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Biomedical subjects

R Huupponen

Publications and source records attributed to R Huupponen.

At least 55 records · Page 3Linked to original sources
PubMed1995

Effects of celiprolol on insulin sensitivity and glucose tolerance in dyslipidemic hypertension.

The effects of celiprolol on insulin sensitivity, glucose tolerance and serum lipids were compared to those of other antihypertensive drugs (beta- or Ca-blocker or ACE-inhibitor) in 23 dyslipidemic non-diabetic patients with controlled hypertension. Hyperinsulinemic euglycemic clamp and independent oral glucose tolerance tests (OGTT) were performed before and 6 months after the study treatment. Six patients out of 23 were randomized to the control group where antihypertensive monotherapy was kept unchanged. Mean glucose disposal rate (M, mean +/- SEM) determined in the clamp test increased in the celiprolol group from 24.4 +/- 2.3 to 34.9 +/- 2.4 mumol/kg/min (p < 0.001). Insulin sensitivity improved during celiprolol treatment independent of the previous treatment. In the control group, M remained practically unchanged (21.6 +/- 3.7 mumol/kg/min). During 2 h OGTT, incremental glucose and insulin AUC decreased in the celiprolol group from 4.5 +/- 0.7 to 2.0 +/- 0.6 mM*h (p < 0.002) and from 113 +/- 16 to 72 +/- 10 mU/l*h (p < 0.005), respectively. There was also a small beneficial change in serum lipids in the celiprolol group: a reduction in serum total cholesterol (-4%), triglycerides (-11%) and LDL-cholesterol (-9%), and an increase in HDL-cholesterol (+6%) and HDL/LDL ratio (+15%). No significant change occurred in the control group. Fasting serum glucose and insulin did not change significantly in either group. In this study with a limited control group, celiprolol improved insulin sensitivity, glucose tolerance and serum lipid profiles of dyslipidemic hypertensive patients.

Adult↗
PubMed1994

Hepatic metabolism and distribution of mifepristone and its metabolites in rats.

The hepatic metabolism of mifepristone was studied in female Wistar rats following oral administration of 10 mg/kg. The extraction of mifepristone by the rat liver was effective, eliminating 80% of the mifepristone. During the absorption phase, the portal serum concentrations of mifepristone were over 10-fold higher than those measured in systemic serum. The serum concentrations of the monodemethylated, didemethylated and hydroxylated metabolites of mifepristone were lower in systemic serum, indicating that the metabolites were also effectively excreted by the rat liver. The distribution of mifepristone and its demethylated metabolites between serum, brain, muscle and adipose tissue was studied in lean and obese Zucker rats following repeated oral administration of 10 mg/kg. The individual serum concentrations of mifepristone varied considerably, from 24-482 ng/ml; the mean (+/- SE) serum concentrations for lean and obese rats were 167 (+/- 86) and 211 (+/- 62) ng/ml respectively. Mifepristone could be measured in brain in each animal, its concentrations being 28% of those measured in serum. Muscle tissue and serum contained approximately similar concentrations of mifepristone. Adipose tissue effectively concentrated mifepristone, and its concentrations were 40-fold higher in fat than in serum. The difference in the concentrations of mifepristone between the lean and obese animals was statistically significant only in brain tissue (P < 0.05). The serum concentrations and brain, muscle and adipose tissue concentrations of mifepristone were significantly correlated (P < 0.05). The distribution of the demethylated metabolites was roughly similar to that of mifepristone. However, their concentrations were significantly higher (P < 0.02) in the obese animals in each tissue type investigated.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1994

Potentiation of the anti-obesity effect of the selective beta 3-adrenoceptor agonist BRL 35135 in obese Zucker rats by exercise.

UNLABELLED: 1. The effects of chronic treatments with a selective beta 3-adrenoceptor agonist and a selective alpha 2-adrenoceptor antagonist and their interactions with physical exercise training were studied in experimental obesity. 2. BRL 35135 (beta 3-agonist, 0.5 mg kg-1 day-1 p.o.), atipamezole (alpha 2-antagonist, 4.0 mg kg-1 day-1 p.o.) and placebo were given to genetically obese male Zucker rats. Half of the rats were kept sedentary whereas the other half were subjected to moderate treadmill exercise training. Body weight gain, cumulative food intake, the neuropeptide Y content of the hypothalamic paraventricular nucleus, brown adipose tissue thermogenic activity (measured as GDP binding), plasma insulin and glucose levels were measured after 3 weeks' treatment and exercise. 3. Treatment with BRL 35135 reduced weight gain by 19%, increased brown adipose tissue thermogenic activity 45-fold and reduced plasma insulin by 50%. Atipamezole slightly increased food intake and neuropeptide Y content in the paraventricular hypothalamic nucleus but had no effect on the other measured parameters. Exercise alone had no effect on weight gain, food intake or thermogenic activity, whereas it reduced plasma insulin and glucose levels. 4. The effect of BRL 35135 on weight gain and thermogenic activity was significantly potentiated by exercise; the reduction in weight gain was 56% in comparison with 19% in sedentary animals. Food intake was significantly reduced in the BRL 35135-treated-exercise-trained animals, although neither beta 3-agonist nor exercise alone affected it. 5. Based on the present results in genetically obese Zucker rats, combination of 03-agonist treatment with a moderate physical training may offer a new feasible approach to the therapy of obesity.- KEYWORDS: BRL 35135; atipamezole; P3-adrenoceptor agonism; M2-adrenoceptor antagonism; brown adipose tissue; thermogenesis;genetic obesity; Zucker rat; exercise; neuropeptide Y

Adipose Tissue↗
PubMed1993

Metformin and brown adipose tissue thermogenetic activity in genetically obese Zucker rats.

The effect of chronic metformin treatment on brown adipose tissue thermogenetic activity was investigated in young genetically obese Zucker rats. The binding of [3H]GDP to brown adipose tissue mitochondria, expression of uncoupling protein mRNA in brown adipose tissue, weight gains and cumulative food intakes were measured in metformin (320 mg/kg orally for 12 days)-treated obese Zucker rats as well as in pair-fed--and in ad libitum--fed control obese rats. The weight gains were identically reduced in the metformin- and pair-fed control group compared to the ad libitum--fed rats. Metformin also significantly reduced cumulative food intake. The binding of [3H]GDP to brown adipose tissue mitochondria and the expression of uncoupling protein mRNA in brown adipose tissue were not modified by metformin. It is concluded that the weight gain reducing effect of metformin in obese Zucker rats is mainly due to reduced food intake and does not involve an effect of metformin on brown adipose tissue thermogenetic activity.

Adipose Tissue, Brown↗
PubMed1993

Effect of chronic treatment with TFMPP, a 5-HT1 receptor agonist, on food intake, weight gain, plasma insulin and neuropeptide mRNA expression in obese Zucker rats.

1-[3-(trifluoromethyl)phenyl]piperazine (TFMPP), a 5-HT1 receptor agonist, decreases food intake in rats when given acutely. The present investigation was performed to study the chronic effects of TFMPP on food intake and weight gain in genetically obese Zucker rats. Neurochemical and endocrine data on possible mechanisms involved in the action of TFMPP were collected at the end of the study. TFMPP (4 mg/kg per day s.c.) significantly reduced food intake on the 1st and 7th days, but no longer on the 14th and 28th days. Reduced food intake was associated with decreased body weight gains during the first two weeks of treatment, but no effect was found thereafter. Plasma insulin concentration was significantly lowered by TFMPP treatment without impairment of glucose homeostasis. In situ hybridization analysis did not reveal changes in the expression of preprocorticotropin-releasing factor mRNA in the paraventricular nucleus or preproneuropeptide Y mRNA in the arcuate nucleus. Chronic TFMPP administration significantly reduced the density of 5-HT2 receptors, as measured by quantitative receptor autoradiography, in the claustrum and cerebral cortex, but not 5-HT1C receptor density in the choroid plexus. It is concluded that the anorectic and weight gain-lowering effects of TFMPP decrease during long-term treatment in obese Zucker rats.

Animals↗
PubMed1993

Plasma concentrations and ocular effects of cyclopentolate after ocular application of three formulations.

1. Eight volunteers received in randomized order two 30 microliters drops of either 1% w/v cyclopentolate hydrochloride or a corresponding amount of cyclopentolate polygalacturonate in saline or in acetate buffer in one eye. Cyclopentolate concentrations in plasma were measured by a radioreceptor assay. 2. Peak plasma drug concentrations of about 3 ng ml-1 occurred within 30 min after all formulations. Occasionally, a second concentration peak in plasma, probably reflecting drug absorption from the gastrointestinal tract, was seen after 2 h. The mean elimination half-life of cyclopentolate was 111 min when all subjects and formulations were considered together. There were no statistically significant differences between the formulations with respect to the time-course of plasma drug concentration. 3. The maximal mydriatic effect was reached within about 15 min and was maintained for several hours, often being 1/3 of its peak value after 30 h. Similarly, an intense cycloplegic response was achieved within a few minutes, the peak changes in the near-point of vision being 9 to 10 dioptres. The cycloplegic response was more intense after one of the polygalacturonate complexes, especially at later time points.

Adult↗
PubMed1993

The analysis of plasma kinetics and beta-receptor binding and -blocking activity of timolol following its small intravenous dose.

Plasma kinetics and beta-receptor blocking and -binding activity of timolol was studied in six healthy volunteers following its intravenous 0.25 mg dose. Timolol concentrations were measured using radioreceptor assay (RRA), blocking activity by comparing the dose ratios (DRs) of the infusion rates of isoprenaline required to increase heart rate by 25 bpm (I25) and binding activity by determining the extent to which timolol occupied beta 1-receptors of rabbit lung and beta 2-receptors of rat reticulocytes in undiluted plasma samples. Timolol was eliminated from plasma with a mean half-life for the elimination phase of 2.6 hours. The dose antagonized potently isoprenaline-induced tachycardia at least for four hours. The effect was excellently correlated with the estimated beta 2-receptor binding activity of timolol in the circulating plasma. In conclusion, the small intravenous timolol dose was eliminated from plasma by a fashion, which was very similar to its eighty-fold higher oral doses reported earlier in the literature. The 0.25 mg dose was of considerable systemic beta-receptor blocking and -binding activity, that may help to explain its reported side-effects following ocular drug administration. The extent to which beta-blocking agents occupy rabbit lung beta 1- and rat reticulocyte beta 2-receptors in the circulation appears to predict the intensity and selectivity of their beta-blocking effects in healthy volunteers.

Adrenergic beta-Antagonists↗
PubMed1993

Metformin and liver glycogen synthase activity in obese Zucker rats.

The effect of chronic treatment with metformin (320 mg/kg/day) on plasma glucose and insulin as well as liver glycogen synthase activity and hepatic glycogen content was studied in obese hyperinsulinemic Zucker rats. Metformin significantly reduced both plasma glucose (by 10%) and insulin levels (by 39%) at fasting but had no effect on hepatic glycogen content or on the basal activity of liver glycogen synthase.

Animals↗
PubMed1992

Determination of metformin in plasma by high-performance liquid chromatography.

A high-performance liquid chromatographic method for the determination of metformin, an oral antidiabetic agent, in plasma is described. Plasma samples containing the internal standard, phenformin, are eluted through Amprep extraction columns before injection into the chromatographic column, packed with microBondapak phenyl. The eluent is monitored at 236 nm. At a mobile phase flow-rate of 1.35 ml/min, the retention times of metformin and phenformin are 2.8 and 5.6 min, respectively. The intra-day coefficients of variation are 1.5 and 4.3% at metformin concentrations of 0.05 and 1 mg/l, respectively.

Animals↗
PubMed1992

Effect of doxazosin on insulin sensitivity in hypertensive non-insulin dependent diabetic patients.

The effect of doxazosin, an alpha 1-adrenoceptor blocking drug, on blood pressure, sensitivity to insulin and serum lipids has been evaluated in 14 hypertensive, non-insulin dependent diabetic patients. The dose was titrated individually upwards from 1 mg until the diastolic blood pressure was below 90 mm Hg, side-effects precluded further dosage increase or the maximum daily dose of 16 mg was achieved. After 12 weeks of treatment (mean doxazosin dose 5.6 +/- 5.1 mg daily), the supine and standing diastolic blood pressure of the patients had declined by about 7 mm Hg, whereas their systolic blood pressure and heart rate were not significantly changed. The metabolic clearance rate of glucose increased from 2.35 to 3.37 ml.min-1.kg-1 during treatment, suggesting improved sensitivity to insulin. Fasting plasma glucose was 11.9 mmol.l-1 before and 10.9 mmol.l-1 after doxazosin therapy (NS). Serum electrolytes and lipids did not change significantly but serum uric acid decreased from 305 to 281 mumol.l-1. Doxazosin may be a useful alternative for the treatment of hypertension in NIDDM patients.

Aged↗
PubMed1992

Subchronic treatment with metformin produces anorectic effect and reduces hyperinsulinemia in genetically obese Zucker rats.

The effect of subchronic metformin treatment on food intake, weight gain and plasma and tissue hormone levels was investigated in genetically obese male Zucker rats and in their lean controls. Metformin hydrochloride (320 mg/kg/day for 14 days in the drinking water) significantly reduced 24 hour food intake both after one and two weeks treatment in obese rats. In contrast, metformin had only a transient effect on food intake in lean animals. The reduced food intake was associated with body weight decrease, particularly in obese rats. Metformin markedly reduced also the hyperinsulinemia of the obese animals without altering their plasma glucose or pancreatic insulin content which may reflect an improved insulin sensitivity after metformin treatment. Metformin did not change plasma corticosterone levels or insulin and somatostatin concentrations in the pancreas. Metformin reduced pyloric region somatostatin content in lean rats. It is concluded that metformin has an anorectic effect and reduces body weight and hyperinsulinemia in genetically obese Zucker rat.

Animals↗
PubMed1992

Effect of insulin on serum amino-terminal propeptide of type III procollagen in non-insulin-dependent diabetes mellitus.

The effect of insulin on the serum levels of the amino-terminal propeptide of type III procollagen (PIIINP) was investigated in patients with non-insulin-dependent diabetes mellitus, whose disease was unsatisfactorily controlled by oral drugs. Before insulin therapy the PIIINP values of the patients (3.2 +/- 1.3 micrograms/l, n = 38) varied within the range of healthy subjects (3.1 +/- 0.6 micrograms/l, n = 50, NS). Insulin therapy (6-20 IU at bedtime plus the oral drugs) improved the glycemic control and increased the serum PIIINP during a 4 week (3.1 +/- 0.9 to 3.8 +/- 1.1 micrograms/l, P less than 0.01, n = 8) and an 8 week period (3.2 +/- 1.3 to 3.8 +/- 1.6 micrograms/l, P less than 0.001, n = 22). The values were still elevated after 6 months on insulin (3.5 +/- 1.5 to 4.0 +/- 1.7 micrograms/l, P less than 0.01, n = 12). Placebo-insulin did not alter the concentration of PIIINP (3.1 +/- 0.6 to 2.8 +/- 0.6 micrograms/l, NS, n = 8) whereas the glycemic control improved and body weight decreased. The PIIINP values correlated with fasting insulin before (r = 0.403, P less than 0.05, n = 30) and after the therapy (r = 0.452, P less than 0.001, n = 60). Insulin therapy, while correcting the hormone deficiency and restoring glucose and protein metabolism, seems to activate the synthesis of type III procollagen in patients with NIDDM. This may promote the atherosclerotic process.

Adult↗
PubMed1992

Hypothalamic neuropeptide expression after food restriction in Zucker rats: evidence of persistent neuropeptide Y gene activation.

The Obese Zucker rat is a model of genetic obesity characterized by hyperphagia, hyperinsulinemia and other endocrine abnormalities. In order to elucidate pathogenetic mechanisms contributing to disturbed feeding behavior in these animals, the effect of food restriction on three hypothalamic neuropeptides involved in the control of food intake was studied. Eighteen male obese and 18 lean Zucker rats were randomly divided into two groups: half of the animals were food-restricted for 2 weeks, while the other half served as controls and were fed ad libitum. The levels of preproneuropeptide Y (preproNPY), preprocorticotropin releasing factor (preproCRF) and preprosomatostatin (preproSOM) mRNAs were determined using in situ hybridization technique. In addition, plasma insulin and corticosterone concentrations were analyzed. Food restriction significantly increased the expression of preproNPY mRNA in the arcuate nucleus in both Zucker phenotypes, while the expressions of preproCRF mRNA in the paraventricular nucleus (PVN) and preproSOM mRNA in the periventricular nucleus (PeV) were not altered. The expression of preproNPY mRNA was significantly greater in control obese animals compared to control lean animals. Food restriction lowered plasma insulin levels, but did not change plasma corticosterone levels. It is concluded that food restriction specifically activates NPY gene transcription in the arcuate nucleus the response being similar in both Zucker phenotypes. The results suggest that orexigenic NPY plays a role in the adaptation to altered feeding status.

Animals↗
PubMed1992

The effect of some macromolecular ionic complexes on the pharmacokinetics and -dynamics of ocular cyclopentolate in rabbits.

The effect of mucoadhesive polymeric vehicles on the mydriatic efficacy, and on the systemic and ocular absorption of cyclopentolate from eyedrops was studied in albino rabbits. Combining cyclopentolate base to polygalacturonic (CY-PGA) or hyaluronic (CY-HA) acid resulted in an increased mydriatic effect when compared with cyclopentolate hydrochloride (CY-HCl). During the first half an hour, the systemic absorption of cyclopentolate was lower after CY-PGA than after CY-HCl. The ocular penetration of cyclopentolate, based on drug concentrations in aqueous humor 30 minutes after the eyedrop instillation, was increased 3 fold when the polygalacturonate complex was used. CY-PGA, as well as other polymeric salts, might offer a possibility to increase the therapeutic index of cyclopentolate.

Absorption↗
PubMed1992

Differential hypothalamic arginine vasopressin response to glucocorticoid receptor antagonism in lean and obese Zucker rats.

The obese Zucker rat (fa/fa) is an animal model for genetic obesity characterized by hyperphagia, hyperinsulinemia, and severe insulin resistance in peripheral tissues. Adrenal steroids seem to play an important role in the onset of fatty syndrome in these animals. There is strong evidence of abnormal regulation of the hypothalamic-pituitary-adrenal axis in obese Zucker rats. Considering the physiological function of arginine vasopressin (AVP) as an adrenocorticotropic hormone secretagogue, the present study was carried out to investigate the role of glucocorticoids in the control of hypothalamic AVP systems in lean and obese Zucker rats. In the first experiment, mifepristone (RU 38486), a glucocorticoid receptor antagonist, was administered for 4 days (10 mg/kg orally twice daily), and the expression of AVP mRNA in hypothalamic paraventricular and supraoptic nuclei was measured using in situ hybridization, and the concentrations of AVP in the pituitary gland and in the median eminence were quantified. Plasma corticosterone levels were also analyzed. Mifepristone treatment resulted in a threefold increase in plasma corticosterone levels in lean Zucker rats, but it did not change corticosterone secretion in obese animals. Mifepristone treatment decreased AVP mRNA levels in lean animals in the supraoptic nuclei, while in obese animals the AVP mRNA content was increased in the paraventricular nuclei. Mifepristone treatment significantly increased the concentration of AVP in the median eminence in lean rats and decreased it in obese animals. Mifepristone treatment did not change concentrations of AVP in the pituitary gland. In the second experiment, mifepristone was given for 4 days (10 mg/kg orally twice daily), and its effects on 24-hour food intake and plasma AVP concentrations were measured.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

The glucocorticoid antagonist mifepristone reveals abnormal regulation of the adrenocortical system in obese Zucker rats.

The effects of the potent glucocorticoid type-II receptor (GR) antagonist, mifepristone, on corticosterone secretion and on expression of preprocorticotrophin-releasing factor (preproCRF) mRNA in the hypothalamic paraventricular nucleus (PVN) and of pro-opiomelanocortin (POMC) mRNA in the pituitary gland were investigated in lean and obese Zucker rats. Treatment with mifepristone for 4 days (10 mg/kg orally twice daily) significantly (P less than 0.05) stimulated corticosterone secretion in lean but not in obese rats. In lean rats the enhanced corticosterone secretion was associated with non-significant increments in the expression of preproCRF mRNA in the PVN and of POMC mRNA in the pituitary gland, while mifepristone significantly (P less than 0.05) reduced the expression of preproCRF mRNA in the PVN of obese Zucker rats. It is concluded that antagonism of GR by mifepristone results in persistent activation of the adrenocortical axis in lean Zucker rats due to blockade of feedback inhibition by circulating corticosterone. In obese animals the abnormal response to mifepristone suggests that the neuroendocrine control of the HPA axis is altered in genetically determined obesity.

Animals↗