Childhood immunization availability in primary care practices.
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Child↗
Biomedical subjects
T J Allen
Publications and source records attributed to T J Allen.
The effect of a chemical phosphatase on single calcium channels and the inactivation of whole-cell calcium current from isolated guinea-pig ventricular myocytes.
A chemical phosphatase, butanedione monoxime (BDM, at 12-20 mM), reduced open probability (P0) of single cardiac L-type Ca2+ channels in cell-attached patches from guinea-pig ventricular myocytes, without effect on the amplitude of single-channel current, the mean open time or the mean shorter closed time, but it increased mean longer closed time and caused a fall in channel availability. A decrease in the mean time between first channel opening and last closing within a trace was principally due to an inhibition of the longer periods of activity. As a result, the time course of the mean currents, which resolved into an exponentially declining and a sustained component, was changed by an increase in the rate of the exponential phase and a profound reduction of the sustained current. Essentially similar results were obtained when studying whole-cell Ba2+ currents. The inactivation of the whole-cell Ca2+ currents was composed of two exponentially declining components with the slower showing a significantly greater sensitivity to BDM, an effect that was much more pronounced in myocytes exposed to isoprenaline with adenosine 5'-O-(3-thiotriphosphate) (ATP[gamma S]) in the pipette solution. The actions of BDM, which are the opposite of those produced by isoprenaline, suggest that the level of phosphorylation affects processes involved in the slow regulation of channel activity under basal conditions and that several sites (and probably several kinases) are involved. Channels with an inherently slow inactivation would seem to be converted into channels with a rapid inactivation by a dephosphorylation process.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Role of endothelium-derived nitric oxide in the pathogenesis of the renal hemodynamic changes of experimental diabetes.
To evaluate the role of nitric oxide (NO) in diabetic hyperfiltration, renal hemodynamic changes and changes in urinary excretion of NO2/NO3 in response to the NO inhibitor nitro-L-arginine methyl ester (L-NAME) and the NO-donating agent glyceryl trinitrate (GTN) were investigated in conscious streptozocin-induced diabetic (D) and age-matched control (C) rats. In all experiments, D rats demonstrated increased glomerular filtration rate (GFR), renal plasma flow (RPF), polyuria, and an increased urinary sodium excretion when compared with C rats. An intravenous bolus of low-dose L-NAME (1 mg/kg body wt) increased modestly systolic blood pressure (sBP) in C rats but had no effect on sBP in D rats. L-NAME induced a marked decrease in GFR and RPF in D rats with no change in filtration fraction (FF). In C rats, no change in GFR was observed, and RPF decreased, resulting in a rise in FF. A supramaximal dose of L-NAME (10 mg/kg body wt) increased sBP in C and D rats to a similar degree. With high-dose L-NAME, GFR decreased in D but not in C rats. There was a greater decrease in RPF in D rats when compared with C animals. An intravenous infusion of GTN induced a modest decrease in sBP in both C and D rats (P < 0.01). There were no changes in GFR and RPF in D rats, but in the C group, GTN increased RPF (P < 0.05) with a tendency for a rise in GFR (P = 0.09). Basal urinary NO2/NO3 excretion was increased in D rats in all experiments.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Disparate effects of castration on renal structure and function in the streptozotocin diabetic rat.
Diabetic children are protected from the complications of diabetes until puberty, suggesting the involvement of a hormonal mechanism. In order to investigate the contribution of sex steroids to the development of diabetic nephropathy, castrated Wistar-Kyoto rats were made diabetic with streptozotocin and compared with intact diabetic rats. In intact rats, 32 weeks of diabetes resulted in hyperfiltration (p = 0.0001) and a marked increase in albuminuria (control, 1.3 x/divided by 1.3 vs diabetes intact, 11.8 x/divided by 1.3 mg/day, p < 0.001). Concomitant structural changes included glomerular basement membrane thickening (diabetes, 199.2 +/- 7.9 vs control, 175.9 +/- 3.9 nm, p = 0.02) and increased mesangial volume (diabetes, 194 +/- 14 vs control, 129 +/- 20 microns 3, p = 0.02). Although castration resulted in blood pressure lowering of 12 mmHg (p = 0.0003), albuminuria increased to the same extent in intact and castrated diabetic rats (castrated diabetic 10.5 x/divided by 1.3 mg/day). Glomerular filtration rate was lower in castrated rats than in intact rats prior to induction of diabetes, but increased similarly with induction of diabetes. Castrated diabetic rats had increased mesangial volume (castrated diabetic, 213 +/- 20 microns 3), but glomerular basement membrane thickness was lower than in intact diabetic rats (castrated diabetic, 179.5 +/- 4.5 nm). Thus, there is a dissociation between basement membrane thickening and albuminuria in this model of diabetic kidney disease. The mechanism of action of castration on glomerular function and structure remains to be elucidated but may relate to indirect effects such as reduction of blood pressure or renal polyol accumulation or a direct effect of sex steroids.
Albuminuria↗
The effects of dietary cholesterol on experimental diabetic nephropathy.
Hyperlipidaemia has been previously shown to accelerate various models of renal disease. The present study has evaluated the effects of dietary cholesterol supplementation on functional and structural aspects of experimental diabetic nephropathy. Control and streptozotocin diabetic male Sprague Dawley rats were randomized to receive a normal diet or a high cholesterol (4% cholesterol + 1% cholic acid) diet. After 32 weeks, serum lipids, glycaemic control, urinary albumin excretion and glomerular ultrastructural parameters were evaluated in the 4 groups. Diabetes was associated with increased total cholesterol and triglyceride levels. Cholesterol supplementation increased total and decreased HDL-cholesterol in control and diabetic rats. Diabetes increased albuminuria but cholesterol supplementation did not influence urinary albumin excretion. In diabetic rats, glomerular basement membrane thickness and glomerular volume were increased but cholesterol supplementation did not influence any glomerular ultrastructural parameter. In control rats, increased dietary cholesterol intake led to an increase in blood pressure and glomerular volume. In contrast to other models of renal disease, experimental diabetic nephropathy does not appear to be exacerbated by dietary cholesterol supplementation.
Albuminuria↗
The use of intracellular dialysis to study signal transduction coupling in the squid giant axon.
The squid giant axon has proved a useful model in the study of ionic channel gating, intracellular homeostasis and receptor-mediated signal transduction leading to generation of intracellular second messengers. In the latter category, previous studies on activation of adenylate or guanylate cyclase have used intact and intracellularly perfused axons to investigate the effects of extra- and intracellular agents on the transduction processes. However, the perfusion of the axon interior washes out many factors which may be important in the processes under study. We introduce here the use of porous cellulose dialysis tubing as a means to circumvent these problems. We find that this dialysis technique is a simple procedure to set-up, and the serotonin/G-protein/adenylate cyclase system can readily be studied in the dialysed axon. This approach should allow investigation under conditions which retain asymmetric transmembrane conditions.
Adenylyl Cyclases↗
Antihypertensive therapy in a model combining spontaneous hypertension with diabetes.
We have compared the effects of the angiotensin converting enzyme inhibitor, perindopril, and a conventional antihypertensive regimen (triple therapy: hydralazine, reserpine and hydrochlorothiazide) on kidney function and albuminuria in hypertensive diabetic rats. Diabetes was induced with streptozotocin in spontaneously hypertensive (SHR) rats and they were randomized to receive no treatment, perindopril or triple therapy. Antihypertensive drugs were commenced at the time of induction of diabetes and continued for 16 weeks. Blood pressure reduction was equal in the groups treated with perindopril or triple therapy. All groups had similar severity of diabetes as determined by body weight, serum glucose and glycated hemoglobin levels. Whereas plasma renin activity rose in both the perindopril and triple therapy groups, it is likely that the effects on angiotensin II levels were opposite since perindopril but not triple therapy was associated with a significant reduction in plasma angiotensin converting enzyme activity. Diabetes was associated with an increase in glomerular filtration rate. At 12 weeks, glomerular filtration rate was higher in the perindopril treated group when compared to the triple therapy group, but neither group treated with antihypertensive therapy was different to untreated diabetic rats. Both drug regimens reduced albuminuria in the diabetic rats to a similar degree apparently independently of their effects on the renin-angiotensin system. Studies in diabetic subjects are warranted to evaluate different classes of antihypertensive drugs with respect to their effects on kidney function, proteinuria and glomerular morphology.
Albuminuria↗
Angiotensin converting enzyme inhibition and calcium channel blockade in incipient diabetic nephropathy. The Melbourne Diabetic Nephropathy Study Group.
Small increases in blood pressure are a feature of incipient diabetic nephropathy, and mean blood pressure often correlates with the degree of albuminuria in such patients. Antihypertensive therapy with angiotensin converting enzyme inhibitors (CEI) or calcium channel blockers (CCB) has been assessed in several studies to determine if either form of treatment modifies incipient diabetic nephropathy and its evolution to established nephropathy. The acute renal hemodynamic effects of CEI differ from those of CCB under certain circumstances. In incipient diabetic nephropathy, therapy with CEI but not CCB tends to reduce filtration fraction, especially in hyperfiltering patients. In hypertensive patients with incipient diabetic nephropathy, both treatments result in a decrease in albuminuria and the responses are mainly dependent on the lowering of systemic blood pressure. In normotensive patients with incipient diabetic nephropathy, a lowering of mean blood pressure with CEI or CCB is not found consistently while effects on albuminuria are difficult to interpret. Short- and long-term therapy with CEI lowers or stabilizes albuminuria. Short-term administration of CCB has at times been associated with increases in albuminuria, but a comparison of CEI and CCB over 12 months in the Melbourne Diabetic Nephropathy Study (MDNS) has shown that both drugs stabilize albuminuria with no significant differences in their effects. Serial analysis of urinary sodium excretion in the MDNS shows that the hypotensive response to CEI in incipient nephropathy is highly dependent on sodium intake, and that sodium intake may modulate albuminuria during both CEI and CCB therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin-Converting Enzyme Inhibitors↗
Role of the GTP-binding protein Gs in the beta-adrenergic modulation of cardiac Ca channels.
In the heart, the guanosine 5'-triphosphate (GTP)-binding protein Gs is activated by hormone binding to beta-adrenergic receptors and stimulates the intracellular cyclic adenosine 3',5'-monophosphate (cAMP) pathway that leads to phosphorylation of L-type Ca channels by the cAMP-dependent protein kinase A. Additionally, Gs can modulate cardiac Ca channels directly in cell-free systems. In order to examine the question of whether these pathways could be separated functionally and whether they act independently or synergistically on L-type Ca channels in intact cells, the whole-cell Ca current (ICa) and the respective current density were measured in guinea-pig ventricular myocytes at 0 mV. The following results were obtained. First, typically, the ICa density increased from 12 to 40 microA/cm2 following application of 1 microM isoproterenol (ISP) to myocytes bathed in solutions containing 1.8 mM CaCl2. However, 1 microM ISP enhanced ICa only from 9 to 17 microA/cm2 after inhibition of the protein kinase A by dialysis of 0.5 mM Rp-cAMPs (the Rp-isomer of adenosine 3',5'-monophosphorothioate) in the presence of 0.5 mM GTP. Withdrawal of GTP from the dialysate attenuated the effects of ISP on ICa. Thus, Rp-cAMPS unmasks a GTP-dependent component of the beta-adrenergic stimulation of ICa, which probably reflects the direct stimulation of Ca channels by Gs under block of cAMP-dependent phosphorylation. Second, in cells under dialysis with 100 or 200 microM cAMP, bath application of 20-40 microM 3-isobutyl-1-methylxanthine (IBMX) enhanced the ICa density to about 41 microA/cm2 indicating saturation of the cAMP pathway. Under this condition, 1 microM ISP was without significant effect on ICa. This result may suggest that direct Gs stimulation is rather ineffective on Ca channels after maximal cAMP-dependent phosphorylation. Alternatively, maximal stimulation of the cAMP pathway may also interfere with the activation of the Gs pathway in intact myocytes. Third, simultaneous application of 1 microM ISP and 40 microM IBMX enhanced ICa up to densities of around 75 microA/cm2 during cell dialysis with 100 microM cAMP, an effect much stronger than that exerted by IBMX alone under similar conditions. Since it seems likely that Gs is activated more quickly, than the cAMP pathway during application of the ISP/IBMX mixture, the latter result suggests that a direct effect of Gs may act to prime L-type Ca channels for cAMP-dependent phosphorylation during beta-adrenergic stimulation of cardiac myocytes.
1-Methyl-3-isobutylxanthine↗
The exchange in intact squid axons.
The exchange in intact axons displays a number of features in common with other systems, but a number of interesting points remain to be examined. Both forward (Nao-Cai) and reverse (Cao-Nai) exchange are sensitive to changes in membrane potential, but potassium depolarization can also stimulate Cao-Nai exchange by chemical activation at a monovalent cation-binding site. By monitoring lithium uptakes into intact axons, activating cations do not appear to be transported on the exchange, but this deserves further examination under more stringent conditions. Cao-Nai exchange in intact axons appears activated by monovalent cations to a greater extent compared to dialyzed axons that exhibit little, if any, shift in the Km for Cao. The catalytic effect of Cai on Cao-Nai exchange seen in dialyzed axons proves elusive to study in intact axons, with or without introduction of Ca chelators. Experiments using ruthenium red suggest that free calcium can be dissociated from Cao-Nai exchange fluxes; this finding is also important to those studies monitoring exchange activity using Ca indicators. The possibility that Ca chelators may effect changes in the kinetics of Na-Ca exchange is a subject that needs further investigation.
Animals↗
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↗
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↗
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↗
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↗
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↗
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↗
Direct and indirect regulation of cardiac L-type calcium channels by beta-adrenoreceptor agonists.
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Adenylyl Cyclases↗
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↗