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T J Allen

Publications and source records attributed to T J Allen.

At least 73 records · Page 4Linked to original sources
PubMed1991

Kidney insulin-like growth factor-I mRNA levels are increased in postpubertal diabetic rats.

Diabetes-associated renal enlargement is more marked in postpubertal than prepubertal rats, and in the postpubertal rat, is associated with increased kidney insulin-like growth factor-I (IGF-I) levels for the first 2 days. In order to determine whether local IGF-I production is the cause of this increase in tissue levels, IGF-I mRNA levels were determined in pre- and postpubertal Sprague-Dawley rats made diabetic with streptozotocin (STZ) and in control rats. RNA was extracted from kidneys and livers of rats at 0 h, 6 h, 12 h and days 1, 2, 3 and 7 after STZ injection. After Northern blotting and hybridization with an oligonucleotide probe complementary to an E domain of the IGF-I cDNA, four distinct bands (7.4, 4.8, 1.8 and 1.0 kb) were found. Densitometric analyses of the most prominent bands (7.4 and 1.0 kb), after normalization for 18S ribosomal RNA content, revealed a 50-100% increase in the kidneys of postpubertal diabetic rats compared with postpubertal controls 12 h after STZ injection (P less than 0.05, diabetes vs control). Between days 2 and 7, kidney IGF-I mRNA levels in postpubertal diabetic rats fell to approximately 50% of control levels (P less than 0.05, diabetes vs control). In contrast, kidney IGF-I mRNA levels in the prepubertal diabetic rats remained unchanged over the 7 days. Liver IGF-I mRNA levels did not rise during the first 24 h and fell to approximately 60% of control levels by day 7 in both pre- and postpubertal diabetic rats (P less than 0.05, diabetes vs control). Increased local IGF-I production may underlie the initiation of renal enlargement associated with diabetes mellitus.

Animals↗
PubMed1990

The effects of manganese and changes in internal calcium on Na-Ca exchange fluxes in the intact squid giant axon.

The effects of manganese chloride were studied on Na-Ca exchange fluxes from intact squid axons. Ca uptakes and Cao-dependent sodium efflux were inhibited half-maximally by 3-7 mM MnCl2. Mn inhibition appears less during Nao-Cai exchange (half-maximal inhibition; 30 mM) than that during Cao-Nai exchange, even when both fluxes were activated with 100 mM Na. The effects of changes in [Ca2+i], effected by Ca-EGTA injection or inhibition of mitochondrial Ca uptake by ruthenium red, were examined on the reverse (Cao-Nai) exchange mode. Ca-EGTA mixtures, designed to raise [Ca2+i] above 2 microM, inhibited Cao-Nai exchange fluxes. Ruthenium red inhibited mitochondrial Ca buffering to effect increases in Cai in the absence of Ca chelators; it activated Nao-Cai exchange fluxes but had little effect on Cao-Nai exchange despite similar reported Km for Cai. The results reflect the difficulty in demonstrating the stimulatory effect of [Ca2+i] on Cao-Nai exchange fluxes in intact axons.

Adenosine Triphosphate↗
PubMed1990

Longitudinal evaluation of the renal clearance of glycated albumin in the diabetic rat.

This study has examined glycation of serum albumin and its role in evolving diabetic proteinuria. Renal clearances of endogenous glycated and nonglycated albumin were studied in groups of normal and streptozotocin-induced diabetic Wistar-Kyoto rats over a 32 week period. Concentrations of glycated and nonglycated albumin in serum and urine were measured by rat albumin radioimmunoassay following separation on m-aminophenylboronate affinity columns. Levels of glycated serum albumin in diabetic rats were significantly higher than in normal rats (5.9 +/- 0.7% vs 4.4 +/- 0.3%, P less than 0.05). Median total urinary albumin excretion increased from 120 micrograms/24 h at baseline to 879 micrograms/24 h (P less than 0.05) 28-32 weeks after induction of diabetes. The renal clearance of glycated albumin was approximately twice as great as that of nonglycated albumin in both normal (P less than 0.01) and diabetic (P less than 0.01) rats. However, the glycated albumin/nonglycated albumin clearance ratio in diabetic rats did not correlate with duration of diabetes or with the level of albuminuria. These results indicate that glycation of albumin does not contribute disproportionately to the development of proteinuria in the diabetic rat, during which median renal albumin clearance increased 7-fold. Other factors, such as glycation of the glomerular filtration surface, may have a more important role in the pathogenesis of proteinuria in experimental diabetes.

Animals↗
PubMed1990

Hyperlipidaemia increases albuminuria in hypertensive and normotensive rats.

1. The effects of a high cholesterol diet on urinary albumin excretion were examined in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats over 36 weeks. 2. Cholesterol feeding resulted in an increase in total-cholesterol and a decrease in HDL-cholesterol without influencing triglyceride levels in both strains. 3. Urinary albumin excretion was significantly elevated in cholesterol-fed SHR and WKY rats. 4. These results suggest that hyperlipidaemia may be important in acceleration of experimental nephropathy.

Albuminuria↗
PubMed1990

Glomerular filtration rate in streptozocin-induced diabetic rats. Role of exchangeable sodium, vasoactive hormones, and insulin therapy.

The interrelationships of sodium and volume status, atrial natriuretic peptide (ANP), plasma renin activity (PRA), insulinlike growth factor I (IGF-I), and kidney weight and their influence on glomerular filtration rate (GFR) were investigated in rats during the first 4 wk of streptozocin-induced diabetes (STZ-D). In each of three experiments, untreated diabetic rats were compared with nondiabetic control rats and rats with varying degrees of glycemic control during insulin therapy. The first experiment evaluated exchangeable sodium, plasma volume, and GFR. In untreated diabetic rats, exchangeable sodium and plasma volume, but not GFR, were increased by approximately 25% compared with control rats. Insulin-treated diabetic rats with plasma glucose levels ranging from 12 to 30 mM had increased GFR, whereas exchangeable sodium and plasma volume were reduced toward control values. Daily insulin therapy, titrated to maintain euglycemia, further reduced exchangeable sodium and plasma volume and decreased but did not normalize GFR. The second experiment evaluated the relationship between vasoactive hormones and GFR. In untreated diabetic rats, plasma ANP levels increased 89% and urinary cyclic GMP (cGMP) excretion increased 94%, with an 85% decrease in PRA, whereas GFR was unchanged. Moderate hyperglycemia (plasma glucose 12-30 mM) was associated with normalized plasma ANP levels and urinary cGMP excretion, a 52% decrease in PRA, and a 13% increase in GFR. The third experiment studied serial changes in food and water intake and vasoactive hormones and end-point measurement of kidney weight, GFR, and plasma IGF-I. In the untreated diabetic group, urinary cGMP excretion was significantly elevated after 3 wk, whereas the reduction in PRA levels was apparent after 1 wk.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Nephropathy in model combining genetic hypertension with experimental diabetes. Enalapril versus hydralazine and metoprolol therapy.

We compared the effects of the angiotensin-converting enzyme inhibitor enalapril and a conventional antihypertensive regimen (hydralazine and metoprolol) on kidney function, albuminuria, and glomerular ultrastructure in hypertensive diabetic and nondiabetic rats. Diabetes was induced with streptozocin at 8 wk of age in spontaneously hypertensive (SHR) rats. Antihypertensive drugs were administered in drinking water from the time of induction of diabetes in all groups. Blood pressure reduction was equal in the diabetic and nondiabetic SHR rats receiving either enalapril or hydralazine plus metoprolol. In diabetic SHR rats, there was a rise in serum creatinine after 32 wk, which did not occur in diabetic rats treated with either antihypertensive regimen or in nondiabetic rats. Both drug regimens reduced albuminuria in diabetic and nondiabetic SHR rats to a similar degree. Enalapril and the combination of hydralazine and metoprolol were associated with decreased glomerular basement membrane thickness and glomerular volume in diabetic and nondiabetic SHR rats without significant effect on fractional mesangial volume. Thus, antihypertensive therapy retards the development of albuminuria, glomerular basement membrane thickening, and glomerular hypertrophy in the rat in the presence or absence of diabetes. No specific benefit of angiotensin-converting enzyme inhibition was observed in these hypertensive models of nephropathy. Human studies comparing the effects of different classes of antihypertensive drugs on kidney function, proteinuria, and glomerular morphology are warranted.

Administration, Oral↗
PubMed1989

Enalapril retards glomerular basement membrane thickening and albuminuria in the diabetic rat.

This study has evaluated the effects of the angiotensin converting enzyme inhibitor Enalapril on glomerular ultrastructure and albuminuria in normotensive and hypertensive diabetic rats. Streptozotocin-diabetes was induced in Wistar Kyoto and spontaneously hypertensive rats. Enalapril was administered in drinking water in diabetic normotensive, control hypertensive and diabetic hypertensive rats. Enalapril therapy prevented an increase in glomerular basement membrane thickness in diabetic normotensive, control hypertensive and diabetic hypertensive rats without any significant effect on fractional mesangial volume. Enalapril decreased albuminuria in diabetic normotensive, control hypertensive and diabetic hypertensive rats. Thus, enalapril retards the development of glomerular basement membrane thickening and albuminuria in the rat, in the presence or absence of hypertension.

Albuminuria↗
PubMed1989

Ramipril reduces albuminuria in diabetic rats fed a high protein diet.

1. Streptozotocin diabetes was induced in Wistar-Kyoto rats fed a 50% protein diet. Animals were randomized to receive either the ACE inhibitor ramipril, 1 mg/L in drinking water (n = 7), or no treatment (n = 7) and were studied for 6 months. Blood glucose, body weight and glomerular filtration rate (GFR) were measured at 0, 1, 4, 8 and 16 weeks of diabetes and urinary albumin excretion was measured every 8 weeks. 2. In both groups, GFR increased significantly within 1 week of induction of diabetes (P less than 0.001) and thereafter remained stable. There was no difference in GFR between the treated and untreated groups. 3. Urinary albumin excretion increased progressively in both groups throughout the study. Ramipril treatment reduced albuminuria by approximately 50% at weeks 16 and 24 (P less than 0.01). 4. The amelioration of diabetic albuminuria by ACE inhibition, in the setting of high dietary protein intake, may have important implications for the treatment of human diabetic nephropathy.

Albuminuria↗
PubMed1989

Triphasic changes in selectivity with increasing proteinuria in type 1 and type 2 diabetes.

Two indices of the selectivity of proteinuria, the immunoglobulin G (IgG)/albumin and the IgG/transferrin clearance ratios, were studied cross-sectionally and serially over 7 years in a cohort of 52 Type 1 and 60 Type 2 diabetic patients without established diabetic nephropathy. In Type 1 and Type 2 diabetic patients with albuminuria less than 30 micrograms min-1, both protein clearance ratios were significantly higher than in 27 control subjects. As albuminuria increased, there was a decrease in both protein clearance ratios. However, at albumin clearances above 90 nl s-1, equivalent to albumin excretion rates of greater than 250 micrograms min-1, a positive correlation was found in Type 2 diabetic patients between protein clearance ratios and albuminuria. In individual Type 1 and Type 2 diabetic patients with progressively increasing proteinuria, serial measurements of selectivity showed a decline in both protein clearance ratios with the onset of microalbuminuria. Episodes of transient microalbuminuria were also associated with a fall in the IgG/albumin clearance ratio. The results suggest that the selectivity of proteinuria undergoes a triphasic change with the development of diabetic nephropathy. In the first phase, proteinuria is non-selective with IgG clearance equal to or exceeding transferrin or albumin clearance. As microalbuminuria develops, there is a progressive increase in selectivity reflecting the preferential excretion of transferrin and albumin compared with IgG. In later stages of nephropathy, as shown in Type 2 diabetic patients with macroalbuminuria, there is a return to non-selective proteinuria.

Albuminuria↗
PubMed1989

Characteristics of a 5-hydroxytryptamine-sensitive adenylate cyclase in intact and intracellularly perfused squid axons.

1. Cyclic AMP metabolism was studied in intact and intracellularly perfused axons. 2. Cyclic AMP content of intact axons lay within the range 10-100 nmol kg-1 axoplasm. This was increased by exposure to caffeine (2-fold) and to 5-HT (15-fold). The caffeine-sensitive cyclic AMP increase was 30-fold larger in the presence of 5-HT. 3. A reduction in sodium concentration from the sea water bathing intact axons attenuated the 5-HT-evoked increase in cyclic AMP content, but had little effect on resting cyclic AMP. This effect was partially reversed by exclusion of external calcium, and suggests that free calcium plays a role in cyclic AMP homeostasis. 4. Prolonged exposure of intact axons to 5-HT (up to 3 h) led to apparent desensitization of the cyclic AMP response. 5. Intracellular perfusion can be used as a method to study adenylate cyclase in a single axon, simply by measuring the cyclic AMP content of the emerging perfusate. 6. Intracellular perfusion revealed micromolar requirements for internal GTP (K0.5 approximately 1-10 microM) and external 5-HT (K0.5 approximately 1-10 microM); a detailed investigation of this observation was limited due to the progressive loss of 5-HT-evoked adenylate cyclase activity with time. This slow loss was not seen during Gpp(NH)p (guanylylimidodiphosphate), NaF or forskolin activation of cyclase activity. 7. In perfused axons, an increase in intracellular calcium stimulated cyclase activated by 100 microM-forskolin but inhibited cyclase activated by 500 microM-Gpp(NH)p or 10 mM-NaF. A reduction in intracellular magnesium from 10 to 4-5 mM attenuated the effects of 5-HT-evoked cyclase activity. 8. Study of the perfused axon allows characterization of the intracellular requirements of a plasmalemmal transduction system which activates adenylate cyclase, whilst maintaining ionic asymmetry across the cell membrane.

Adenylyl Cyclases↗
PubMed1988

The effects of nitroprusside and putative agonists on guanylate cyclase activity in squid giant axons.

cGMP content of axoplasm from the giant axon of Loligo forbesi was investigated after subjecting the axon to various treatments. Repetitive electrical stimulation or depolarisation by high K+ caused no change in cGMP content. Glutamate and serotonin were also without effect. The nicotinic agonist carbachol (100 microM) increased cGMP levels by 90% (n = 5). A large transient elevation of cGMP content was evoked by external nitroprusside (10 nM-20 microM in intact axons. Nitroprusside injected into both extruded axoplasm and intact axons also increased cGMP content, the stimulation being considerably higher in intact axons where the axolemma was also present. Nitroprusside was also active in axons where the soluble cytoplasmic components were washed out by internal perfusion.

Animals↗
PubMed1988

Genetic hypertension accelerates nephropathy in the streptozotocin diabetic rat.

To evaluate whether hypertension is a cause or just an association with diabetic renal disease, diabetes was induced in both normotensive Wistar-Kyoto and spontaneously hypertensive rats (WKY and SHR). Animals were assessed monthly for 8 months before sacrifice. When compared to normotensive diabetic rats (WKY-STZ), hypertensive diabetic rats (SHR-STZ) had an earlier and more rapid rise in urinary albumin excretion. In addition, SHR-STZ had increased glomerular basement membrane thickness when compared to WKY-STZ or SHR. In a separate experiment, Enalapril therapy (35 mg/L) was administered in drinking water to WKY-STZ and SHR-STZ. Enalapril significantly reduced blood pressure in both animal groups, and this was associated with a decrease in urinary albumin excretion. The SHR-STZ model has accelerated nephropathy as determined by both functional and structural parameters. Angiotensin-converting enzyme inhibition is associated with a reduction in albuminuria in both hypertensive and normotensive models of diabetic nephropathy.

Albuminuria↗
PubMed1988

Effects of genetic hypertension on diabetic nephropathy in the rat--functional and structural characteristics.

Streptozotocin (STZ) diabetes was induced in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. Body weight, blood pressure, renal function, glycaemic control and proteinuria were assessed monthly for 32 weeks. At 32 weeks, the animals were killed and glomerular basement membrane (GBM) thickness and fractional mesangial volume were measured. There was no significant difference in renal function between diabetic SHR and diabetic WKY. Diabetic SHR showed an earlier and larger rise in total proteinuria and urinary albumin excretion than diabetic WKY. Urinary albumin excretion was increased more than tenfold in diabetic SHR compared to diabetic WKY after 32 weeks of diabetes. GBM thickness was significantly increased in diabetic SHR compared with diabetic WKY. Both diabetic WKY and diabetic SHR showed mesangial expansion when compared to their nondiabetic counterparts. On the other hand, both hypertensive models showed increased glomerular volume, which was not influenced by the presence of diabetes. The diabetic SHR model has features of accelerated nephropathy, as evidenced by increased albuminuria and GBM thickness. This suggests that pre-existing hypertension may play an important role in the progression of diabetic renal disease.

Animals↗
PubMed1988

Effect of glycaemic control on glomerular filtration rate in the streptozotocin diabetic rat.

1. Diabetes was induced in 32 adult Wistar-Kyoto rats with streptozotocin (60 mg/kg). Fourteen rats remained untreated, 10 received insulin three times per week, and eight received insulin daily. Fourteen non-diabetic rats served as controls. 2. Exchangeable sodium and plasma volume were elevated in the untreated diabetic rats. Treatment normalized these parameters. 3. Glomerular filtration rate (GFR) was elevated in the untreated diabetic group and the group receiving insulin three times per week compared with the control group. Daily insulin treatment restored GFR towards control values. 4. Plasma atrial natriuretic factor was similar in untreated diabetic rats and non-diabetic rats.

Animals↗
PubMed1986

Accelerated progression of diabetic nephropathy in the spontaneously hypertensive streptozotocin diabetic rat.

Streptozotocin (STZ)-diabetes was induced in spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats with their litter mates serving as controls. The animals were studied for 6 months and blood pressure, weight, urinary and serum glucose, creatinine clearance, total proteinuria and albuminuria were measured monthly. With induction of diabetes, there was a significant rise in creatinine clearance in the hypertensive diabetic animals (SHR-STZ). SHR-STZ (n = 6) developed higher levels of total proteinuria than WKY-STZ (n = 5) although the rise from basal levels was only apparent after 20 weeks of diabetes. All SHR-STZ developed albustix positive proteinuria after 6 months of diabetes. In the first 12 weeks after onset of diabetes, albuminuria increased to a greater degree in SHR-STZ than in WKY-STZ. This occurred before there was a detectable rise in total proteinuria. The SHR-STZ model of genetic hypertension and diabetes may be suitable for the evaluation of antihypertensive therapy in human diabetic renal disease.

Albuminuria↗
PubMed1986

Comparison of the effects of potassium and membrane potential on the calcium-dependent sodium efflux in squid axons.

Experiments are described in which the [Ca]o-dependent component of 22Na efflux is monitored under conditions of membrane potential control by voltage clamp. The apparent affinity of the efflux system for external Ca is very low in choline sea water (apparent KD approximately 50 mM); but increases dramatically when choline is replaced isosmotically by Li or K (apparent KD approximately 1-2 mM). Ca influx changes in a parallel fashion. Tris behaves much like choline and guanidinium is about two-thirds as effective as Li. Replacement of Li by K has little effect on the apparent affinity for external Ca but brings about a small (30-40%) increase in the maximal flux. The increase in maximum flux can be removed by electrical hyperpolarization to the potential before application of K and, in the absence of K, can be mimicked by electrical depolarization. These experiments suggest that the stimulatory effect of K on the Ca-dependent Na efflux into Li sea water is electrical in origin. Partial replacement of choline by K stimulates the Ca-dependent Na efflux; but only part of this stimulation can be removed by electrical hyperpolarization and, in the absence of K, electrical depolarization only brings about a relatively small stimulation. This is because only part of the stimulation that follows addition of K to choline sea waters is electrical in origin: the rest reflects an increase in the apparent affinity for external Ca that is brought about by K acting chemically. The maximum efflux into K is about 40% higher than that into choline. That this may reflect an electrical effect is supported by the observation that electrical depolarization increases the flux into choline sea water containing 110 mM-Ca where the Ca-binding site is close to saturation. The voltage clamp was used to determine the voltage dependence of the Ca-dependent Na efflux into Li sea water, choline sea water and choline sea water containing 100 mM-Na. In all three cases the flux increased with depolarization and was still rising at +70 mV. The dependence on potential was not very steep, an e-fold increase occurred over approximately 50 mV.

Animals↗