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Biomedical subjects

R Donnelly

Publications and source records attributed to R Donnelly.

At least 73 records · Page 4Linked to original sources
PubMed1998

Evidence that oxidized proteins are substrates for N-terminal arginylation.

While the posttranslational N-terminal arginylation of proteins has been demonstrated in a variety of eukaryotic cells including neurons and their axons, the targets of the reaction are poorly understood. Several lines of evidence suggest that arginylation may be a cytoprotective mechanism used by cells to target oxidatively damaged (and thus potentially toxic) proteins for degradation. In the present experiments, we have begun to test this hypothesis by incubating oxidized test proteins in a rat brain extract capable of arginylating endogenous proteins. Bovine serum albumin, pancreatic ribonuclease-A and the A-chain of insulin were chosen as test proteins and either oxidized by metal catalyzed oxidation or purchased in their oxidized forms and incubated with the extract and [3H]Arg. SDS PAGE of the incubation product showed [3H]Arg migrating with the oxidized forms of BSA and RNase but not with the un-oxidized form of BSA. Following incubation with the oxidized A-chain of insulin, analysis of the [3H]product by SDS PAGE and HPLC showed co-migration of [3H]Arg with A-chain standards and amino acid sequencing showed [3H]Arg at the N-terminus of the A-chain of insulin. The data suggest that oxidative damage to a protein may be a signal for its N-terminal arginylation.

Animals↗
PubMed1998

Lacidipine: effects on vascular pressor responses throughout the dosage interval in normotensive subjects.

AIMS: To assess the duration and consistency of the pharmacological activity of the dihydropyridine calcium antagonist drug, lacidipine. METHODS: Eight healthy normotensive young males participated in a double-blind randomised crossover comparison of single and multiple doses (for 2 weeks) of lacidipine and placebo. The calcium antagonist effects were quantified at 2, 6 and 24 h post dose by the extent of the attenuation of the pressor responses to the intravenous administration of the vasoconstrictors angiotensin II and noradrenaline. RESULTS: After 2 weeks of treatment, lacidipine consistently and significantly attenuated the pressor responses to both agents at 2 h post dose. At 6 and 24 h post dose there was a significant and progressive decline in the effectiveness of lacidipine in attenuating the pressor responses and for the response to angiotensin II there was no statistically significant effect at either 6 or 24 h post dose. CONCLUSIONS: These results indicate that there is an obvious 'peak' in the pharmacological activity of lacidipine at about 2 h post dose and that this activity is not fully and consistently maintained throughout 24 h.

Adult↗
PubMed1998

Mechanisms of insulin resistance and new pharmacological approaches to metabolism and diabetic complications.

1. Resistance to insulin-mediated glucose transport and metabolism has been identified as a primary mechanism in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM) and as a target for drug development. The aetiology of insulin resistance is likely to be multifactorial, but the present review focuses on candidate post-receptor mechanisms of insulin resistance, particularly protein kinase C (PKC), and the metabolic and genetic significance of beta3-adrenoceptors (beta3-AR) in adipose tissue. 2. Multiple lines of evidence suggest that isoform-selective activation of PKC phosphorylates and down-regulates one or more substrates involved in glucose transport and metabolism (e.g. glycogen synthase and the insulin receptor) and recent studies have shown increased expression of calcium-independent isozymes (PKC-epsilon and PKC-theta) in the membrane fraction of skeletal muscle in fructose- and fat-fed rat models of insulin resistance. In addition, there is separate evidence that glucose-induced PKC activation plays an important role in the micro- and macrovascular complications of diabetes. 3. New pharmacological approaches to NIDDM and obesity have focused on insulin-sensitizing agents (e.g. troglitazone), beta3-AR agonists, anti-lipolytic drugs (e.g. the adenosine A1 receptor agonist GR79236) and selective inhibitors of PKC isoforms (e.g. the inhibitor of PKC-beta LY333531). Experimental studies with GR79236 show that this drug ameliorates the hypertriglyceridaemia induced by fructose feeding and that the reduction in fatty acid levels is associated with secondary improvements in glucose tolerance. 4. Recent insights into the pathogenesis of NIDDM and its associated complications have been used to develop a range of new therapeutic agents that are currently showing promise in clinical and preclinical development.

Animals↗
PubMed1998

Metabolic effects of thioctic acid in rodent models of insulin resistance and diabetes.

1. The antioxidant thioctic acid (TA) has been used in the treatment of diabetic neuropathy and recent studies have suggested that TA also has pancreatic and peripheral effects that improve glucose transport and metabolism. In the present study, the metabolic effects of TA were evaluated in rodent models of insulin resistance (fructose-fed Sprague-Dawley rat) and insulin deficiency (streptozotocin (STZ)-induced diabetic rat). Oral and intravenous glucose tolerance tests (OGTT and IVGTT, respectively) were performed in conscious rats after treatment with 50 mg/kg per day TA or vehicle for 5 days. 2. Fructose feeding for 7 days induced insulin resistance and impaired glucose tolerance and hypertriglycerideaemia. Treatment of fructose-fed rats with TA had no significant effect on fasting or stimulated glucose levels or on fasting triglyceride concentrations (e.g. the area under the curve for glucose (AUCglu) following OGTT was 1233 +/- 67 and 1284 +/- 59 in fructose-fed rats treated with either TA (n = 12) or vehicle (n = 12), respectively). Similarly, TA had no significant effect on IVGTT profiles in fructose-induced insulin resistance. 3. Low-dose STZ (80 mg/kg, i.p., over 2 days) induced hyperglycaemia, but TA had no significant glucose-lowering effects in STZ-diabetic rats (AUCglu (OGTT) following oral administration was 5507 +/- 27 and 5450 +/- 27 in TA (n = 12) and vehicle-treated (n = 12) rats, respectively). Nor did pretreatment with TA affect the diabetogenic response to STZ. 4. In contrast with previous in vitro studies reporting favourable metabolic effects of TA, the present study shows that after short-term oral therapy there are no significant improvements in glucose tolerance in rodent models of insulin resistance and insulin deficiency. Thioctic acid is unlikely to be of therapeutic benefit as an anti-diabetic drug in clinical practice.

Animals↗
PubMed1998

Is there a concentration-effect relationship for sulphonylureas?

Sulphonylureas have remained the mainstay of oral therapy for type 2 (non-insulin-dependent) diabetes mellitus (NIDDM). They stimulate insulin release from pancreatic beta cells. Pharmacokinetic differences between the various sulphonylureas are of clinical importance in terms of the time to onset of action, timing of drug administration in relation to food intake, magnitude and duration of the glucose-lowering effect and the risk of serious hypoglycaemia. Recent studies with improved analytical sensitivity have shown that the elimination half-life of glibenclamide is longer than previously thought and that 2 metabolites of glibenclamide have significant hypoglycaemic activity. Furthermore, single dose studies in healthy volunteers using an integrated pharmacokinetic-pharmacodynamic model have identified clear concentration-effect relationships for both glibenclamide and its metabolites after oral and intravenous administration. Under multiple dose conditions, kinetic-dynamic relations have been identified with shorter-acting drugs in dosages that give discontinuous sulphonylurea exposure. However, at continuous exposure, i.e. sustained 24-hour therapeutic concentrations in plasma, there is evidence indicating the development of tolerance, which may be caused by downregulation of beta cell sensitivity. As more sophisticated concentration-effect studies appear, it has become evident that currently recommended maximum daily doses of many sulphonylureas are too high.

Diabetes Mellitus, Type 2↗
PubMed1997

Short-term metabolic and haemodynamic effects of GR79236 in normal and fructose-fed rats.

The adenosine (A1) receptor agonist, GR79236 (N-[(1S,trans)-2-hydroxycyclopentyl]adenosine), inhibits catecholamine-induced lipolysis in vitro, but the short-term metabolic and haemodynamic effects have not been previously reported in the fructose fed model of insulin resistance, dyslipidaemia and hypertension. This study reports the effects of GR79236 (1 mg/kg/day for 8 days) on nonesterified free fatty acid and triglyceride metabolism, oral and i.v. glucose tolerance, blood pressure and heart rate, and insulin sensitivity, in normal rats and rats fed a fructose-enriched diet. In normal rats, GR79236 significantly reduced fasting glucose (25%), free fatty acid (50%) and triglyceride (55%) concentrations, and improved glucose tolerance (AUC[glu] 21.2 +/- 1.3 vs. 16.5 +/- 1.1 mmol h/l, p < 0.05). Fructose feeding induced a state of insulin resistance and dyslipidaemia, as shown by an increase in steady-state plasma glucose levels (7.1 vs. 6.1 mmol/l), impaired i.v. glucose tolerance and a 3-fold rise in fasting triglyceride levels; fructose-fed rats also developed a significant increase in blood pressure. GR79236 ameliorated the effects of fructose feeding on fatty acid and triglyceride levels, and blood pressure, and improved i.v. glucose tolerance in fructose-fed rats. The hypotriglyceridaemic effect was due to a reduction in triglyceride secretion rate (17.3 +/- 1.7 vs. 30.2 +/- 1.1). Thus, in normal rats and in a dietary-induced rodent model of insulin resistance, dyslipidaemia and hypertension, GR79236 has lipid-lowering and glucose-lowering activity, as well as haemodynamic effects, which are potentially useful for treating both the metabolic and haemodynamic features of insulin resistance and NIDDM in humans.

Adenosine↗
PubMed1997

Chimeric erythropoietin-interferon gamma receptors reveal differences in functional architecture of intracellular domains for signal transduction.

Binding of interferon gamma (IFN-gamma) causes oligomerization of the two interferon gamma receptor (IFN-gammaR) subunits, receptor chain 1 (IFN-gammaR1, the ligand-binding chain) and the second chain of the receptor (IFN-gammaR2), and causes activation of two Jak kinases (Jak1 and Jak2). In contrast, the erythropoietin receptor (EpoR) requires only one receptor chain and one Jak kinase (Jak2). Chimeras between the EpoR and the IFN-gammaR1 and IFN-gammaR2 chains demonstrate that the architecture of the EpoR and the IFN-gammaR complexes differ significantly. Although IFN-gammaR1 alone cannot initiate signal transduction, the chimera EpoR/gammaR1 (extracellular/intracellular) generates slight responses characteristic of IFN-gamma in response to Epo and the EpoR/gammaR1. EpoR/gammaR2 heterodimer is a fully functional receptor complex. The results demonstrate that the configuration of the extracellular domains influences the architecture of the intracellular domains.

Humans↗
PubMed1997

Detection and treatment of hypertension in patients with non-insulin-dependent diabetes mellitus: does the 'rule of halves' apply to a diabetic population?

The extent to which hypertension is detected and adequately treated in the general population is often described by the 'rule of halves', but corresponding figures for patients with non-insulin-dependent diabetes mellitus (NIDDM), based on current American Diabetes Association (ADA) criteria, have not been previously reported. This study looked at the detection and management of hypertension among 2331 consecutive patients with NIDDM attending for annual complications assessment. Hypertension was defined according to ADA criteria, i.e. systolic blood pressure (sBP) > 140 mmHg and/or diastolic blood pressure (dBP) > 90 mmHg. A total of 69% of patients were hypertensive, with proportionately more women in the hypertensive group (48 versus 39%, P < 0.002). Among those with hypertension, 59% were taking antihypertensive drugs but only 31% of treated hypertensives were adequately controlled. Thus, hypertension affects roughly two-thirds of patients with NIDDM and compared with treatment strategies reported in the literature for the non-diabetic population (summarised in the 'rule of halves'), proportionately more hypertensive patients with NIDDM are treated with BP-lowering drugs (59%) but proportionately less (31%) have adequate BP control.

Australia↗
PubMed1997

Is insulin resistance in the spontaneously hypertensive rat related to changes in protein kinase C in skeletal muscle?

The mechanism of insulin resistance in the spontaneously hypertensive rat (SHR) has not been clearly identified, but protein kinase C (PKC) has been implicated as a mechanism of insulin resistance in obesity and diabetes mellitus and in a diet-induced (fructose-fed) model of insulin resistance and hypertension. This study compared PKC enzyme activity (cytosol and particulate fractions) and expression of the muscle-specific isoform, PKC-theta (Western blotting), in red (soleus) and white (tensor fascia latae) hindlimb muscles from SHR (n = 12) and WKY (n = 12) rats. SHRs were hypertensive and insulin resistant, as shown by higher insulin (188 +/- 34 v 169 +/- 22 pmol/L), triglycerides (1.65 +/- 0.07 v 1.38 +/- 0.06 mmol/L), and nonesterified fatty acids (0.99 +/- 0.05 v 0.78 +/- 0.04 mmol/L) concentrations. PKC activity was significantly greater in the membrane fraction, compared with the cytosol, but there were no significant differences either in PKC activity or subcellular distribution, or expression of PKC-theta, between the two strains. Thus, insulin resistance in the SHR (in contrast to the fructose-fed dietary model of insulin resistance and hypertension) is not related to changes in PKC signaling or expression of PKC-theta in skeletal muscle.

Animals↗
PubMed1997

The euglycaemic hyperinsulinaemic clamp: an evaluation of current methodology.

1. The recognition of the role of insulin resistance in disease states and the recent development of new drugs that modify insulin-dependent metabolism has led to increased use of the euglycaemic hyperinsulinaemic clamp to measure in vivo insulin sensitivity, but several key aspects of the technique are poorly documented in the literature. 2. We have evaluated the reproducibility and intersubject variation of measurements of insulin sensitivity in groups of insulin-sensitive and insulin-resistant subjects and assessed the effects of hand warning on haemodynamic and metabolic responses. 3. Subjects participated in one of two protocols: (i) 18 healthy male volunteers and 18 patients with hypertension and glucose intolerance were clamped on two occasions, 1 week apart with measurements of insulin sensitivity (M) derived after 120 and 180 min of hyperinsulinaemia; and (ii) six healthy volunteers were clamped on one occasion with simultaneous sampling of antecubital and 'arterialized' (dorsal hand) venous blood for comparison of plasma glucose concentrations and oxygen saturation and a further six volunteers were clamped on two occasions with and without the use of hand warming. 4. Measurements of M derived after 120 min (M120) and 180 min (M180) of hyperinsulinaemia were reproducible: the coefficients of repeatability (mg/kg per min) of M120 and M180 were 1.0 and 0.9 for volunteers and 1.0 and 1.0 for the patient group, respectively. The intersubject variation in insulin stimulus was high: coefficients of variation for M180 were 22% for volunteers compared with 38% for the patient group. In volunteers compared with the patient group, hand warming significantly increased venous oxygen saturations (95 +/- 2 vs 79 +/- 18%, respectively) and glucose concentrations (5.2 +/- 0.2 vs 4.5 +/- 0.4 mmol/L, respectively) and measurements of M were significantly higher using arterialized compared with antecubital venous blood. However, local hand warming was associated with systemic vasodilatation: blood pressure decreased (e.g. 6 mmHg diastolic; P < 0.05) with a compensatory increase in heart rate (8 b.p.m.). 5. In conclusion, clamps of 120 and 180 min duration yielded measurements of M that were reproducible. The technique is much more robust when used in the context of a crossover design because of the significant (20-40%) intersubject variation in M, even among apparently homogeneous male volunteers. Hand warming effectively arterializes venous blood and gives significantly higher M values, but induces systemic vasodilation, which may confound measurements of M.

Adult↗
PubMed1997

Effects of budesonide and fluticasone on 24-hour plasma cortisol. A dose-response study.

Comparison of the risk-benefit profiles of different inhaled glucocorticoids has been limited by inadequate information about the dose-response relationships for efficacy relative to side effects. Fluticasone propionate (FP) is twice as effective as budesonide (BUD), but the potency ratio of FP:BUD with respect to suppression of cortisol production is unknown. The effects of 5 d of treatment with BUD (800, 1,600, and 3,200 micrograms/d via pMDI) and FP (750, 1,500, and 2,000 micrograms/d via pMDI) on integrated area under the curve of 24-h plasma cortisol profiles (AUC24 h) were compared in a randomized, placebo-controlled, seven-period crossover study in normal male volunteers (n = 28). Plasma cortisol concentrations were measured during the last 24 h of each treatment period. Each treatment (except BUD 800 micrograms) produced significant dose-dependent reductions in AUC24 h compared with placebo; e.g., percent reductions in AUC24 h were 23, 41, and 69% for the three doses of BUD, and, correspondingly, 46, 85, and 93% for the three doses of FP. Model-derived measurements of dose potency ratios showed that FP was 2.9 times more potent than BUD in reducing AUC24 h (95% CI, 2.5 to 3.5) and 3.1 times more potent in reducing 8:00 A.M. plasma cortisol (95% CI, 2.4 to 4.0). Thus, on a microgram-for-microgram notional dose basis, the systemic effects of a given dose of FP on AUC24 h cortisol were equivalent to the effects of three times the dose of BUD.

Administration, Topical↗
PubMed1996

Use of fluoxetine to treat dominance aggression in dogs.

OBJECTIVE: To evaluate fluoxetine for the treatment of owner-directed dominance aggression in dogs. DESIGN: Prospective study. ANIMALS: 9 dogs of various breeds, ages, and either sex determined to have owner-directed dominance aggression. PROCEDURE: Placebo and fluoxetine (1 mg/kg of body weight) were compared for the treatment of owner-directed dominance aggression in a single-blind crossover study. Owners were instructed to record aggressive and nonaggressive responses of their dogs daily on a canine-overt aggression chart for the 5-week duration of the study. Total aggression scores (linear and geometric) were calculated for each week of the study. The frequency of individual responses was also analyzed independently. RESULTS: Fluoxetine resulted in a significant (P = 0.01) reduction in owner-directed dominance aggression after 3 weeks of treatment. No particular aggressive response accounted for the overall reduction in aggression. CLINICAL IMPLICATIONS: Fluoxetine may be useful in the management of dominance aggression in dogs.

Aggression↗
PubMed1996

Comparative effects of indapamide and captopril on blood pressure and albumin excretion rate in diabetic microalbuminuria.

Nephropathy affects about one third of diabetic patients and its onset can be predicted almost a decade in advance by detecting small quantities of albumin in the urine (microalbuminuria). Thus, detection of proteinuria or microalbuminuria in diabetic patients carries important implications and merits intervention. Strategies for delaying the relentless progression of microalbuminuria to diabetic nephropathy and ultimately end-stage renal failure are focused on improving glycemic control and reducing blood pressure. Studies with beta-blockers, calcium antagonists, diuretics, and angiotensin-converting enzyme (ACE) inhibitors in hypertensive diabetics with microalbuminuria have shown a significant reduction in urinary albumin excretion rates (AER), with effective lowering of blood pressure. In a crossover study, we compared the effects of captopril versus indapamide as monotherapy for 12 weeks on AER and blood pressure in 31 diabetic patients with established microalbuminuria. The 2 drugs were equally effective in reducing AER (average reduction 30-40%) and had comparable antihypertensive effects.

Albuminuria↗
PubMed1996

Ethnic differences in the prevalence of hypertension and proteinuria in NIDDM.

There are large ethnic differences in both the prevalence of diabetes and the pattern of clinical complications, especially diabetic nephropathy and coronary heart disease. The aim of this study was to compare ethnic differences in the prevalence of two important risk factors, hypertension and proteinuria, among 1845 consecutive patients with non-insulin-dependent diabetes mellitus (NIDDM) undergoing annual complications assessment. Using a well-established database and systematic methods of data collection, information on clinical, demographic and laboratory variables was compared among seven ethnic groups: Anglo-Celtic (n = 896), Italian (n = 246), Greek (n = 209), Arabic (n = 147), Chinese (n = 131), Indian (n = 115) and Aborigine (n = 101). The odds ratios (OR) for developing hypertension (relative to Anglo-Celtic subjects) were lower in all ethnic groups, especially Arabs (OR = 0.4), Indians (OR = 0.4) and Aborigines (OR = 0.6). By contrast, the odds ratios for proteinuria (relative to Anglo-Celts) were consistently higher in all ethnic groups, e.g. Arabs (OR = 3.0) and Aborigines (OR = 3.1), even after correction for age, duration of diabetes and glycaemic control. Thus, relative to Anglo-Celtic patients, other ethic groups are less likely to have hypertension and more likely to have proteinuria. These findings may have important implications for understanding the ethnic differences in onset and progression of diabetic nephropathy.

Arabs↗
PubMed1996

Genomic organization and promoter analysis of the gene ifngr2 encoding the second chain of the mouse interferon-gamma receptor.

A clone containing the gene ifngr2 for the second chain (IFN-gamma R2) of the mouse interferon gamma receptor complex was isolated from a cosmid library made of 129/Sv mouse genomic DNA. Sequence analysis revealed that the second chain is encoded by 7 exons. The complete gene spans about 17 kb of the genomic DNA. In the 5'-flanking region several transcription initiation sites between 27 and 136 nucleotides upstream from the translation initiation codon were mapped. This region has a high GC content, but no TATA or CAAT box. Potential binding sites were found for transcription factors Sp1, AP-2, NF1, EGR and NF kappa B. Promoter activity was assayed with a series of constructs with firefly luciferase as a reporter gene, under the control of the promoter fragments of various lengths. This region showed promoter activity in transiently transfected Chinese hamster ovary cells.

Animals↗
PubMed1995

The effects of rilmenidine and atenolol on mental stress, dynamic exercise and autonomic function in mild to moderate hypertension.

1. The effects of 4 week treatment with rilmenidine or atenolol on tests of mental stress, dynamic exercise, autonomic function and psychometric tests were evaluated in a randomized, double-blind, placebo-controlled, cross-over study. 2. After a 4 week placebo run-in, 12 patients with essential hypertension (blood pressure [BP] 160/95 +/- 15/7 mmHg) received rilmenidine 1-2 mg day-1, and atenolol 50-100 mg day-1, each for 4 weeks, with a 4 week placebo wash-out between drug treatments. 3. Both agents produced a comparable reduction in supine and erect BP. During the mental arithmetic test, BP and heart rate (HR) responses were similar for rilmenidine and atenolol. 4. During bicycle exercise, the increase in HR was significantly greater after rilmenidine (+50 vs 41 beats min-1, P = 0.04). During recovery, the areas under the curve for diastolic BP (46,450 vs 51,400 mmHg s, P = 0.02) and HR (49,445 vs 63,597 beats min-1 s, P = 0.001) were significantly less with atenolol than rilmenidine. 5. Neither rilmenidine nor atenolol affected mental performance as judged by arithmetic and psychomotor tests. Physiological responses to autonomic function tests (deep breathing, facial immersion, isometric handgrip and cold pressor) were preserved with both drugs. The standing to lying ratio was higher on atenolol (P = 0.01) and Valsalva ratio was higher on rilmenidine (P = 0.03). 6. In conclusion, rilmenidine and atenolol exerted comparable antihypertensive effects both at rest and during mental and dynamic stress. Atenolol attenuated HR responses to dynamic exercise and the Valsalva manoeuvre; rilmenidine did not interfere with the physiological responses of BP and HR during autonomic function tests.

Adrenergic beta-Antagonists↗