Search PubMed⌕ Search

Biomedical subjects

B L Mirkin

Publications and source records attributed to B L Mirkin.

At least 55 records · Page 3Linked to original sources
PubMed1983

Protein carboxyl-O-methyltransferase activity in cultured C-1300 neuroblastoma cells.

Protein carboxylmethyltransferase (PCM) has been identified in a variety of tissues derived from neural crest anlage, including in vivo C-1300 murine neuroblastoma (MNB). These observations have stimulated interest in further defining the role of PCM as a potential modulator of neoplastic cell behavior. The subcellular distribution and kinetic behavior of PCM have been characterized in a tissue culture line derived from the C-1300 murine neuroblastoma (clone NB41A3). The specific and total activities of PCM in the presence and absence of exogenous substrate were determined in subcellular fractions of MNB cells prepared by differential centrifugation. In the presence of exogenous substrate (+ gelatin), 40% of the total PCM activity was present in the 100,000 g supernatant fraction and 41% in the 800 g particulate fraction, whereas the higher specific activity of PCM was present in the 100,000 g supernatant fraction. Enzyme activity measured in the absence of gelatin, which reflects the concentration of endogenous methyl acceptor proteins in a cell fraction, was negligible. This activity represented less than 1.6 and 0.4% of the total PCM activity present in the 800 g particulate and 100,000 g soluble fractions respectively. Cytosolic PCM had an apparent Km of 13.9 x 10(-6) M for AdoMet and a Vmax of 33 pmoles per min per mg protein. Cytoplasmic PCM was inhibited competitively by S-adenosylhomocysteine (Ki equal 0.2 microM). These data demonstrate that the specific activity of PCM was greatest in the soluble component of subcellular fractions prepared from cultured MNB cells. This distribution pattern of PCM is similar to that observed in the C-1300 MNB tumor grown in situ and in non-malignant tissues. In contrast to the latter tissues, cultured MNB cells exhibited low PCM activity when assayed in the absence of exogenous substrate.

Adenosine↗
PubMed1983

Antihypertensive effect and elimination kinetics of captopril in hypertensive children with renal disease.

The efficacy and safety of captopril were studied in 10 patients with secondary hypertension (renal parenchymal disease, four patients; renal artery stenosis, two; and renal transplant rejection, four). Captopril was administered according to a dose titration protocol that randomized the initial three doses (0.5, 1.0, and 2.0 mg/kg) of drug to one of six possible sequences. All patients received diuretics prior to and during captopril therapy. A significant reduction in mean blood pressure was observed in all 10 patients during the initial dose titration. No correlation was observed between captopril dose and magnitude of the blood pressure reduction. The onset of antihypertensive action began approximately 15 minutes after each orally administered dose and reached the nadir approximately 1 1/2 hours later. Blood pressure returned to predrug levels between 6 and 10 hours after the dose. A significant reduction in systolic and diastolic blood pressure was noted in all subjects after 1 week of captopril treatment and was maintained during the course of continuous therapy in nine of 10 patients. Captopril combined with hydrochlorothiazide produced a satisfactory therapeutic response in five patients; in four others, additional antihypertensive drugs were required. No significant adverse effects were observed. Plasma renin activity determined prior to initiation of captopril was not predictive of blood pressure response to the drug. The clearance of captopril from patients with kidney failure ranged from 14.1 to 18.8 ml/min/kg in five subjects with creatine clearance between 10 and 21 ml/min/1.73 m2.

Adolescent↗
PubMed1983

Circulatory and humoral responses of sympathectomized fetal sheep to hypoxemia.

In fetal sheep, hypoxemia causes arterial hypertension, bradycardia, a redistribution of blood flow, and an increase in plasma vasopressin and catecholamine concentrations. To assess the role of the sympathetic nervous system in mediating these responses, we administered 6-hydroxydopamine to 11 chronically catheterized fetal sheep. Some of the responses to acute hypoxemia, achieved by administration of a low-O2 gas mixture to the ewe, were similar to those in intact fetal sheep. Fetal arterial O2 tension decreased from 22 +/- 3 to 12 +/- 3 (SD) Torr; fetal heart rate decreased transiently; combined ventricular output and umbilical-placental blood flow, as measured by the radionuclide-labeled microsphere technique, were maintained; cerebral, myocardial, and adrenal blood flow increased, and pulmonary blood flow decreased. However, there was no significant change in arterial pressure or blood flow to the peripheral, renal, and splanchnic circulations in the chemically sympathectomized fetuses in response to hypoxemia. The sympathetic nervous system is important in certain fetal vascular responses to hypoxemia but is not necessary for vascular responses in certain critical organs and thus is not crucial for fetal survival during hypoxia.

Animals↗
PubMed1982

Determinants of the diuretic response to furosemide in infants with congestive heart failure.

A wide interindividual variation in the degree of diuresis produced following treatment with furosemide has been observed in infants with congestive heart failure. A method of pharmacokinetic analysis that separates drug disposition from renal response to furosemide was used to compare the effect of this agent in infants with congestive heart failure with the effect seen in infants with fluid retention secondary to noncardiac factors. No differences in the drug elimination rate, urinary drug excretion, or renal diuretic response between the 2 groups were seen. Infants in both groups exhibited a wide range in all variables examined. The marked interindividual variation in response originates from decreased delivery of furosemide to its site of action in some patients and a decreased responsiveness to the drug in others.

Diuresis↗
PubMed1982

Influence of salt depletion and hydralazine-induced vasodilatation on accuracy of selective renal vein sampling in patients with essential hypertension and renal artery stenosis.

The diagnostic accuracy of renal vein renin (RVR) analyses was evaluated in 63 hypertensive patients treated with sodium depletion and/or hydralazine prior to selective renal vein sampling. A positive RVR study (i.e., lateralization of RVR) was defined as a ratio greater than or equal to 1.5 when RVR from the kidney with renal artery stenosis was compared to RVR from the contralateral kidney. Approximately 40% of patients with essential hypertension had positive RVR studies. Among patients with renal artery stenosis, surgical outcome was correctly predicted in 5 of 8 patients (63%) treated with sodium depletion, whereas outcome was accurately predicted in 11 of 12 patients (92%) treated with hydralazine. These observations demonstrate that a high percentage of patients with essential hypertension have positive RVR studies despite arteriographically normal renal vasculature. Results obtained in patients with renal artery stenosis suggest that stimulation of renin secretion by hydralazine may be of particular advantage prior to renal vein sampling. However, additional data are required to confirm whether activation of specific mechanisms for renin release improves the reliability of the RVR test.

Adolescent↗
PubMed1982

Biological maturation and beta-adrenergic effectors: pre- and postnatal development of the adenylate cyclase system in the rabbit heart.

The relationship between biological maturation and adenylate cyclase activity was studied in membrane preparations of rabbit ventricular muscle. Basal adenylate cyclase activity was lower in the adult than in the 1-day-old neonate or 27-day-old fetus. Maximal stimulation of adenylate cyclase by isoproterenol was 2.5 times greater and the EC50 values were 2-fold higher in the adult than the 27-day-old fetus or 1-, 7- and 12-day-old neonate. No significant differences in isoproterenol- or Mg++-stimulated activity were observed among the younger age groups nor was the Mg++-stimulated Vmax of adenylate cyclase significantly affected by biological maturation. Sodium fluoride, guanyl-5'yl imidodiphosphate and GTP also stimulated adenylate cyclase activity in a dose-dependent fashion similar to isoproterenol. Sodium fluoride (2.5-10 mM) increased adenylate cyclase activity in the adult to a significantly greater extent than the 1-day-old neonate. Guanyl-5'yl imidodiphosphate and GTP (0.1-10.0 microM) augmented adenylate cyclase activity to approximately the same degree (although some small differences were observed) in the fetus, neonate and adult. However, when guanyl-5'yl imidodiphosphate was preincubated with membrane preparations before in vitro assay, adenylate cyclase activity was increased 10-fold in the adult, whereas membranes from 1-day-old animals were unaffected. These data suggest that the processes regulating hormonal and pharmacological activation of adenylate cyclase are modified during biological maturation.

Adenylyl Cyclases↗
PubMed1982

Characterization of protein carboxyl-O-methyltransferase in the spontaneous in vivo murine C-1300 neuroblastoma.

Protein carboxy-O-methyltransferase (PCM) activity was determined in subcellular fractions prepared from C-1300 neuroblastoma tumors following transplantation and growth in male A/J mice. Fractions were obtained by differential centrifugation, and PCM activity was determined in all fractions in the presence (+gel) and absence (-gel) of an exogenous substrate, gelatin. Sixty % of the PCM activity in the absence of exogenous substrate (-gel) was contained in the crude 800 X g particulate fraction, whereas 80% of the PCM activity in the presence of gelatin (+gel) was present in the postmicrosomal (100,000 X g) supernatant. The latter fraction also contained the highest specific activity of PCM. A Km of 3.2 X 10(-6) M and a Vmax of 5.3 pmol per mg protein per min were obtained for PCM activity (+gel) in the high-speed supernatant. Cytoplasmic PCM was highly sensitive to competitive inhibition by S-adenosylhomocysteine and the S-adenosyl-homocysteine analogs sinefungin and A-9145C with Ki values of 0.64, 0.47, and 0.05 microM, respectively. These data demonstrate that PCM present in murine neuroblastoma has characteristics similar to those of PCM isolated from other adrenergic and neuronal tissues. S-Adenosyl-homocysteine analogs may be useful probes for studying the role of PCM as a modulator of cell function in neurogenic and neoplastic tissues.

Animals↗
PubMed1981

Prevention of cyclophosphamide-induced antidiuresis by furosemide infusion.

In patients receiving high-dose cyclophosphamide therapy (HDCPT), urinary flow rate, serum sodium concentration, and renal free-water clearance frequently decrease in the 24 hr after drug. High urinary flow rates, which may minimize other cyclophosphamide-related symptoms, are difficult to achieve in the face of the antidiuretic effect. Five patients receiving a total of 30 doses of HDCPT (greater than 50 mg/kg) were studied to assess the effect of continuous furosemide infusion on cyclophosphamide antidiuresis. In two patients receiving various diuretic regimens, only the continuous infusion of furosemide was associated with maintenance of high urinary flow rates and normal serum sodium concentrations. Four patients studied prospectively while receiving HDCPT maintained renal free-water clearance as well as high constant urinary flow rates and normal serum sodium concentrations. Concurrent studies of furosemide disposition revealed that renal excretion of furosemide was unchanged during the continuous infusion and that the diuretic effect was sustained throughout the therapeutic course. The only furosemide-related side effect identified was hypokalemia, which was easily managed with potassium chloride given intravenously.

Adolescent↗
PubMed1981

The kinetics of red blood cell electrolyte alterations following digoxin administration. A report of two pediatric cases.

Serial determinations of plasma and red blood cell (RBC) Na+, K+, and Mg++ concentrations were obtained in 2 children following digoxin administration. Treatment with digoxin was associated with a 50-70% increase in the RBC Na+ concentration, whereas the RBC K+ concentration decreased by 7-10%. RBC electrolyte changes paralleled plasma digoxin levels in the child who was digitalized slowly, whereas the maximum shift in RBC electrolyte concentration occurred 48 h after peak plasma digoxin concentrations were observed in the child who had received a single dose of digoxin. These results suggest that Na+/K+-ATPase inhibition may continue after clearance of digoxin from the plasma. The use of plasma digoxin concentration to diagnose toxicity may be limited in the special case of children who have received a single large dose of digoxin.

Child, Preschool↗
PubMed1981

Furosemide disposition in normal and proteinuric rats: urinary drug-protein binding as a determinant of drug excretion.

We have demonstrated recently that the binding of furosemide (FSM) to urinary proteins causes a decrease in the diuretic response that is proportional to the degree of proteinuria. Further studies were conducted to determine whether urinary drug-protein interactions also altered the renal excretion of FSM. Rats were treated with puromycin aminonucleoside to produce proteinuria. Renal FSM clearance was directly related to urinary protein excretion rate (r = 0.550, P less than .005), a relationship that was more striking when FSM clearance was normalized to glomerular filtration rate (r = 0.781, P less than .001). This relationship was not explained by changes in serum protein concentration or glomerular filtration rate. In order to understand the mechanism of this relationship, normal and nephrotic rats were studied during experimental conditions designed to alter urinary pH. In normal animals urinary acidification induced by HCl infusion produced a profound decrease in renal FSM clearance compared to animals with the more alkaline urine that followed NaHCO2 or acetazolamide pretreatment. This alteration in renal FSM clearance during urinary acidification was not observed in nephrotic animals, despite comparable changes in urinary pH. The diuretic response to FSM did not differ among the normal animals despite the alteration in renal FSM clearance, indicating that the reduction of renal FSM clearance was due to tubular reabsorption of FSM distal to its site of action. These data suggest that urinary drug protein binding may impair the tubular reabsorption of drugs and thereby enhance their renal clearance.

Animals↗
PubMed1980

Disposition and pharmacodynamics of diuretics and antihypertensive agents in renal disease.

The pharmacodynamic actions and disposition of diuretic and antihypertensive agents may be significantly modified in subjects with renal disease. Most studies on this question have dealt with alterations in the elimination kinetics of these drugs and, while they generate descriptive data, minimal insight about changes in dose-response relationships or mechanisms of drug action are provided by such investigations. Several basic principles which may serve as useful guidelines in determining how renal failure will influence the response to drugs have been considered. They include the following: degree of renal malfunction, intrinsic toxicity of the drug, alternative pathways for drug metabolism and elimination, elimination pharmacokinetics and dose-response characteristics. Several classes of diuretic agents (thiazides, furosemide) and antihypertensive drugs (hydralazine, methylopda, propranolol, prazosin, and clonidine) have been used as models to define how basic knowledge of renal and non-renal pathways for elimination of drugs and their pharmacodynamic actions may assist in establishing rational therapeutic regimens for these agents in patients with renal failure.

Antihypertensive Agents↗
PubMed1980

Metabolic disposition of methyldopa in hypertensive and renal-insufficient children.

The serum levels of methyldopa and its principle metabolites were assessed in 22 hypertensive children, of whom 13 had impaired renal function. A significant correlation was found between the magnitude of the renal dysfunction and the serum levels of methyldopa, alpha-methyldopa-sulfate, alpha-methyldopamine, and alpha-methyldopamine-sulfate. The patients were divided into 2 groups: those with normal (serum creatinine less than or equal to 1.0 mg/100 ml) and those with abnormal (serum creatinine greater than 1.0 mg/100 ml) renal function. The serum level of alpha-methyldopa-sulfate and not of methyldopa was elevated in those with renal dysfunction. The serum levels of alpha-methyldopamine and, in particular, its 3-0 sulfate conjugate were markedly elevated in patients with renal disease. These data suggest that the enhanced sensitivity to methyldopa in patients with impaired renal function may be due in part to alpha-methyldopamine.

Adolescent↗
PubMed1980

Clinical response of hypertensive children to long-term minoxidil therapy.

The long-term effects of minoxidil were evaluated in 11 hypertensive children (5 male, 6 female) who used minoxidil for a minimum of 6 months. The selection of these patients for minoxidil therapy was made on the basis that their systolic and diastolic blood pressures were greater than the 99th percentile for aged-matched normals, despite their use of at least three other antihypertensive drugs. The starting daily dose of minoxidil was between 0.1 and 0.2 mg/kg, administered in two divided doses (maximum, 5 mg/kg/24 hr). They also received propranolol and either hydrochlorothiazide or furosemide throughout the period of study. A significant reduction in blood pressure was noted 1 week after starting minoxidil. Although blood pressure continued to decrease during the following 2 weeks in association with an increase in minoxidil dosage, the levels of blood pressure recorded throughout the remainder of the period of evaluation did not differ significantly from the values at 1 week. All children developed hypertrichosis over the overhead, trunk, and extremities, regardless of drug dosage. This remitted in all cases within 3 months after minoxidil was discontinued. No other adverse reactions were observed.

Antihypertensive Agents↗