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Biomedical subjects

M Koulu

Publications and source records attributed to M Koulu.

At least 91 records · Page 5Linked to original sources
PubMed1989

Inhibition of monoamine oxidase by moclobemide: effects on monoamine metabolism and secretion of anterior pituitary hormones and cortisol in healthy volunteers.

1. Single oral doses (100, 200 and 300 mg) of moclobemide, a reversible inhibitor of monoamine oxidase (MAO) with predominant effects on the A-type of the enzyme, were administered to eight young, healthy male volunteers in a double-blind, random-order, placebo-controlled study. The investigation was thereafter continued in an open fashion by administering a single 10 mg dose of the MAO-B inhibitor deprenyl to the same subjects. 2. Deamination of catecholamines was powerfully and dose-dependently inhibited by moclobemide, as evidenced by up to 40% decreases in the urinary excretion of deaminated catecholamine metabolites, corresponding increases in the excretion of non-deaminated, methylated metabolites, and up to 79% average decreases in the plasma concentration of 3,4-dihydroxyphenylglycol (DHPG), a deaminated metabolite of noradrenaline (NA), and up to 75% average decreases in the plasma concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC), a deaminated metabolite of dopamine. The urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA) was only slightly reduced. In contrast, deprenyl, in a dose which almost totally inhibited MAO-B activity in blood platelets, did not appreciably affect the plasma concentrations of DHPG or DOPAC. 3. Due to the rapid, reversible, dose-dependent and MAO-A specific effect of moclobemide on plasma concentrations of DHPG, it is suggested that DHPG in plasma may be a useful indicator of the magnitude and duration of MAO-A inhibition in man. 4. Sympatho-adrenal function at rest was not significantly altered by moclobemide, as judged by unchanged plasma catecholamine concentrations and stable blood pressure and heart rate recordings. 5. Monoamine oxidase type B activity in blood platelets was slightly (less than 30%) and transiently inhibited after moclobemide. 6. The secretion of prolactin was dose-dependently stimulated by moclobemide, whereas the plasma concentrations of growth hormone (hGH) and cortisol remained unchanged.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Pharmacological effects of medetomidine in humans.

Single i.v. doses of medetomidine have been administered to healthy male volunteers in three clinical phase I studies. After an initial open dose-finding study, double-blind, placebocontrolled designs were used. The highest dose tested was 120 micrograms. Medetomidine was well tolerated. It caused dose-dependent decreases of blood pressure (max 22/14 mmHg), heart rate (max 14/min) and cardiac output (max 21%) without subjective sensations of hemodynamic changes or other unexpected side-effects. However, a clear dose-dependent sedative effect, both subjective and objective, and a decrease in salivation was seen after single i.v. doses. Medetomidine had a powerful and dose-dependent effect in reducing noradrenaline (by a maximum of 75%) and increasing human growth hormone levels in plasma. All the observed pharmacological effects are well compatible with an alpha 2-agonistic action of the drug and resemble those seen after i.v. administration of clonidine. However, medetomidine appeared to be more potent and short-acting than clonidine.

Adrenergic alpha-Agonists↗
PubMed1988

Chronic treatment with SCH 23390, a selective dopamine D-1 receptor antagonist, decreases dopamine metabolism in rat caudate nucleus.

Chronic treatment (18 days; 0.1 and 0.5 mg/kg per day) with the selective dopamine (DA) D-1 receptor antagonist, SCH 23390, significantly reduced the concentration of homovanillic acid (HVA) and the ratios of HVA/DA and DOPAC/DA in the nucleus caudatus of the rat but did not change the metabolism of DA in the prefrontal cortex, substantia nigra or the A10 area. Furthermore, the concentrations of noradrenaline were dose dependently decreased in the A10 area during SCH 23390 treatment. It is concluded that chronic DA D-1 receptor blockade causes changes in the metabolism of DA similar to those caused by classical neuroleptics.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

A central 6-hydroxydopamine lesion prevents fluphenazine-induced increase in plasma homovanillic acid.

Plasma and brain levels of the dopamine metabolite, homovanillic acid, were measured in rats after acute and chronic treatment with fluphenazine. After acute administration, homovanillic acid levels were increased in the whole frontal cortex, caudate nucleus, nucleus accumbens, anterior cingulate (supragenual) cortex, prefrontal cortex and plasma. Following chronic administration, the effects of single doses of fluphenazine in increasing homovanillic acid were markedly attenuated in the caudate nucleus, nucleus accumbens, the whole frontal cortex, anterior cigulate cortex and plasma, but not in the prefrontal (anteromedial) cortex. Following fluphenazine administration plasma homovanillic acid levels were correlated with homovanillic acid concentrations in whole frontal cortex (r = 0.63, p less than 0.01) and caudate nucleus (r = 0.51, p less than 0.05). Further, prior intracerebroventricular administration of 6-hydroxydopamine prevented the fluphenazine-induced increase in plasma homovanillic acid. These data suggest that in the rat, plasma and brain (caudate nucleus and whole frontal cortex) homovanillic acid levels change in a similar fashion during acute and chronic neuroleptic administration.

Animals↗
PubMed1988

Somatostatin concentrations in discrete hypothalamic nuclei of genetically obese Zucker rats.

Hypothalamic somatostatin concentration was determined in 6.5 to 9 months old male and female genetically obese fatty (fa/fa) and lean (Fa/-) Zucker rats. Similar somatostatin levels were found in fatty and lean animals in the hypothalamic regions previously known to contain the highest hormone levels (median eminence and arcuate, periventricular and ventromedial nuclei). The fatty animals were grossly obese and had a pronounced hyperinsulinemia.

Animals↗
PubMed1988

Acute effects of medetomidine, a selective alpha 2-adrenoceptor agonist, on anterior pituitary hormone and cortisol secretion in man.

Single iv doses (25, 50 and 100 micrograms) of medetomidine, a selective alpha 2-adrenoceptor agonist of the imidazole type, were administered to 8 healthy male volunteers in a randomized, double-blind, placebo-controlled study. The concentration of hGH in plasma was powerfully and dose-dependently increased. The plasma level of cortisol was dose-dependently decreased, whereas TSH showed a slight but statistically significant increase. Plasma levels of PRL, FSH and LH were unaffected by the drug. Medetomidine appears to resemble other alpha 2-adrenoceptor agonists, notably clonidine, in its endocrine effects. Its high selectivity and short duration of action make it a suitable tool for studies of the physiology and pharmacology of alpha 2-adrenoceptors in man.

Adrenergic alpha-Agonists↗
PubMed1988

Evaluation of the systemic anticholinergic activity of nasally administered ipratropium bromide.

Plasma concentrations of nasally inhaled ipratropium bromide were analyzed in eight healthy volunteers by using a sensitive radioreceptor assay (RRA). The rate of saliva secretion, heart rate and changes in visual accommodation were quantitated in order to measure possible systemic anticholinergic drug effects. 240 micrograms of ipratropium bromide (40 micrograms each nostril, repeated twice at 15 min intervals) were inhaled nasally in a double blind, randomized, placebo-controlled experiment. Ipratropium bromide absorbed fast, and peak plasma concentrations of the drug (257 +/- 55 pg/ml) were detected as soon as 5 min after the last inhalation (at 35 min from the beginning). The plasma levels of ipratropium bromide decreased rapidly, being only 86 +/- 7 pg/ml one hour after the last inhalation. These low concentrations of ipratropium bromide indicate that only a small portion of it absorbs after nasal application, which is consistent with the lack of any systemic anticholinergic drug effects in our subjects. It is concluded that nasally applied ipratropium bromide is not likely to cause systemic anticholinergic side-effects, even in doses exceeding the therapeutic recommendations.

Absorption↗
PubMed1987

Diabetes-induced changes in monoamine concentrations of rat hypothalamic nuclei.

Streptozotocin-induced diabetes produced marked alterations of monoamine concentrations in several hypothalamic nuclei of male and female rats. Norepinephrine (NE) concentrations were significantly elevated in the median eminence (ME), supraoptic nucleus (SON) and periventricular nucleus (PEVN) in both sexes of diabetic rats. NE concentrations in the suprachiasmatic nucleus (SCN) and ventromedial nucleus (VMN) of male and female diabetic animals remained unaltered. Serotonin (5-HT) concentrations were increased in PEVN of male and female diabetic rats. No significant changes in hypothalamic dopamine (DA) concentrations were observed. Insulin treatment reversed the diabetes-related changes in monoamine concentrations in most of the nuclei. The significance of these biochemical changes relative to the endocrine and behavioral abnormalities in diabetes is discussed.

Animals↗
PubMed1987

Adrenal catecholamine metabolism and myocardial adrenergic receptors in streptozotocin diabetic rats.

Adrenal medullary function and myocardial adrenergic receptors were investigated in streptozotocin-treated diabetic rats. The animals were rendered diabetic by a single i.v. injection of streptozotocin (STZ, 65 mg/kg) and killed 60 days after treatment. Adrenal tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH), and phenylethanolamine N-methyltransferase (PNMT) activities were increased by 52, 28 and 39%, respectively, in the STZ diabetic rats. In addition, adrenal concentrations of dopamine (+52%) norepinephrine (+46%), and epinephrine (+33%) were elevated significantly (P less than 0.05). Increased adrenal TH activity reflected an increased Vmax, but no change in Km. Receptor densities (Bmax), determined by [3H]prazosin and [3H]dihydroalprenolol binding, were decreased by 24 and 25%, respectively, in the myocardium of 60-day diabetic rats. Insulin-induced chronic hypoglycemia in the STZ diabetic rats produced a marked increase in the adrenal TH concentration (Vmax, +65% or +225%, respectively), as compared to control or diabetic rats, without changes in the affinity (Km) for the substrate. These results suggest that the STZ diabetic rat has abnormalities of catecholaminergic function of the adrenal medulla and myocardial adrenergic receptors, which may contribute to the development and maintenance of many of the hemodynamic and metabolic defects described in this animal model of diabetes mellitus.

Adrenal Glands↗
PubMed1987

Sedative and cardiovascular effects of medetomidine, a novel selective alpha 2-adrenoceptor agonist, in healthy volunteers.

1. Single intravenous doses (25, 50 and 100 micrograms) of medetomidine (MPV-785, an imidazole derivative), a selective alpha 2-adrenoceptor agonist, were administered to eight healthy male volunteers in a double-blind, placebo-controlled study. 2. The following dose-related effects, all of which were compatible with an agonistic action of the drug at alpha 2-adrenoceptors, were noted: reductions of systolic and diastolic blood pressure (maximum 18/11 mm Hg), heart rate (maximum 10 beats min-1), saliva secretion (maximum 84%) and noradrenaline levels in plasma (maximum 70%). 3. Dose-dependent sedation or impairment of vigilance was also observed, both by subjective and objective (critical flicker fusion threshold) assessments, with the highest dose actually inducing sleep in five of the subjects. 4. The observed effects were in general agreement with those previously seen after intravenous administration of the centrally acting antihypertensive alpha 2-adrenoceptor activating drug, clonidine, but of a shorter duration. 5. The relative importance of alpha 2-adrenoceptors located in peripheral tissues and in the central nervous system for the drug's cardiovascular effects could not be determined, but the high lipid solubility of the compound and the rapid onset of sedation are in favour of a major central component. 6. Medetomidine may be a useful tool for the investigation of the physiology and pharmacology of alpha 2-adrenoceptors in man. In addition, the therapeutic and diagnostic uses of the compound should be investigated in pathological conditions related to increased sympathetic neuronal activity.

Adrenergic alpha-Agonists↗
PubMed1987

Hypokalaemia and other non-bronchial effects of inhaled fenoterol and salbutamol: a placebo-controlled dose-response study in healthy volunteers.

1. The hypokalaemia-inducing effects of two widely used inhaled antiasthmatic beta 2-adrenoceptor agonists, fenoterol and salbutamol, were compared in six healthy male volunteers. 2. Each drug was administered in three different doses, 400, 600 and 800 micrograms, which were repeated three times with 30 min intervals (total doses 1200, 1800 and 2400 micrograms in 1 h). The treatments were given at 1 week intervals in random order in a single-blind fashion. 3. The concentration of potassium in plasma was dose-dependently reduced by both drugs with peak effects 75-90 min after the first inhalations. The hypokalaemic effect of fenoterol was significantly greater than that of equal doses of salbutamol (average +/- s.d. reductions of 1.13 +/- 0.32 and 0.67 +/- 0.25 mEq l-1, respectively, after the highest doses, P less than 0.05). Concomitantly, decreases were noted in the amplitude of the T-wave on the ECG. 4. The concentration of cyclic AMP in plasma was measured and used as an indicator of systemic beta 2-adrenoceptor agonistic effects of the drugs. Increases in cAMP were a close mirror image of the drugs' effects on potassium in plasma. 5. Plasma renin activity, noradrenaline in plasma and heart rate were also dose-dependently increased by the treatments, whereas blood pressure remained unaltered. 6. While the clinical significance of hypokalaemia induced by inhaled beta 2-adrenoceptor sympathomimetics still is a matter of debate, our results point to possible differences between therapeutically equipotent doses of fenoterol and salbutamol in their propensity to cause hypokalaemia and other acute non-bronchial effects.

Administration, Inhalation↗
PubMed1986

Circadian covariation of norepinephrine and serotonin in the locus coeruleus and dorsal raphe nucleus in the rat.

We report robust correlations between concentrations of the neurotransmitters norepinephrine and serotonin in the locus coeruleus and the dorsal raphe nucleus of the brainstem in rats analyzed at 7 different time points over 24 h. We found similar circadian rhythmicities for both monoamines with acrophases just before the onset of the dark period. The monoamine concentrations diminished and the significant intercorrelation between norepinephrine and serotonin in the locus coeruleus disappeared during the night suggestive of a noradrenergic stimulation of dorsal raphe serotonin during the day. Timing of experiments is crucially important in studies on brain monoaminergic indices and their interrelationships.

Animals↗
PubMed1986

Serotonin turnover in discrete hypothalamic nuclei and mesencephalic raphe nuclei of young and adult spontaneously hypertensive rats.

Serotonin levels and turnover were analyzed in discrete forebrain and mesencephalic nuclei of young (4-week-old) and adult (14-week-old) spontaneously hypertensive rats and age-matched normotensive control Wistar Kyoto rats. Most changes observed were age-dependent, and occurred only in young, early hypertensive rats. Both serotonin levels and the accumulation rate of 5-hydroxy-tryptophan after L-amino acid decarboxylase inhibition were higher in the nuclei periventricularis and paraventricularis of the hypothalamus of young hypertensive rats than in controls. In addition, 4-week-old spontaneously hypertensive rats showed higher 5-hydroxytryptophan accumulation rates in the nuclei supraopticus and dorsomedialis of the hypothalamus than controls. The only difference in serotonin metabolism found in adult hypertensive rats was high serotonin concentration in the median eminence of the hypertensive animals. Our results suggest the presence of anatomically specific, age-dependent alterations in serotonin metabolism, localized to selected hypothalamic nuclei in young hypertensive rats. These data support a role for the hypothalamic serotonin in the development of the spontaneous (genetic) hypertension in the rat.

5-Hydroxytryptophan↗
PubMed1986

Association between increased serotonin metabolism in rat brainstem nuclei and development of spontaneous hypertension.

Spontaneously hypertensive rats have increased brain stem serotonin turnover localized to the nuclei raphe magnus, raphe pallidus, tractus solitarius and reticularis lateralis. It occurs only in young animals coinciding with the development of hypertension. In the locus coeruleus, increased serotonin metabolism is present during both the early and the established phase of hypertension. Our results provide evidence for serotonergic overactivity in specific brainstem nuclei during the development of spontaneous hypertension in the rat.

Age Factors↗
PubMed1986

Chronic corticosterone administration in rats: behavioral and biochemical evidence of increased central dopaminergic activity.

Chronic corticosteroid treatment in humans in frequently complicated by behavioral changes. The present study suggests that chronic steroid administration in rats has distinct neurochemical consequences which are behaviorally relevant. Ten male Sprague-Dawley rats received 7 daily injections of corticosterone, following which they exhibited increased caudate homovanillic acid as well as an attenuated decline in vertical and ambulatory movement (functional measures of dopamine activity) compared to placebo-treated rats. A subgroup of steroid-treated rats which was more behaviorally responsive to corticosterone also showed increased caudate 5-hydroxyindole acetic acid and decreased prefrontal cortex dopamine and serotonin. These results are discussed in relation to the known behavioral side effects of chronic corticosteroid administration in man and the psychiatric manifestations of naturally occurring states of hypercortisolemia.

Animals↗
PubMed1986

Increased catecholamine metabolism in the locus coeruleus of young spontaneously hypertensive rats.

Young, 4-week-old spontaneously hypertensive rats (SHR) had significantly higher concentrations of dopamine and 3,4-dihydroxyphenylacetic acid and a faster rate of accumulation of L-dihydroxyphenylalanine after decarboxylase inhibition in the locus coeruleus than age-matched Wistar-Kyoto rats, whereas the norepinephrine levels were similar to each other. In the brainstem, these changes were restricted to the locus coeruleus and were not present in adult, 14-week-old rats with established hypertension. These results are suggestive of a noradrenergic overactivity in the locus coeruleus of young SHR, coinciding with the development of the hypertension.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1986

Diabetes-induced alteration in brain monoamine metabolism in rats.

Concentrations of monoamines and their metabolites as well as the activities of tyrosine hydroxylase (TH) and of choline acetyltransferase were investigated in various brain regions of control and streptozotocin-treated Sprague-Dawley rats. The animals were rendered diabetic by a single i.v. injection of streptozotocin (65 mg/kg) and killed 10, 30 and 90 days after the treatment. During the course of diabetes, progressive decreases in the activity of TH and a marked increase in the concentration of norepinephrine were observed in several brain regions, including thalamus, hypothalamus, medulla and midbrain. This inverse relationship between TH activity and norepinephrine content was also seen in the pons but only in the 90-day diabetic animals. Lower TH activity in the hypothalamus of 30-day diabetic rats reflected a decreased Vmax, but no difference in the Km. The number of alpha adrenergic receptors was increased significantly in the hypothalamus, medulla and midbrain of the 30-day diabetic rats. The concentrations of dopamine and serotonin in various brain regions of the 10- and 30-day diabetic rats were generally not significantly different from controls. Concentrations of the acidic metabolites of these neurotransmitters, dihydroxyphenylacetic acid and 5-hydroxyindolacetic acid, were, however, greatly reduced. The activity of choline acetyltransferase, a marker of presynaptic cholinergic neuron activity, remained unaltered during the course of diabetes. These data suggest that uncontrolled diabetes is associated with a significant disturbance of brain monoamine metabolism.

Animals↗