Biomedical subjects

I B Abrass

Publications and source records attributed to I B Abrass.

At least 37 records · Page 2Linked to original sources

PubMed1990

Effects of metoprolol on rest and exercise cardiac function and plasma catecholamines in chronic congestive heart failure secondary to ischemic or idiopathic cardiomyopathy.

To define the effects of 2 months of metoprolol therapy on cardiac function, aerobic performance and sympathetic nervous system activity, metoprolol (75 to 100 mg/day) was administered to 10 patients with chronic congestive heart failure (CHF). Metoprolol was discontinued in 2 patients because of worsening CHF. In the remaining 8 patients, peak oxygen uptake increased significantly (14.8 +/- 3.0 to 16.1 +/- 2.5 ml/kg/min, p less than 0.05) as did the oxygen pulse (9.0 +/- 2.2 to 12.6 +/- 1.8 ml/beat, p less than 0.02). Resting heart rate (87 +/- 18 to 62 +/- 9 beats/min, p less than 0.05) and peak exercise heart rate (133 +/- 13 to 105 +/- 30 beats/min, p less than 0.02) were both reduced. Mean resting ejection fraction increased from 0.15 +/- 0.06 to 0.25 +/- 0.11 and peak exercise ejection fraction also tended to increase (0.19 +/- 0.11 to 0.28 +/- 0.15, difference not significant). Both resting plasma norepinephrine (613 +/- 706 to 303 +/- 142 pg/ml, p less than 0.05) and epinephrine (71 +/- 50 to 40 +/- 21 pg/ml, p less than 0.05) were reduced. Circulating lymphocyte beta-adrenergic receptor number was unchanged (1,334 +/- 292 to 1,344 +/- 456 receptors/cell, difference not significant). It is concluded that metoprolol therapy is associated with improvements in rest and exercise ventricular performance and maximal aerobic capacity. These improvements are associated with a decline in resting sympathetic nervous system activity.

Aged↗

PubMed1990

Body fat distribution in healthy young and older men.

Central and/or intraabdominal (IA) fat is an independent predictor of obesity-related metabolic abnormalities in young and middle-aged subjects. The elderly are "fatter" at any given relative weight and often have similar metabolic abnormalities. In this study we compare body composition, circumferences, and specific fat depots areas in a population of healthy young and older men. Although the two groups were similar in body mass index and percent body fat, their distribution of adiposity was different. The young subjects had 16% and 10% larger thigh (p = .0001) and arm (p less than .01) circumferences respectively, while the ratio of waist-to-hip circumference was greater in the older subjects (0.93 +/- 0.04 vs 0.97 +/- 0.04, p = less than .01). The most striking differences between the groups were noted on computed tomography, with a twofold greater IA fat area (72.6 +/- 38.2 vs 143.6 +/- 56.2 cm2, p less than .0001), and a twofold lesser thigh subcutaneous fat area (156.3 +/- 69.3 vs 82.4 +/- 29.7 cm2, p less than .001) in the older subjects. We conclude there is an age-related central and intraabdominal redistribution of adipose mass, even in healthy older subjects. Since these changes occur in the absence of clinical disease, the associations between metabolic abnormalities and a central and or IA distribution of adiposity in the elderly must be investigated further.

Adipose Tissue↗

PubMed1990

Effect of exercise on insulin action, glucose tolerance, and insulin secretion in aging.

To assess the effect of exercise training on the insulin resistance and impaired pancreatic B-cell function of aging, we studied 13 healthy older men (ages 61-82 yr) before and after 6 mo intensive endurance exercise. An index of insulin sensitivity (SI) was measured using Bergman's minimal model. Intravenous glucose tolerance was quantified using the glucose disappearance constant (KGlc) while oral glucose tolerance was assessed after a 100-g glucose load. B-cell function was evaluated by measuring the acute insulin response (AIR) to glucose injection at fasting glucose (AIRGlc) and the AIR to arginine at multiple clamped glucose levels. Exercise produced an endurance training effect as demonstrated by an 18% increase in maximum O2 consumption (VO2max) [38.2 +/- 1.4 to 45.0 +/- 1.1 (SE) ml.kg fat-free mass-1.min-1, P less than 0.001]. An unchanged fasting glucose (5.3 +/- 0.2 to 5.4 +/- 0.2 mM) despite a reduced fasting insulin (61 +/- 6 to 48 +/- 6 pM, P less than 0.01) suggested exercise training improved insulin sensitivity. This was confirmed by a 36% increase in SI from 3.47 +/- 0.41 to 4.71 +/- 0.42 x 10(-5) min-1/pM (P = 0.01). Intravenous glucose tolerance did not change as measured by KGlc, which was 1.46 +/- 0.09 before and 1.48 +/- 0.16%/min after exercise training. Likewise, the incremental glucose response to oral glucose (633 +/- 49-618 +/- 45 mM.min) was unchanged. B-cell function was decreased as reflected by AIRGlc (351 +/- 73-245 +/- 53 pM, P less than 0.01) and the AIRArg at maximal glycemic potentiation (AIRmax, 1,718 +/- 260-1,228 +/- 191 pM, P less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1990

The biology and physiology of aging.

This discussion was selected from the weekly staff conferences in the Department of Medicine, University of California, San Francisco. Taken from a transcription, it has been edited by Homer A. Boushey, MD, Professor of Medicine, and Nathan M. Bass, MD, PhD, Associate Professor of Medicine, under the direction of Lloyd H. Smith, Jr, MD, Professor of Medicine and Associate Dean in the School of Medicine.

Aged↗

PubMed1989

Beta 2-adrenergic receptor regulation after transfection into a cell line deficient in the cAMP-dependent protein kinase.

A mouse beta 2-adrenergic receptor (beta 2AR) DNA clone was transfected and expressed in a mouse adrenocortical tumor cell line (Kin8) that lacks both beta 2AR and cAMP-dependent protein kinase (PKA). The receptor displayed a characteristic beta 2AR agonist binding profile that was similar to that observed in beta 2AR-transfected PKA+ mouse adrenocortical tumor cells (Y1). Isoproterenol treatment of beta 2AR-transfected Kin8 and Y1 cells resulted in a rapid loss of surface beta 2AR, as determined by the binding of the hydrophilic beta 2AR radioligand [3H]CGP 12177 [( 3H]CGP), followed by a decrease in adenylate cyclase activity. Sequestration of beta 2AR in Kin8 cells was beta 2AR agonist specific, temperature dependent, and rapidly reversible. Repeated treatment and recovery from isoproterenol incubation resulted in a cycling of surface [3H]CGP binding. The reappearance of [3H]CGP binding following short isoproterenol treatment was not affected by cycloheximide treatment of the cells. Prolonged incubation of beta 2AR-transfected Kin8 cells with isoproterenol resulted in the down-regulation of beta 2AR protein without a change in beta 2AR mRNA levels. Polysome profiles of control and down-regulated cells revealed that translation of beta 2AR mRNA is inefficient and does not change upon prolonged agonist treatment. Protein synthesis was required to reverse the down-regulation of beta 2AR. These results indicate that neither sequestration nor down-regulation of beta 2AR depends on PKA.

Adenylyl Cyclases↗

PubMed1988

Isoproterenol response following transfection of the mouse beta 2-adrenergic receptor gene into Y1 cells.

The beta 2-adrenergic receptor (beta 2AR) gene was isolated from a mouse genomic library, sequenced and shown to share 93% identity with the hamster beta 2AR cDNA at the amino acid level. This mouse beta 2AR genomic clone was transfected into the Y1 mouse adrenal cortex tumor cell line. Northern blot and S1 nuclease analysis showed that the beta 2AR-transfected cells expressed an mRNA of the appropriate size to encode the receptor. Membrane receptor number and affinities for various beta-adrenergic agonists demonstrated that the transfected clone encoded a beta 2AR protein product. Incubation of the transfected Y1 cells, which do not normally possess beta 2AR, with the beta 2AR agonist, isoproterenol, resulted in an increase in the rate of steroid secretion by these cells as well as a rapid change in cell morphology. This response was fully blocked by the beta 2AR antagonist, propranolol. Prolonged incubation of the cells with isoproterenol resulted in agonist insensitivity and an 80% reduction in membrane receptor number.

Amino Acid Sequence↗

PubMed1987

A study of training in clinical pharmacology of the elderly.

Training of physicians in geriatrics is essential to improving health care for the elderly. Considering the frequent use, cost, and side effects of drugs in the elderly, knowledge in clinical pharmacology is an important component of that training. The present study surveyed 68 geriatric medicine, 27 geropsychiatry, and 46 clinical pharmacology fellowship programs in the United States for the clinical geropharmacology content of their programs. In geriatric medicine, 73% of the programs had formal didactic material, 58% had formal training in this area during clinical experiences, and 43% formally interacted with clinical pharmacology faculty or fellows. In geropsychiatry these numbers were 79%, 67%, and 31%, respectively. In clinical pharmacology, 34% of the programs had formal didactic content, 9% had clinical experience on a specific geriatrics unit, and 14% had clinical experiences in a long-term care facility. Although some training in clinical geropharmacology exists in fellowship training programs, clearly there is much room for expansion and improvement in this important area of health care of the elderly.

Fellowships and Scholarships↗

PubMed1986

Temperature and isoproterenol modulation of beta-adrenergic receptor characteristics.

Since agonists and temperature affect receptor affinity, and since these factors may influence the actual determination of receptor affinity, we assessed the in vitro effects of temperature and isoproterenol on the high and low affinity states of beta-adrenergic receptors in rat membrane preparations. There was a temperature-dependent decrease in beta-adrenergic receptor agonist affinity which was further promoted by the presence of isoproterenol. The decrease in receptor agonist affinity was reflected by a decrease in the number of receptors in the high affinity state. These data suggest that receptor desensitization may occur in membrane preparations in vitro and that the present methodology used to assess agonist affinity in vitro may itself alter the very properties being measured.

Animals↗

PubMed1986

Beta-adrenergic agonist-mediated desensitization in senescent rats.

The capacity of senescent rats to develop the catecholamine refractory state was investigated in CDF (F-344) rats of 3 and 24 months of age. Beta-adrenergic receptor number, receptor-agonist affinity, and adenylate cyclase activity in heart membranes were assessed, following the chronic in vivo administration of the beta-adrenergic agonist, metaproterenol. Drug treatment leads to marked myocardial hypertrophy, receptor down-regulation, and reduced isoproterenol-stimulated adenylate cyclase activity. The extent of catecholamine-refractoriness was not different in the older rats, indicating the catecholamine desensitization of myocardial beta-adrenergic responsiveness is not impaired in senescence. Receptor agonist affinity and the percent of receptors in the high-affinity state decrease with age. These parameters are further reduced by agonist treatment but to a lesser extent in the older animals. Thus, the effects of age and agonist desensitization are not additive and suggest that aged animals may already be partially desensitized.

Adenylyl Cyclases↗

PubMed1985

Cholesterol modulation of beta-adrenergic receptor characteristics.

Cholesterol, a major structural component of plasma membranes, has a profound influence on cell surface receptor characteristics and on adenylate cyclase activity. beta-Adrenergic receptor number, adenylate cyclase activity, and receptor-cyclase coupling were assessed in rat lung membranes following preincubation with cholesteryl hemisuccinate. beta-Adrenergic receptor number increased by 50% without a change in antagonist affinity. However, beta-adrenergic receptor affinity for isoproterenol increased 2-fold as a result of an increase in the affinity of the isoproterenol high-affinity binding site. The increase in agonist affinity did not potentiate hormone-stimulated adenylate cyclase activity, which decreased 3-fold following cholesterol incorporation. However, the ratio of isoproterenol to GTP-stimulated activity was unchanged with cholesterol. Stimulation distal to the receptor by GTP, NaF, GppNHp, Mn2+ and forskolin also demonstrated 50-80% reduced enzyme activity following cholesterol incorporation. These data suggest that membrane cholesterol incorporation decreases catalytic unit activity without affecting transduction of the hormone signal.

Adenylyl Cyclases↗

PubMed1985

Characterization of the beta-adrenergic receptor of the rat peritoneal macrophage.

The beta-adrenergic receptor was characterized on BCG-activated rat peritoneal macrophage membranes by radio-ligand binding studies. Saturable binding with [125I]iodocyanopindolol (125I-ICYP) was demonstrated. With Scatchard analysis, rat macrophages demonstrate approximately 1000 receptors per cell with a Kd of 5 X 10(-11) M for 125I-ICYP. Competition curves with (-) and (+) propranolol at concentrations below 10(-6) M confirmed stereospecificity. The potency of various ligands to compete for 125I-ICYP binding sites followed the order: propranolol greater than isoproterenol greater than epinephrine greater than norepinephrine with apparent Kd of 2.0 X 10(-9), 3.9 X 10(-7), 1.0 X 10(-5), and 2.5 X 10(-5) M, respectively. Isoproterenol-stimulated adenylate cyclase activity was two-fold above basal activity. The potential physiologic significance of a beta-adrenergic receptor on rat peritoneal macrophages was suggested by a dose-dependent decrease in phagocytosis of soluble, model immune complexes (aggregated gamma-globulin) by macrophages incubated with metaproterenol. We conclude that the rat macrophage has a beta-adrenergic receptor and that catecholamines may thereby modulate macrophage function.

1-Methyl-3-isobutylxanthine↗

PubMed1985

Desensitization and resensitization of beta-adrenergic receptors in a smooth muscle cell line.

Exposure to the beta-adrenergic agonist, metaproterenol, elicits extensive receptor loss and desensitization of adenylate cyclase activity in the hamster DDT1, MF-2 cell line. The reappearance of beta-adrenergic receptors and restoration of adenylate cyclase activity were investigated. Receptor reappearance was investigated under conditions in which lost receptors were not detectable either on the cell surface or within the cell. Exposure to metaproterenol resulted in a 3-5-fold decrease in beta-adrenergic receptor affinity for agonist, an 85% reduction in beta-adrenergic receptor number per cell, and a 65% reduction in isoproterenol-stimulated adenylate cyclase activity without any change in NaF-stimulated enzyme activity. The rate of reappearance of the lost receptors was proportional to the concentration of metaproterenol to which the cells were initially exposed. Metaproterenol, at a concentration of 250 microM, induced long-term receptor loss which required 16 days in fresh media devoid of metaproterenol before the full complement of receptors reappeared. This prolonged receptor loss may be due to residual metaproterenol; however, the resensitization of isoproterenol-stimulated adenylate cyclase activity was restored 2 days after removal of metaproterenol. The lag period for the reappearance of receptors was shortened by incubation with either the beta-adrenergic antagonist, nadalol, or the glucocorticoid, methylprednisolone. Both pharmaceuticals reversed receptor down-regulation and up-regulated receptor number in control cells, although the extent and time course of restoration were different. These data suggest that the process of resensitization in DDT1 cells involves rapid restoration of adenylate cyclase activity and a slower reappearance of receptors over a time period of six population doublings.

Adenylyl Cyclases↗

PubMed1984

The effect of age and cholesterol on the rat lung beta-adrenergic system.

To assess the influence of membrane lipid composition on beta-adrenergic receptor number and adenylate cyclase activity in aging, we investigated the effect of cholesteryl hemisuccinate on these parameters in lung membranes of 3-, 12-, and 24-month-old CDF (F-344) rats. When cholesteryl hemisuccinate (0.5 mg/ml) was incubated with lung membranes, beta-adrenergic receptor density was increased by 70%. This effect was the same for each age group studied and indicated that the density of both basal and CHS-sensitive receptors is unaltered in rat lung with age. Forskolin, NaF, p[NH]ppG, and isoproteronol-stimulated adenylate cyclase activity is 30% lower in lung membranes from aged rats. Since enzyme activity is affected by the lipid environment and membrane composition often changes with age, we assessed adenylate cyclase activity following cholesteryl hemisuccinate incorporation. There was up to a 75% decrease in adenylate cyclase activity following cholesteryl hemisuccinate incorporation in lung membranes in each of the three age groups. In untreated membranes, there was no significant difference in cholesterol or lipid phosphate content with age. These data suggest that cholesterol content does not account for alterations in senescent rat lung adenylate-cyclase activity.

Adenylyl Cyclases↗

PubMed1984

The Sepulveda VA Geriatric Evaluation Unit: data on four-year outcomes and predictors of improved patient outcomes.

Data from its first four operating years indicate that the Sepulveda VA Geriatric Evaluation Unit is having consistent beneficial effects on patient care. These benefits include improved diagnostic accuracy, reduced use of drugs, improved functional status, and improved placement location. However, not all patients benefit equally, and differences between patient responses highlight the need to select those who will benefit most from relatively costly Geriatric Evaluation Unit services. Discriminant and regression analyses were performed on 98 consecutive patients to determine which patients admitted to the Geriatric Evaluation Unit would show greatest improvement in terms of placement, functional status, one-year survival, and living location, and which patients would be treated most efficiently in terms of length of stay. Patient characteristics on admission significantly associated with discharge home included a relatively high functional and cognitive status, the absence of an unstable medical problem, and not being expected to need nursing home placement by the referring physician. The latter two factors alone predicted actual placement location on the next 101 patients admitted to the Geriatric Evaluation Unit with high predictive accuracy (88.5 per cent). Factors predictive of patients whose functional status would improve on the Geriatric Evaluation Unit included absence of an unstable medical problem and being over 75 years old (predictive accuracy was 82.5 per cent). Two major factors associated with long patient stays on the Geriatric Evaluation Unit were low functional status scores and not living in own home or with family. These analyses indicate criteria that may be useful in selecting patients for inpatient geriatric evaluation and rehabilitation programs.

Activities of Daily Living↗

PubMed1983

The thermal lability of adenylate cyclase: mechanisms of stabilization.

The thermal inactivation of adenylate cyclase was investigated in human lymphocytes and in the N-protein deficient cyc- S49 mouse lymphoma cell line. The enzyme is rapidly inactivated at 37C with a t1/2 of 5.5 and 4.5 min respectively in human and cyc- membranes. Thermal inactivation is prevented by at least two mechanisms. The first mechanism involves ATP which stabilizes adenylate cyclase in a concentration dependent manner similar to the Km of ATP for cAMP formation. However, the inhibition of inactivation does not require Mg++ while the enzyme catalysis of ATP to cAMP does. The second mechanism involves substances which activate the enzyme. The human lymphocyte enzyme is equally stabilized by either NaF, GppNHp, or forskolin. In contrast, the cyc- enzyme is fully stabilized by forskolin but only partially stabilized by NaF. When human erythrocyte N-protein extract is added to cyc- membranes, NaF fully stabilizes the enzyme. These data suggest that an activated N-protein is instrumental in stabilizing adenylate cyclase and that there is some N-protein component in cyc- membranes through which NaF may be exerting its stabilizing action.

Adenosine Triphosphate↗

PubMed1983

Decreased beta-adrenergic agonist affinity and adenylate cyclase activity in senescent rat lung.

Beta-adrenergic receptor affinity for the agonist, isoproterenol, and coupling to adenylate cyclase assessed by Hill plots were investigated at both 23 degrees C and 37 degrees C in Fischer 344 rats of 4, 13, and 25 months of age. Apparent dissociation constants for isoproterenol at 23 degrees C were unaltered in the three age groups (2.0 +/- .3; 2.2 +/- .3; 2.6 +/- .3 X 10(-7)M, respectively). At 37 degrees C, however, the apparent dissociation constants increased progressively with age (6.9 +/- .9;8.6 +/- .6;13.2 +/- 1.4 X 10(-7)M). Hill coefficients were less than 0.7 for all age groups, suggesting the presence of two binding sites that have been described as a low (uncoupled) and a high (coupled) affinity state. In the presence of guanylylimidodiphosphate the apparent dissociation constant increased in all age groups and there was no longer a difference among age groups at 37 degrees C (14.1 +/- 2.7; 13.6 +/- 1.7; 14.8 +/- 2.4 X 10(-7)M). Basal adenylate cyclase activity (17 +/- 1 vs. 25 +/- 3 pmols cAMP/mg/min) as well as isoproterenol (27 +/- 5 vs. 60 +/- 11), NaF (116 +/- 8 vs. 209 +/- 24), and forskolin (70 +/- 6 vs. 124 +/- 14) stimulated activity were reduced in 25 compared to 4-month-old animals. The data suggest that in lungs from senescent rats there is a decrease in beta-adrenergic agonist affinity of the high affinity binding site and no change in the affinity of the low affinity binding site. Additionally, adenylate cyclase activity is reduced in senescent compared with young rats, and this reduction may be due to decreased activity of the catalytic unit. Both these changes may contribute to the diminished hormonal responsiveness of senescence.

Adenylyl Cyclases↗

PubMed1982

Lymphocyte beta-adrenergic refractoriness induced by theophylline or metaproterenol in healthy and asthmatic subjects.

Beta-adrenergic refractoriness was assessed in human lymphocytes following in vivo administration of the beta-adrenergic agonist, metaproterenol, the phosphodiesterase inhibitor, theophylline, or both concomitantly, to normal and asthmatic subjects. In normal subjects both beta-adrenergic receptor number and isoproterenol stimulated cAMP response decreases during therapy with metaproterenol (59 +/- 3; 51 +/- 16% of control, respectively), theophylline (76 +/- 6; 78 +/- 16), or concomitant metaproterenol and theophylline (47 +/- 4; 69 +/- 13). The asthmatic subjects were of two types; one type responding to metaproterenol or theophylline therapy by down regulation of receptor number to zero or near zero values, and a second group of asthmatics insensitive to down regulation of receptor number. The results suggest that the induction of the refractory state is different between asthmatics and non-asthmatics, and that there may be a role for cAMP in the development of beta-adrenergic refractoriness, in vivo.

Asthma↗

PubMed1982

Urinary incontinence in elderly nursing home patients.

Among elderly nursing home patients, urinary incontinence is a prevalent and costly condition. In seven nursing homes studied, 419 (50%) of the elderly patients were incontinence of urine. Most had been incontinent at admission (64%), had more than one incontinent episode per day or a catheter (72%), and had concomitant fecal incontinence (64%). The majority of incontinent patients had substantial cognitive impairment and limitations in mobility. The severity of these impairments was related to the extent of incontinence. Complications such as urinary tract infection and skin breakdown occurred in almost 45% and were more common in patients with catheters. Physicians recorded incontinence as a problem, or any efforts to evaluate it, in the nursing home records of less than 15% of these patients.

Aged↗