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Biomedical subjects

T J Allen

Publications and source records attributed to T J Allen.

85 records · Page 5Linked to original sources
PubMed1986

Influence of membrane potential on calcium efflux from giant axons of Loligo.

Experiments are described in which Ca efflux is monitored in axons under voltage clamp. As Ca efflux consists of more than one component, conditions were sought where one component predominates. Thus external Na-dependent Ca efflux can be studied in relative isolation either at pH 9.0 or in fully poisoned axons immersed in Ca-free media; external Ca-dependent Ca efflux can be studied in fully poisoned axons immersed in Na-free media and the Na-independent, energy requiring, pump is best examined in Na and Ca-free sea waters. Both in unpoisoned axons at pH 9.0 and fully poisoned axons at pH 7.8, the external Na-dependent Ca efflux is activated by hyperpolarization and inhibited by depolarization. Depolarizations achieved either electrically or by exposure to high K are roughly comparable and the inhibition brought about by high K can largely be removed by electrical hyperpolarization to the initial resting potential. In both Na sea waters and choline sea waters containing 100 mM-Na, Ca efflux is increased e-fold over approximately 50 mV. In choline sea water, external Ca-dependent Ca efflux from fully poisoned axons is unaffected by voltage over the range -80 to -30 mV. But addition of K or Li activates the flux and this activation is increased by hyperpolarization and decreased by depolarization, suggesting that the activating cation may also be transported into the axon. The Na-independent, energy-requiring, flux is inhibited by electrical hyperpolarization and stimulated by electrical depolarization. External K also stimulates the flux and part of this stimulation can be removed by electrical hyperpolarization. These data show that the energy-dependent pump is sensitive to membrane potential in the physiological range and suggest that it may be an electrogenic process. The finding that voltage affects the energy-dependent (uncoupled) pump and external Na-dependent fluxes in opposite directions may help explain why the total Ca efflux from intact axons responds to potential in a very variable manner.

Animals↗
PubMed1978

Metabolism of 7,12-dimethylbmethylbenz(a)anthracene by macrophages and uptake of macrophage-derived metabolites by respiratory tissues in vitro.

Cultured mouse macrophages and tracheal and lung tissue each produced the same ethyl acetate-soluble derivatives of 7,12-dimethylbenz(a)anthracene (DMBA). The derivatives produced in the different cultures were indistinguishable by thin-layer chromatography and by high-pressure liquid chromatography but differed in their relative proportions. The greatest difference was seen between lungs and macrophages. The predominant metabolite produced by lungs was 8,9-dihydro-8,9-dihydroxy-7,12-dimethylbenz(a)anthracene, while macrophages produced equal quantities of both 8,9-dihydro-8,9-dihydroxy-7,12-dimethylbenz(a)anthracene and a second uncharacterized derivative, Metabolite B, at low DMBA doses (less than 0.05 microgram/ml medium) and primarily Metabolite B at higher DMBA doses (greater than 0.05 microgram/ml medium). Macrophages released the majority of the ethyl acetate-soluble metabolites that they produced into the surrounding medium. With the exception of 8,9-dihydro-8,9-dihydroxy-7,12dimethylbenz(a)anthracene, these derivatives were accumulated within tracheal and lung tissue when these organs were cocultivated with macrophages in the presence of DMBA.

9,10-Dimethyl-1,2-benzanthracene↗
PubMedDate not supplied

Glomerular filtration rate in early experimental diabetes.

A noninvasive single injection technique for the measurement of glomerular filtration rate (GFR) using technetium99m diethylene triamine pentaacetic acid (DTPA) was developed for use in the rat. GFR measurements obtained by the technique correlated well with those obtained by Cr51 EDTA infusion (R = 0.95, n = 7). The coefficient of variation was 8.4%. GFR was measured over 4 weeks in diabetic and control rats. GFR increased with time in both groups, with no difference between the groups; however, when corrected for body weight, diabetes was associated with an increased GFR (diabetic 13.6 +/- 1.7 vs. control 10.4 +/- 0.1 ml/min/kg p less than 0.001). Insulin treated rats had higher GFRs than untreated diabetics (p less than 0.05), but GFR/kg was reduced to that of nondiabetic controls. High protein intake in diabetic rats caused an increase in GFR after 1 week of diabetes, but this was not sustained by the fourth week. Genetic hypertension and angiotensin converting enzyme (ACE) inhibition with ramipril had no effect on GFR in diabetic rats. We conclude that serial measurement of GFR in the diabetic rat is accurate and reproducible. Genetic hypertension, high protein intake, and ACE inhibition have little effect on GFR in experimental diabetes.

Angiotensin-Converting Enzyme Inhibitors↗
PubMedDate not supplied

Natural history of early diabetic nephropathy: what are the effects of therapeutic intervention? Melbourne Diabetic Nephropathy Study Group.

Several studies have shown that lowering of blood pressure slows the rate of progression of diabetic renal disease. Some placebo-controlled studies have also shown that angiotensin-converting enzyme (ACE) inhibitors decrease or stabilize albuminuria in incipient nephropathy and slow the rate of progression of advanced nephropathy. However, it is not yet clear if prolonged treatment with ACE inhibitors or with other agents exerts a specific renoprotective effect in incipient diabetic nephropathy. It is proposed that such an effect should be independent from changes in systemic blood pressure and should be characterized by amelioration of the rate of rise of albumin excretion rate (AER) and the rate of fall of glomerular filtration rate (GFR) and independence from changes in other parameters known to influence AER (glycemic control, protein intake, sodium intake). In addition, there should be evidence that the potentially reversible effects of therapeutic intervention on AER and GFR are translated to long-term changes in renal function and structure. This paper reviews the evidence on which the concept of renoprotection is based, with particular reference to choice of end points, heterogeneity of study groups, and complexities of the disease process, and relates this evidence to the natural history of nephropathy in type I and type II diabetes. Based on the above, an assessment is made of the comparative effects of ACE inhibitors and other antihypertensive agents on AER and GFR. It is suggested that longitudinal intra-individual analysis of both variables may be necessary in order to determine whether ACE inhibitors exert greater renoprotection than calcium channel blockers or other antihypertensive agents.

Albuminuria↗
PubMedDate not supplied

Diabetic vascular hypertrophy and albuminuria: effect of angiotensin converting enzyme inhibition.

The role of angiotensin-converting enzyme (ACE) inhibition with ramipril on mesenteric vascular hypertrophy and urinary albumin excretion was explored in a normotensive model of experimental diabetes. Serial measurements of albuminuria were performed in Sprague-Dawley control, diabetic rats, and diabetic rats treated with ramipril. Over 24 weeks, urinary albumin excretion showed a continuous rise in the untreated diabetic rats. Ramipril prevented the increase in albuminuria over the whole study period. After 6 months, animals were perfused with glutaraldehyde and sacrificed for measurement of mesenteric vessel wall/lumen ratio and kidney weight. Diabetes was associated with increased mesenteric wall/lumen ratio and kidney weight. ACE inhibition, despite no effect on glycemic control, attenuated mesenteric vascular hypertrophy but did not decrease kidney weight. In addition to the well-described renoprotective effects of ACE inhibition in diabetes, this class of agents may have a favorable effect on diabetic vascular disease.

Albuminuria↗
PubMedDate not supplied

Long-term intraindividual variability of serum lipids in patients with type I and type II diabetes.

The objective of this study was to estimate the long-term intraindividual variability of lipid levels in adult type I and type II diabetic patients. Total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and hemoglobin A1c were measured every 3-6 months in 135 patients attending the Austin Hospital diabetes clinic. Analysis was performed on 60 diabetic patients (33 type I and 27 type II) who had not been treated with lipid lowering drugs and who met the inclusion criteria of at least five measurements [mean +/- standard error of the mean (SEM), 9.5 +/- 0.4; range, 5-17] collected over a minimum of 4 years (5.1 +/- 0.1; 4-6.5 years). Total variability, expressed as coefficient of variation, was 8.8 +/- 0.4% for total cholesterol, 23.9 +/- 1.5% for triglycerides, 10.2 +/- 0.5% for HDL cholesterol, and 12.0 +/- 0.5% for LDL cholesterol. Biological variability, derived from total and analytical variability, was higher than previous estimates in nondiabetic subjects for total cholesterol and HDL cholesterol but similar for triglycerides and LDL cholesterol. No relationship was observed between total lipid variability and diabetes type, age, baseline or mean lipid levels, duration of follow-up, or the number of samples per patient. Men demonstrated greater variability than women for total cholesterol (men 9.5 +/- 0.5%, n = 34, women 7.9 +/- 0.5%, n = 26, p < 0.01) and triglycerides (men 26.5 +/- 2.2%, women 20.4 +/- 1.4%, p = 0.03). Total lipid variability was also unrelated to baseline or mean hemoglobin A1c or to the change in hemoglobin A1c during the study as a whole. However, the change in hemoglobin A1c was associated with the change in total cholesterol (r = 0.30, p < 0.03) and the change in LDL cholesterol (r = 0.27, p < 0.05). In conclusion, long-term intraindividual lipid variability in adult diabetic subjects is higher for total and HDL cholesterol than previously published values in nondiabetic subjects. Variability of triglycerides is at least double that of total cholesterol, HDL cholesterol and LDL cholesterol. Biological variability, not measurement error, accounts for the greatest proportion of total variability for all lipid parameters. Confidence levels calculated from these data have implications for the initiation of lipid lowering therapy and in monitoring the effects of intervention.

Adult↗
PubMedDate not supplied

Intracellular Ca indicator Quin-2 inhibits Ca2+ inflow via Na/Ca exchange in squid axon.

Until recently, intracellular free calcium has been amenable to measurement and investigation only in cells large enough to permit either microinjection of a suitable Ca sensor such as a aequorin or arsenazo III or insertion of a Ca-sensitive microelectrode. This constraint on cell size was removed by the development of the fluorescent Ca2+ -sensitive dye Quin-2 and its acetoxymethyl ester, which can be introduced into a wide range of cell types. A major requirement of any intracellular Ca2+ indicator is that it should not disturb intracellular Ca2+ homeostasis and Quin-2 is generally considered to be satisfactory in this respect. We now report that injection of Quin-2 into squid (Loligo forbesi) axons can almost completely abolish one component of Ca2+ entry--intracellular Na+ (Nai)-dependent Ca2+ inflow, which occurs via Na/Ca exchange. Mixtures of Ca and Quin-2 that buffer an ionized Ca2+ at close to physiological concentrations also block Nai-dependent Ca2+ influx but these same mixtures fail to block the extracellular Na+ (Na0)-dependent extrusion of Ca2+, showing that Quin-2 acts specifically on Ca2+ inflow.

Aminoquinolines↗
PubMedDate not supplied

Oleate oxidation and mitochondrial substrate selection in vascular smooth muscle.

The purpose of this study was to determine the contribution of long-chain fatty acids relative to other mitochondrial substrates in active vascular smooth muscle (VSM). Hog carotid arteries were isometrically contracted in physiological saline solution containing 0.71 mM U-(13)C-oleic acid (bound to albumin at a ratio of 6.8:1), 5 mM 1-(13)C-glucose and 1 mM acetate in the presence or absence of 5 mM carnitine for 6 h at 37 degrees C. Substrate oxidation was determined using (13)C-isotopomer analysis of glutamate. Although oxidation of oleic acid could not be measured at physiological concentrations [0.5 mM (1:1)], oleic acid oxidation was approximately 5% of the total substrates oxidized at the higher concentration examined. Although insignificant, carnitine increased oleic acid oxidation to approximately 8%, and resulted in a decrease in endogenous lipid oxidation, which was 2-12% of the total substrates oxidized. Oxidation of glucose and acetate did not significantly change due to the inclusion of oleic acid in the incubation solutions. Therefore, we conclude that exogenous long-chain fatty acids are minor contributors to substrate oxidation (approximately 5%) in VSM compared to other mitochondrial substrates, such as glucose and acetate, which account for approximately 80% of the substrates oxidized by VSM.

Acetates↗