Biomedical subjects

R Virtanen

Publications and source records attributed to R Virtanen.

At least 19 recordsLinked to original sources

PubMed1992

Continuous alpha 2-adrenoceptor blockade by atipamezole decreases neocortical high-voltage spindle activity in rats.

The present study investigates the effects of a subchronic continuous infusion of atipamezole, a potent and selective alpha 2-adrenoceptor antagonist, on neocortical high-voltage spindle (HVS) activity in rats. Six days' subcutaneous infusion of atipamezole (0.125 mg/kg per h) with osmotic minipumps decreased HVS activity significantly. The HVS activity-decreasing effect of atipamezole persisted at the same level throughout the infusion. A single subthreshold dose of an alpha 2-adrenoceptor agonist, guanfacine (0.001 mg/kg i.p.), did not affect HVS activity either before or after the continuous atipamezole treatment. The central alpha 2-adrenoceptor blocking effect of atipamezole (0.1 mg/kg per h s.c.) was confirmed to be at the same level after one, three or seven days' infusion, as assessed by measuring the antagonism of detomidine-induced mydriasis in the rat. The serum concentration of atipamezole (0.1 mg/kg per h s.c.) increased slightly from day 3 (37 +/- 11 ng/ml) to day 7 (45 +/- 4 ng/ml). In conclusion, the results of the study suggest that the suppressant effects of atipamezole on neocortical high-voltage spindle activity are preserved during subchronic continuous treatment. In addition, alpha 2-adrenoceptor blockade, as measured in the rat mydriasis model, persists at the same level during subchronic infusion.

Adrenergic alpha-Antagonists↗

PubMed1992

Dexmedetomidine-induced ocular hypotension in rabbits with normal or elevated intraocular pressures.

This study covered the ocular hypotensive effects of the stereoisomers of the alpha 2-adrenoceptor agonist medetomidine. The dextro-isomer, dexmedetomidine, is known from pharmacologic experiments to be a specific, potent, and selective full agonist at alpha 2-adrenoceptors, whereas the levo-enantiomer seems to be almost inactive. Thus, the levo-isomer (0.5 mg/ml, 25 microliters) had no significant effect on intraocular pressure. After unilateral topical administration, dexmedetomidine (0.5 mg/ml, 25 microliters) lowered intraocular pressure bilaterally in normal rabbits and in rabbits with intraocular pressure elevated after laser irradiation of the pigmented trabecular band of the anterior chamber angle. In the treated (ipsilateral) eye of normal rabbits, a maximum decrease of 4.6 +/- 0.6 mmHg was observed at 2 hr post treatment. In the contralateral eye, the maximum decrease was 4.1 +/- 0.5 mmHg at 1 hr after treatment. In rabbits with laser-induced elevation of intraocular pressure, the maximum decrease in treated hypertensive eyes was 13.5 +/- 0.3 mmHg 1 hr after dexmedetomidine administration. These results indicate that the selective alpha 2-adrenoceptor agonist, dexmedetomidine, is a potent and effective drug for decreasing intraocular pressure in rabbits.

Administration, Topical↗

PubMed1991

Central alpha 2-adrenoceptors are highly stereoselective for dexmedetomidine, the dextro enantiomer of medetomidine.

To determine whether different alpha 2-adrenoceptor-mediated functions have different stereochemical requirements in the central nervous system, we studied the pharmacological activities of the purified optical enantiomers of medetomidine (dl-4-[1(2,3-dimethylphenyl)ethyl]-1H-imidazole), a specific and selective agonist of alpha 2-adrenoceptors. We found that dexmedetomidine (the dextro enantiomer) had the pharmacological activity of medetomidine. Dexmedetomidine had hypotensive and bradycardic actions in anaesthetized rats as well as sedative (decreased spontaneous locomotor activity and prolonged sleep induced by hexobarbital in rats), analgesic (attenuated a writhing response induced by acetic acid in mice) and midriatic actions in rats. The potency of dexmedetomidine was slightly greater than that of medetomidine. 1-Medetomidine was generally without pharmacological activity, but it showed some sedative and analgesic properties at high doses. Although the findings obtained with l-medetomidine might indicate some deviation from strict homogeneity, these experiments demonstrate that the different alpha 2-adrenoceptor-mediated functions have similar stereochemical requirements in the central nervous system.

Acetates↗

PubMed1991

The effects of atipamezole, an alpha-2 antagonist, on the performance of young and aged rats in the delayed nonmatching to position task.

The present experiments were undertaken to study whether pharmacological activation of the noradrenergic system would improve age-related deficits in short-term memory. Thus, we investigated the effects the single dose administration (0.1, 0.3, 0.9 and 2.7 mg/kg, subcutaneously) or atipamezole, a specific alpha-2 adrenoceptor antagonist, had on the performance of young and aged rats in a delayed nonmatching to position task. After substantial training, aged rats made more errors at longer delays (4-30 seconds) than did young rats, although the percent correct responses at short delays (0-2 seconds) did not differ between young and aged rats. Atipamezole (0.1-0.9 mg/kg) did not improve the performance of young and aged rats in this task. Moreover, the highest dose (2.7 mg/kg) used increased the number of omissions and increased the latency to collect food pellets, indicating disruption of the performance of rats in this task. According to the present results, alpha-2 antagonist (administered peripherally at a single dose), which increases the release of noradrenaline, did not improve age-related deficit in short-term memory in rats.

Adrenergic alpha-Antagonists↗

PubMed1991

Effects of dexmedetomidine, a novel imidazole sedative-anesthetic agent, on adrenal steroidogenesis: in vivo and in vitro studies.

Inhibition of steroidogenesis may be produced perioperatively by imidazole compounds, such as the hypnotic agent etomidate, with potentially serious consequences for patient morbidity and mortality. Dexmedetomidine, ([+]4-[1-[2,3-dimethylphenyl]-ethyl]-1H-imidazole), another imidazole compound with anesthetic like properties, is now being used perioperatively. Therefore, we investigated the effects of dexmedetomidine on steroidogenesis as well as on binding to glucocorticoid receptors in a series of in vitro and in vivo animal studies. The effect of dexmedetomidine, 10(-8)-10(-3) M, on adrenocorticotrophic hormone (ACTH) stimulated release of corticosterone was assessed in isolated rat adrenal cells. To characterize dexmedetomidine interactions with the glucocorticoid receptor, dexmedetomidine's ability to compete for [3H]dexmethasone binding sites was studied in renal tubular cells. The effect of dexmedetomidine, 80 micrograms/kg subcutaneously, on ACTH-stimulated release of cortisol was studied in separate cohorts of dogs at various time intervals during and after anesthesia was given. To compare the inhibitory effects of etomidate and dexmedetomidine on steroidogenesis, ACTH-stimulated release of cortisol was studied in dogs treated with anesthetic doses of either dexmedetomidine (80 micrograms/kg IV) or etomidate (1 mg/kg IV). Finally, dogs were given dexmedetomidine by continuous subcutaneous infusion for 7 days at sedative doses after which their cortisol response to ACTH was determined. At dexmedetomidine concentrations greater than 10(-7) M, a dose-dependent inhibition of corticosterone release was detected in response to ACTH stimulation in vitro. At these high dexmedetomidine concentrations, [3H]dexamethasone binding was not affected. In the in vivo dog experiments, basal cortisol levels decreased and the cortisol response to ACTH was blunted 3 h after dexmedetomidine administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex↗

PubMed1991

Comparison of the behavioral and neurochemical effects of the two optical enantiomers of medetomidine, a selective alpha-2-adrenoceptor agonist.

Medetomidine (MED) is a veterinary sedative whose mode of action is activation of alpha-2 adrenoceptors. Because the carbon atom which separates the two ring systems is methylated, there is a center of stereochemical asymmetry in the molecule. The resulting enantiomers, d-MED and l-MED have recently become available for study. The biological activity of MED, as is now demonstrated in rats in vivo, seems to reside almost exclusively in the d-MED form. Only at extremely high doses (e.g., 10 mg/kg) does l-MED exert any effects, interpreted as alpha-2 adrenoceptor antagonism. In contrast, doses of d-MED as low as 30 micrograms/kg cause sedation, hypothermia and induce neurochemical changes in norepinephrine and 5-hydroxytryptamine metabolism in brain characteristic of alpha-2-agonists (decreases in concentrations of biogenic amine metabolites, turnover and increases in concentration of parent amine). The most sensitive neurochemical indicator of the alpha-2-agonist action of d-MED was the concentration of unconjugated 3-methoxy-4-hydroxy-phenyethylene glycol in rat cerebral spinal fluid, doses of d-MED as low as 10 micrograms/kg caused a significant reduction in this norepinephrine metabolite. Simultaneous administration of the specific alpha-2 adrenoceptor antagonist, atipamezole (1 mg/kg), effectively inhibited the behavioral and most of the neurochemical actions of d-MED (100 micrograms/kg). It is concluded that the enantiomers of MED may be extremely useful in elucidating structure action relationships at alpha-2 adrenoceptors.

Adrenergic alpha-Agonists↗

PubMed1991

Arthroscopic synovectomy in the treatment of patients with juvenile rheumatoid arthritis.

Since January 1982, operative arthroscopy in the knee joint has been performed by us to 22 patients with juvenile rheumatoid arthritis, by whom synovectomy was considered to be indicated. The age of the patients varied from 5 to 16 years. In general anaesthesia, in the connection of arthroscopy, the abrasion of the hypertrophic synovial membrane was made by Stryker's chondrotome. The surgical debris was evacuated by suction. The mobilisation of the knee joint was started 2 days after the operation, and most of the patients walked on the fifth postoperative day. The arthroscopic synovectomy is considered to be a safe operation and, in our opinion, a good alternative method for synovectomy. Rehabilitation time is decisively shorter and, if necessary, operative arthroscopy can easily be repeated, without disturbing scars.

Adolescent↗

PubMed1990

Chronic dexmedetomidine, a selective alpha 2-agonist, decreases serotonin but not noradrenaline turnover in rat brainstem nuclei.

The effects of a chronic treatment with dexmedetomidine, the active d-isomer of a selective alpha 2-agonist, medetomidine, on the metabolism and turnover of catecholamines and indoleamines in discrete rat brain stem and mesencephalic nuclei were investigated. Chronic dexmedetomidine (3 or 10 micrograms/kg per h for 14 days, delivered by osmotic minipumps) did not change the basal concentrations of noradrenaline, dopamine or 3,4-dihydroxyphenylacetic acid, or the rates of accumulation of 3,4-dihydroxyphenylalanine after inhibition of decarboxylase by NSD 1015. In contrast, the concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and/or 5-HIAA/5-HT were significantly reduced in the nucleus tractus solitarii, raphe dorsalis, locus coeruleus, A1-C1 area, A9 and A10 areas after 10 micrograms/kg per h of dexmedetomidine. The accumulation of 5-hydroxytryptophan was significantly reduced in the locus coeruleus and nucleus tractus solitarii. It is concluded that chronic dexmedetomidine treatment significantly decreases the turnover of 5-hydroxytryptamine in discrete brainstem and mesencephalic nuclei, while the rate of synthesis of noradrenaline in the same areas is not changed.

Adrenergic alpha-Agonists↗

PubMed1990

5-HT3 receptor antagonist ondansetron does not alter effects of amphetamine on DA metabolism.

The present study was carried out to elucidate the effect of ondansetron, a selective 5-HT3 receptor antagonist, on amphetamine-induced changes in monoamine metabolism in major ascending dopamine (DA) neurons. Amphetamine (2 mg kg-1 s.c.) significantly decreased the concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in nucleus caudatus and nucleus accumbens. Pretreatment with ondansetron (0.1 mg kg-1 and 1 mg kg-1 s.c., 15 min before amphetamine) failed to modify the effects of amphetamine. It is concluded that acute blockade of central 5-HT3 receptors by ondansetron does not prevent amphetamine-induced changes in monoamine metabolism in nigrostriatal or mesolimbic dopaminergic areas.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1989

Effects of acute GR38032F (odansetron), a 5-HT3 receptor antagonist, on dopamine and serotonin metabolism in mesolimbic and nigrostriatal dopaminergic neurons.

The acute administration of GR38032F, a selective 5-HT3 receptor antagonist, did not change the concentrations of dopamine (DA) or 5-hydroxytryptamine (5-HT) or their deaminated metabolites in nucleus caudatus, nucleus accumbens or substantia nigra. Pretreatment with GR38032F failed to modify the haloperidol-induced activation of DA turnover. It is concluded that the blockade of central 5-HT3 receptors by GR38032F under these experimental conditions does not result in alternations in metabolism of DA or 5-HT in major ascending dopaminergic areas.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1989

Medetomidine--a novel alpha 2-adrenoceptor agonist: a review of its pharmacodynamic effects.

1. The pharmacodynamic effects of medetomidine, a novel alpha 2-adrenoceptor agonist, are reviewed. 2. In receptor binding experiments, and in isolated organ preparations medetomidine shows high specificity and selectivity to alpha 2-adrenoceptors. Its alpha 2/alpha 1 selectivity ratio is 1620 compared to 220 of clonidine. It is a highly potent full agonist at alpha 2-adrenoceptors, a fact that also distinguishes it from clonidine. 3. Medetomidine induces a dose-dependent decrease in the central release and turnover of norepinephrine (NE) measured as changes in metabolite concentrations or using pharmacological intervention techniques. 4. The selectivity, specificity and potency of medetomidine is further supported by various in vivo experiments showing dose-dependent hypotensive, bradycardic, sedative, anxiolytic mydriatic, hypothermic and analgesic effects. 5. The pharmacological, neurochemical and behavioral effects of medetomidine can be inhibited by prior, simultaneous or subsequent administration of selective and specific alpha 2-antagonists. 6. In humans medetomidine is well-tolerated and pharmacodynamic effects including e.g. dose-dependent decrease of vigilance, blood pressure, heart rate, salivary secretion and plasma NE are compatible with an agonistic action at alpha 2-adrenoceptors.

Adrenergic alpha-Agonists↗

PubMed1989

Evaluation of anaesthetic potency of medetomidine-ketamine combination in rats, guinea-pigs and rabbits.

In many animal species ketamine hydrochloride is combined with xylazine, an alpha 2-adrenoceptor agonist, to achieve anaesthesia. The purpose of this study was to evaluate the anaesthetic efficacy of various dose combinations of another alpha-2-adrenoceptor agonist medetomidine and ketamine in rats, guinea pigs and rabbits. Both sexes of all three species in groups of five were used. In rats, dose combinations medetomidine/ketamine, both in mg/kg, used were 0.25/60, 1.0/60 and 0.5/70; in guinea pigs 0.5/40 and in rabbits 0.5/25 and 0.5/60. In rats and rabbits the righting reflex was lost within 2-3 min. In rats with doses 0.25/60 and 0.5/75 other reflexes disappeared, reappearing after 20-25 min and 60-70 min in males, the respective values being 120-140 min and 150-180 in females. The righting reflex reappeared after 130-135 and 160-190 min in males and 240 and greater than 300 min in females in the order above. In guinea pigs irrespective of route of ketamine administration all reflexes remained. In rabbits, a dose 0.5/25 caused disappearance of ear pinch reflex. We conclude that the medetomidine-ketamine combination can be used in rats and rabbits as an anaesthetic, and in guinea pigs only for immobilization.

Adrenergic alpha-Agonists↗

PubMed1989

Pharmacological profiles of medetomidine and its antagonist, atipamezole.

Medetomidine, (+/-)-4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, is a very potent, selective and specific full agonist at both pre- and postsynaptic alpha 2-adrenoceptors as demonstrated in several models both in vitro and in vivo. In receptor binding experiments the alpha 2/alpha 1 selectivity ratio of medetomidine is 1620 compared to 260, 220 and 160 for detomidine, clonidine and xylazine, respectively. The alpha 2-adrenoceptor activity of medetomidine resides predominantly in its d-enantiomer (dexmedetomidine). Medetomidine induces a dose-dependent decrease in the release and turnover of noradrenaline, dopamine and serotonin in the CNS as measured by changes in metabolite concentrations or using pharmacological intervention techniques. Inhibition of sympathetic tone in the CNS by medetomidine leads for a characteristic pattern of pharmacodynamic responses including e.g. hypotension, bradycardia, sedation, relief of anxiety, analgesia and hypothermia. The potent, dose-dependent sedative effects of medetomidine have been demonstrated in several classical animal models (e.g. decrease in spontaneous motility in rats and mice, potentiation of barbiturate-induced anaesthesia in rats and mice, induction of sleep in young chicks). At high doses medetomidine has hypnotic of anaesthetic effects, a property which distinguishes it clearly from detomidine, clonidine and other alpha 2-agonists. The pharmacological, neurochemical and behavioral effects of medetomidine can be inhibited by prior, simultaneous of subsequent administration of a selective and specific alpha 2-antagonist, atipamezole. Besides verifying that the main pharmacodynamic effects of medetomidine are alpha 2-mediated, this finding forms a strong basis for the use of atipamezole as a reversing agent against medetomidine-induced effects in veterinary practice.

Adrenergic alpha-Agonists↗

PubMed1989

Effects of acute administration of medetomidine on the behaviour, temperature and turnover rates of brain biogenic amines in rodents and reversal of these effects by atipamezole.

The effects of acute administration of medetomidine in rodents were examined. Low doses (2.5 micrograms/kg) were anxiolytic, higher doses (10-100 micrograms/kg) sedating, and above 100 micrograms/kg medetomidine treated rats lost their righting reflex and were hypothermic. These higher doses of medetomidine inhibited the release of noradrenaline (NA), dopamine and serotonin in the central nervous system, inhibition of NA release being the most sensitive to medetomidine. All the above effects could be antagonized by administration of suitable doses of the alpha 2-antagonist, atipamezole, indicating that the actions of medetomidine were mediated via activation of alpha 2-adrenoceptors.

Adrenergic alpha-Agonists↗

PubMed1988

Characterization of the selectivity, specificity and potency of medetomidine as an alpha 2-adrenoceptor agonist.

Medetomidine (4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole) was tested for alpha 2-adrenoceptor agonist activity and compared to several reference agents. In binding studies carried out with rat brain membrane preparations, medetomidine showed high affinity for alpha 2-adrenoceptors, as measured by the displacement of [3H]clonidine (Ki 1.08 nM compared to 1.62, 3.20, 6.22 and 194 nM for detomidine, clonidine, UK 14,304 and xylazine, respectively). The affinity of medetomidine for alpha 1-adrenoceptors, as measured by [3H]prazosin displacement, was much weaker, yielding a relative alpha 2/alpha 1 selectivity ratio of 1620 which is 5-10 times higher than that of the reference compounds. Medetomidine caused a concentration-dependent inhibition of the twitch response in electrically stimulated mouse vas deferens with a pD2 value of 9.0 compared to that of 8.6, 8.5, 8.2 and 7.1 for detomidine, clonidine, UK 14,304 and xylazine, respectively. The effect of medetomidine was antagonized by idazoxan. In anaesthetized rats, medetomidine caused a dose-dependent mydriasis which could be reversed by alpha 2-adrenoceptor blockade. In receptor binding experiments and isolated organs medetomidine had no affinity or effects on beta 1-, beta 2-, H1, H2, 5-HT1, 5-HT2, muscarine, dopamine, tryptamine, GABA, opiate and benzodiazepine receptors. Based on these results, medetomidine can be classified as a potent, selective and specific alpha 2-adrenoceptor agonist.

Adrenergic alpha-Agonists↗

PubMed1988

Therapeutic applications of drugs acting on alpha-adrenoceptors.

For over a decade it has been known that clonidine and alpha-methyldopa lower blood pressure by activating central and peripheral alpha-2-adrenoceptors and prazosin likewise by antagonizing alpha-1-adrenoceptors. During the 1980s, the number of therapeutic indications for drugs which act via these classes of alpha-adrenoceptors has expanded greatly, particularly the non-cardiovascular applications of drugs acting on alpha-2-adrenoceptors. Novel alpha-2-agonists such as detomidine and medetomidine have been introduced into veterinary medicine as sedative/analgesics. It is possible that these and other compounds with better alpha-2-adrenoceptor selectivity than clonidine may be used in human medicine to ease symptoms of anxiety in drug- and alcohol-related withdrawal syndromes, and as preanaesthetic agents. Several novel alpha-2-adrenoceptor antagonists, such as idazoxan and atipamezole, have been developed with improved selectivity compared to the traditional antagonist at these receptors, yohimbine. At present none of these new compounds are registered for use, but several are undergoing clinical trials for a variety of therapeutic applications such as depression (idazoxan), arousal of animals sedated with alpha-2-agonists (atipamezole), and adult-onset diabetes (DG-5128). The established use of yohimbine in the treatment of male sexual impotence has been reconfirmed and several of the above compounds may be evaluated in the future to treat this disorder.

Adrenergic alpha-Agonists↗

PubMed1986

Effects of yohimbine and idazoxan on monoamine metabolites in rat cerebrospinal fluid.

Effects of two alpha 2-adrenoceptor antagonists, idazoxan and yohimbine, on the concentrations of monoamine metabolites in cisternal cerebrospinal fluid (CSF) of freely moving rats were investigated. Both drugs caused a dose-dependent, up to 250% increase in the concentration of 3-methoxy-4-hydroxyphenylglycol (MHPG) in CSF indicating enhanced release, metabolism and turnover of noradrenaline in the central nervous system (CNS). In addition, a similar increase in homovanillic acid (HVA) in CSF was observed, while the level of 5-hydroxyindoleacetic acid was unchanged. The present results demonstrate the usefulness of monitoring drug-induced alterations in noradrenergic activity in the CNS by measurement of free MHPG in repeatedly collected cisternal CSF samples from awake rats. The possibility that the observed increase in the concentration of HVA after the highly specific alpha 2-antagonist idazoxan reflects increased noradrenergic rather than dopaminergic neuronal activity is discussed.

Amines↗

PubMed1986

Re-evaluation of drug-interaction with alpha-adrenoceptors in vivo and in vitro using imidazole derivatives.

The critical spatial dimension requirements for drug interaction with alpha-adrenoceptors were examined using imidazole derivatives MPV 295 and its semi-rigid analogue MPV 305 T (= trans) or MPV 305 C (= cis). The ethenyl bridge bond between the phenyl and imidazole moieties of MPV 305 prevents it achieving the critical spatial dimensions of the phenethylamines (e.g. norepinephrine). MPV 295 (0.03-10 mg/kg i.v.) and the trans-extended MPV 305 T (0.01-1 mg/kg i.v.) were hypotensive and bradycardic in anesthetised rats. In pithed rats, MPV 295 and MPV 305 T induced vasoconstriction, the doses giving a 50 mmHg rise in mean arterial pressure being 34.5 and 11.5 ug/kg, respectively. The pressor activity of MPV 295 was antagonized by idazoxan (1 mg/kg i.v.) but not by prazosin (0.1 mg/kg i.v.), whereas that of MPV 305 T was antagonized by prazosin and to a greater extent by idazoxan. Both compounds inhibited the increase in heart rate produced by electrical stimulation of the cardioaccelerator sympathetic nerve fibres in the pithed rats. The doses which induced a 50% inhibition of sympathetic transmission were 49.0 and 38.0 ug/kg for MPV 295 and MPV 305 T, respectively. This peripheral sympatho-inhibitory action was antagonized by idazoxan. Both compounds inhibited the twitch response of electrically stimulated mouse vas deferens, the pD2 values being 7.59 and 7.89 for MPV 295 and MPV 305 T, respectively. In the rat anococcygeus muscle only MPV 305 T was active (pD2 4.84). The cis-folded MPV 305 C was practically inactive in pithed rats and in rat anococcygeus muscle. According to the results, the strengthening of the ethano bridge of MPV 295 to that of MPV 305 T, thus preventing it fitting into the proposed dimensions of alpha-agonists, does not lead to a decrease in alpha-adrenoceptor mediated activities. Therefore, the spatial dimension requirements among imidazoles are different from those among the phenethylamines, supporting the concept that imidazoles interact differently with alpha-adrenoceptors when compared to the phenethylamines.

Animals↗