEPO) therapy for anemia in chronic renal failure patients could have unfavorable renal effects since reversal of anemia can raise blood pressure and accelerate experimental glomerular injury. Thus, the effects of r-HuEPO on renal and systemic hemodynamics and the progression of renal disease were studied in predialysis chronic renal failure patients. The clearances of inulin and p-aminohippurate, fractional excretions of albumin and immunoglobulin G, cardiac output, plasma renin activity and aldosterone concentration were assessed at baseline, after short-term r-HuEPO (n = 4) or placebo (n = 4) therapy, and after long-term r-HuEPO for all patients (n = 8). In addition, the slope of l/serum creatinine with time was determined before and during continued r-HuEPO therapy. In contrast to placebo therapy, hematocrit increased with r-HuEPO from 32 to 37% after 7.6 +/- 2.7 weeks (mean +/- SD). Antihypertensive drug therapy was increased in 2 patients in each group. Renal function, cardiac output, plasma renin activity and aldosterone did not change significantly in either group. After 18 +/- 9 weeks of therapy for all patients, hematocrit increased from 31 to 39%. Antihypertensive drug therapy was increased in 5 patients and decreased in 1. Renal function decreased while proteinuria tended to increase. Cardiac output, plasma renin activity and aldosterone did not change. During 37 +/- 22 weeks of r-HuEPO therapy, the slope of l/serum creatinine did not worsen in any patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗