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Biomedical subjects

R Donnelly

Publications and source records attributed to R Donnelly.

At least 91 records · Page 5Linked to original sources
PubMed1995

Expression of multiple isoenzymes of protein kinase C in airway smooth muscle.

Protein kinase C (PKC) has been implicated in the control of airway smooth muscle (ASM) tone, and abnormalities in PKC-dependent signaling may be associated with asthma. PKC exists in different isoforms, but the pattern of their expression in ASM has not been previously reported. Accordingly, the purpose of the present study was to identify which isoforms of PKC are expressed in ASM. Tissue samples of canine ASM were homogenized and subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis, followed by immunoblotting with a range of antipeptide antibodies to PKC-alpha, -beta I, -beta II, -gamma, -delta, -epsilon, -eta, -theta, and -zeta. Positive controls were run in parallel with ASM. Immunoblots revealed a mixture of both calcium-dependent and calcium-independent isozymes: PKC-beta I and PKC-beta II were the only conventional isoforms detected; PKC-delta, PKC-epsilon, and the new muscle-specific isoform, PKC-theta, were all expressed in ASM, but the lung-specific isoform, PKC-eta, was not detected. The calcium- and phospholipid-independent isoform, PKC-zeta, was also present. Thus, expression of a wide variety of both calcium-dependent and calcium-independent isoforms suggests a complex, multifunctional role of PKC in ASM.

Animals↗
PubMed1995

Effects of low sodium diet and unilateral nephrectomy on the development of carbohydrate-induced hypertension.

Since there appear to be important interactions between mechanisms of salt-sensitive and carbohydrate-sensitive hypertension, the goal of this study was to evaluate the effects of greatly reducing dietary salt intake and removal of one kidney (to increase salt sensitivity) on the hemodynamic and metabolic responses to carbohydrate-enriched diets in three different rat strains. All three strains of laboratory rat developed significant increases in fasting plasma insulin (1-2 fold, p < 0.03) and triglyceride (2-3 fold, p < 0.01) concentrations in response to fructose (or sucrose) enriched diets, irrespective of salt content. Blood pressure increased significantly in response to carbohydrate feeding in both Sprague-Dawley (S-D) and Dahl salt-sensitive rats, but not in Fischer 344 rats, and decreasing salt intake had no effect on the development of carbohydrate-induced hypertension: e.g., delta BP in S-D rats was +20 mmHg after the fructose-0.5% NaCl diet as compared with +19 mmHg after fructose-0.02% NaCl, and delta BP in Dahl salt-sensitive rats was +22 mmHg after fructose-0.02% NaCl. Finally, nephrectomy neither accentuated the degree of hypertension in fructose-fed S-D rats, nor increased blood pressure in fructose-fed Fischer 344 rats. These results emphasize the strain specific characteristics of carbohydrate-induced hypertension in rats, and indicate that the hemodynamic responses of different rat strains to dietary carbohydrate are not modified by either decreasing salt intake or removing one kidney.

Animals↗
PubMed1995

Comparative effects of rilmenidine and atenolol on tests of autonomic function and mental and dynamic exercise in patients with essential hypertension.

The aim of the present study was to compare the effects of rilmenidine (1-2 mg/day) and atenolol (50-100 mg/day) on tests of mental arithmetic, bicycle exercise, and autonomic function. Twelve male patients with mild-to-moderate hypertension (blood pressure, 160/95 +/- 15/7 mm Hg; age range, 32 to 60 years) completed a randomized, double-blind, crossover study. Both drugs were well tolerated and, after 4 weeks of monotherapy, were associated with significant reductions in supine and erect BP. Hemodynamic responses to mental arithmetic were similar for both drugs, and neither agent affected mental performance as judged by psychomotor testing. The increase in heart rate during bicycle exercise was significantly greater with rilmenidine (50 vs. 41 beats/min, p = 0.04), and during the postexercise recovery phase, areas under the curve for diastolic blood pressure and heart rate were smaller after atenolol than after rilmenidine: 46,450 versus 51,400 mm Hg.s (p = 0.02) and 49,445 versus 63,597 beats/min.s (p = 0.001), respectively. In conclusion, rilmenidine and atenolol exert comparable antihypertensive effects both at rest and during mental and dynamic exercise. Although atenolol blunted the heart rate responses to dynamic exercise and the Valsalva maneuver, rilmenidine showed no interference with physiological hemodynamic responses of blood pressure and heart rate during tests of sympathetic and parasympathetic function.

Adult↗
PubMed1994

Crohn's disease and myasthenia gravis: a possible role for thymectomy.

A female patient with a three year history of Crohn's disease of the colon developed myasthenia gravis. Despite diversion of the faecal stream by an ileostomy, and total colectomy, the patient had continuing problems with perineal and perianal abscesses and fistulas. Her myasthenia gravis became unresponsive to anti-cholinergics so a thymectomy was performed. The perineal and perianal disease improved subsequently. This case supports the theory that functional disturbances of the thymus may have a role in the pathogenesis of inflammatory bowel disease.

Adult↗
PubMed1994

Expression of the major isoenzyme of protein kinase-C in skeletal muscle, nPKC theta, varies with muscle type and in response to fructose-induced insulin resistance.

The ability of insulin to stimulate glucose uptake by skeletal muscle varies as a function of muscle type, but the biochemical mechanisms that regulate insulin-mediated glucose transport under normal conditions and in pathological states of insulin resistance are poorly understood. We evaluated differences in the expression of nPKC theta (the major isoform of protein kinase-C in skeletal muscle) in hind limb muscles of different fiber type composition from normal Sprague-Dawley rats and rats made insulin resistant by feeding a fructose-enriched diet. In total muscle homogenates from normal rats, the amount of nPKC theta per unit total protein quantified by immunoblotting using a specific antipeptide antibody was 2.5 times higher in pure white muscle (tensor fascia latae) compared with red muscle (soleus), with two mixed muscles showing intermediate expression. The development of insulin resistance after a fructose-enriched diet was associated with significant increases in diacylglycerol and nPKC theta mass in the membrane fraction of tensor fascia latae, but fructose feeding had no effect on conventional PKC enzyme activity and immunoreactive protein. Thus, expression of nPKC theta varies as a function of muscle type, and fructose-induced insulin resistance appears to be associated with diacylglycerol-mediated isoenzyme-specific changes in nPKC theta in white muscle.

Animals↗
PubMed1994

Concentration-effect analysis of antihypertensive drug response. Focus on calcium antagonists.

Although individualised antihypertensive therapy is widely recommended, prospective methods for optimising treatment are hampered by the paucity of basic information about dose-plasma concentration-response relationships for commonly used drugs. Concentration-effect analysis has been applied to a number of therapeutic areas. With antihypertensive drugs this approach has clearly identified direct relationships between pharmacokinetic and pharmacodynamic profiles within individual patients. Thus, either a linear or nonlinear model can be used to quantify the antihypertensive drug response in terms of parameters that incorporate pharmacokinetic and pharmacodynamic information. Furthermore, these models take account of placebo effects and time-dependent changes in blood pressure and drug concentrations during a dosage interval. Concentration-effect analysis has been used to characterise the responses to a range of calcium antagonist drugs. These studies have demonstrated that these analyses are useful for optimising dosage schedules, identifying determinants of blood pressure response, and predicting steady-state profiles of blood pressure (including peak/trough effects) after administration of a single ('test') dose. This mode of analysis warrants early inclusion in the clinical development of any new antihypertensive agent, so that the familiar difficulties in identifying the optimum dosage range are avoided.

Antihypertensive Agents↗
PubMed1994

Pressor and subpressor doses of angiotensin II increase insulin sensitivity in NIDDM. Dissociation of metabolic and blood pressure effects.

There is evidence that the renin-angiotensin system may be involved in the metabolic as well as the cardiovascular features of diabetes and that pressor doses of angiotensin II (ANG II) increase insulin sensitivity in parallel with blood pressure (BP) in healthy subjects, but the effects of ANG II on insulin sensitivity have not been previously reported in patients with non-insulin-dependent diabetes mellitus (NIDDM). In a randomized, double-blind, placebo-controlled, crossover study, 11 patients with NIDDM attended 3 study days to evaluate the effects of a 3-h infusion of subpressor and pressor doses of ANG II on whole body insulin sensitivity using the euglycemic hyperinsulinemic clamp. BP and heart rate were recorded, and blood samples were collected for serum insulin, C-peptide, potassium, catecholamines, plasma renin activity, and plasma ANG II concentrations. Plasma levels of ANG II (means +/- SD) were 9 +/- 4, 29 +/- 9, and 168 +/- 47 pmol/ml after placebo, low dose infusion, and high dose infusion, respectively. The higher dose of ANG II was associated with significant increases in BP (e.g., 18 mmHg systolic BP at 150 min) and plasma aldosterone. Whole body insulin sensitivity was 23.8 +/- 12.7 mumol glucose.kg-1.min-1 after placebo and 30.6 +/- 12.7 and 27.2 +/- 13.3 following low and high dose ANG II infusions, respectively (P < 0.05, analysis of variance). In summary, acute infusion of ANG II, with or without an increase in BP, increases insulin sensitivity in normotensive patients with NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Salt-sensitive and carbohydrate-sensitive rodent hypertension: evidence of strain differences.

It is well-established that diets enriched either with salt or simple sugars are associated with variable increases in blood pressure, but the interrelationship between carbohydrate- and salt-sensitive hypertension has received comparatively little attention. The effects of varying salt intake on blood pressure responses to a fructose-enriched diet were examined in a variety of common laboratory rat strains. Sprague-Dawley, Fischer 344, and Wistar rats were placed on diets enriched in fructose, salt, or a combination of both for 12 days. Measurements of blood pressure (tail-cuff) and fasting plasma insulin concentrations were recorded before and after dietary intervention. In response to the fructose-enriched diet (normal salt), all strains developed a significant increase in plasma insulin (1-2 fold, p < 0.05). However, only Sprague-Dawley rats showed an increase in blood pressure in response to the fructose-enriched diet (21 mmHg, p < 0.05). A high salt diet increased blood pressure only in Fischer 344 rats (10 mmHg, p < 0.05), but the combination of high fructose and high salt increased blood pressure significantly in both Fischer 344 and Wistar rats (mean of 19 mmHg, p < 0.05). In conclusion, the ability of a fructose-enriched diet to increase blood pressure varies as a function of strain, and can be modulated by changes in salt intake.

Animals↗
PubMed1994

Prediction and optimisation of the antihypertensive response to nifedipine.

The predictability of the long term antihypertensive response to nifedipine in individual patients has been assessed by an analysis based upon the concentration-effect parameters defined following the first dose administration of 20 mg nifedipine (Retard). The predicted and measured reductions in blood pressure during steady state nifedipine treatment were compared for the trough and peak responses and there was reasonable agreement for the group of patients as a whole. However, when the measured and predicted blood pressure profiles were compared for each individual patient there was close agreement for the majority of patients but there were significant discrepancies in a few cases. Further analysis of the steady state concentrations in these cases revealed that there was no change in their responsiveness to nifedipine and that discrepancies were directly attributable to inappropriate compliance with the drug regimen. The analysis was further extended to simulate the blood pressure responses to alternative fixed dosage regimens. Assessment of these simulations suggests that blood pressure control with nifedipine Retard is significantly improved by three times daily drug administration.

Blood Pressure↗
PubMed1994

Effects of gemfibrozil on triglyceride metabolism in Dahl salt-sensitive rats.

Hypertriglyceridemia is a common feature of patients with increased blood pressure as well as several rodent models of hypertension. The goal of this study was to evaluate the effects of gemfibrozil on established abnormalities of triglyceride (TG) secretion and TG clearance in the Dahl salt-sensitive rat. Consequently, Dahl salt-sensitive rats received 12 days treatment with gemfibrozil (30 mg/kg/day) or vehicle by p.o. gavage and the following measurements were made: 1) fasting plasma TG levels; 2) TG secretion rate after suppression of TG removal with Triton WR 1339; 3) TG removal rate (half-time of disappearance of prelabeled very low density lipoprotein); and 4) lipoprotein lipase (LPL) activity and mRNA in soleus muscle, fat and liver tissues. Gemfibrozil produced a 50% reduction in fasting plasma TG concentrations, with no effect on TG secretion rate (17 +/- 2 vs. 15 +/- 1 mg/100 g b.wt./hr). The half-time of prelabeled very low density lipoprotein-TG removal was significantly lower in drug-treated animals (3.9 +/- 0.3 vs. 6.1 +/- 0.9 min), and this was associated with a tissue-specific increase in LPL activity in soleus muscle (153 +/- 5 vs. 135 +/- 5 U/g, P < .02). Expression of LPL mRNA, relative to beta-actin mRNA, was similar in both groups of rats. Thus, in this rodent model of hypertension and dyslipidemia, gemfibrozil lowers plasma TG levels by 50% with no effect on TG secretion; the hypotriglyceridemic effect is due mainly to an increase in TG removal rate associated with a post-transcriptional increase in LPL activity in skeletal muscle.

Adipose Tissue↗
PubMed1993

The pharmacodynamics and pharmacokinetics of the combination of nifedipine and doxazosin.

In a single-blind study 12 normotensive men took nifedipine 20 mg (Group 1, n = 6) or doxazosin 2 mg (Group 2, n = 6), followed by the combination. Each subject attended on four 9-h study days for evaluation of the effects of single and multiple doses of the monotherapy and the effects of adding single and multiple doses of the second drug. Measurements of BP, HR, plasma drug concentrations, and apparent liver blood flow were recorded. The combination was generally well tolerated. BP was consistently lower with the combination than with either monotherapy: for example, average erect BP was 108/61 (Group 1) and 112/62 mmHg (Group 2) compared with 122/66 and 116/68 during steady-state monotherapy. The introduction of nifedipine in Group 2 was associated with a significant increase in liver blood flow at 1.5 h: 1560 vs 1050 ml.min-1 during monotherapy with doxazosin. There was no significant kinetic interaction. In particular, the steady-state AUC of doxazosin was unaffected by the addition of nifedipine: 257, 307, 301, and 256 ng.ml-1.h for the 4 study days (Group 2).

Adult↗
PubMed1993

Pharmacodynamic modeling of the antihypertensive response to amlodipine.

The distinctive pharmacokinetic characteristics of amlodipine, particularly the long half-life, are presumed to translate directly to a prolonged duration of action, but the concentration-effect relationship for the antihypertensive response has not been clearly established. In this study of 12 patients with essential hypertension, treatment with 5 mg amlodipine once daily has been evaluated with use of an integrated pharmacokinetic-pharmacodynamic model to calculate individual patient responsiveness for the decrease in blood pressure per unit change in drug concentration. Amlodipine concentrations were well correlated with the placebo-corrected reductions in blood pressure in individual patients and responsiveness, for example, for erect systolic blood pressure was -3.1 +/- 0.9 mm Hg/ng/ml. By characterizing the concentration-effect relationships in individual patients, this study has confirmed that the plasma concentration-time profile is an appropriate index of the effect-time profile, as reflected by an antihypertensive response that is sustained throughout 24 hours with relatively little trough-to-peak variability.

Adult↗
PubMed1993

Effects of angiotensin II on insulin sensitivity: a placebo-controlled study.

1. There is evidence that hyperinsulinaemia increases the aldosterone response to angiotensin II, and that angiotensin-converting enzyme inhibitor drugs enhance peripheral glucose utilization, but the direct effects of angiotensin II on insulin sensitivity have not been reported previously. 2. In a randomized, double-blind, placebo-controlled, cross-over study, 12 healthy male subjects attended on 3 study days for the evaluation of the effects of a subpressor (1 ng min-1kg-1) and pressor (5 ng min-1kg-1) infusion of angiotensin II on whole-body insulin sensitivity using the euglycaemic hyperinsulinaemic clamp. Frequent measurements of blood pressure and heart rate were recorded and blood samples were collected for determination of serum insulin, C-peptide and K+ concentration, plasma renin activity and plasma angiotensin II concentration. 3. Plasma angiotensin II concentrations (means +/- SD) were 11 +/- 5 pg/ml after placebo, and 27 +/- 9 and 125 +/- 28 pg/ml after low and high dose angiotensin II, respectively. The higher dose of angiotensin II was associated with significant increases in blood pressure (e.g. 13 mmHg systolic blood pressure at 150 min) and serum aldosterone concentration. Whole-body insulin sensitivity was 10.5 +/- 2 mg of glucose min-1kg-1 after placebo, and 10.5 +/- 2.2 and 10.9 +/- 3.4 mg of glucose min-1kg-1 after low and high dose angiotensin II (not significant). 4. Angiotensin II had no effect on hyperinsulinaemia-induced reductions in serum potassium and triacylglycerol concentrations. 5. Thus, acute infusion of angiotensin II for 3 h, with or without an increase in blood pressure, has no effect on whole-body insulin sensitivity.

Adult↗