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Biomedical subjects

N T Kärki

Publications and source records attributed to N T Kärki.

At least 19 recordsLinked to original sources
PubMed1988

Cardiovascular and sedative alpha-adrenoceptor effects of detomidine-like arylalkyl imidazoles and associated derivatives.

The effects of detomidine (4-[(2,3-dimethylphenyl)methyl]-1H-imidazole, Domosedan) and its congeners, MPV compounds, are evaluated in the cardiovascular system and related to their sedative action using clonidine and xylazine for reference purposes. The structure of the MPV compounds had been modified with methyl substituents in the phenyl ring, with differing lengths in the alkyl bridge, and with variations in the imidazole terminus. The lipophilicity of the test compounds had been estimated in terms of apparent partition coefficients in the octanol/buffer (pH 7.4, 24-26 degrees C) using the HPLC technique. The lipophilicity of the MPV compounds was found to be higher than for either clonidine or xylazine, suggesting a more rapid penetration into the central nervous system. Some of these 21 MPV compounds were hypotensive and bradycardic in anaesthetized rats. Interestingly a number of these MPV compounds were only bradycardic but not clearly hypotensive after i.v. administration to anaesthetized rats, this being most obvious in the case of the 2,5-dimethylphenyl derivative MPV 867. A further characteristic distinguishing between the central and peripheral alpha-adrenoceptors regulating cardiovascular tone was a distinct inability of some derivatives active at peripheral cardiac presynaptic (pithed rats) and central (young chicks) alpha 2-adrenoceptors to reduce blood pressure in anaesthetized rats. The sedative action of the compounds after i.m. injection into 2- to 5-day-old chicks was in general related to their central hypotensive and bradycardic effect in anaesthetized rats, and with peripheral vasopressor and sympatho-inhibitory activity in pithed rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed1987

Aryl hydrocarbon hydroxylase in lymphocytes and lung tissue from lung cancer patients and controls.

The inducibility of aryl hydrocarbon hydroxylase (AHH) activity in peripheral mitogen-treated lymphocytes, and of AHH and other monoxygenase activities in lung samples, was studied in 41 patients--34 with pulmonary carcinoma, 4 with a benign lung tumour and 3 with chronic obstructive pulmonary disease. Lymphocyte AHH induction alone was studied in 43 non-smoking and 37 smoking surgical patients. Absolute induced and non-induced AHH activities were at about the same level in the lymphocytes from the lung cancer patients as in those from the non-smoking controls, whereas the activities in smoking controls were about 100% higher. The mean inducibility ratios were very similar in all groups, ranging from 4.4 in the benign tumour patients to 5.4 in both control groups. Thymidine incorporation was on average about 40% lower in the lymphocytes from the lung cancer patients. AHH activity was detectable in all the peripheral lung samples, both normal or tumorous tissue, and its inter-individual variation was more than 67-fold. ECDE activity was also detectable in all the samples studied and its correlation with AHH activity was statistically significant (r = 0.888), suggesting that the same enzyme metabolizes both substrates. ERDE was detectable only in the samples with the highest AHH and ECDE activities. There was no correlation between basal or induced lymphocyte AHH activities and lung tissue AHH activity, but there were statistically significant correlations between lung AHH activity and the inducibility ratio with (r = 0.618) or without correction by thymidine incorporation (r = 0.442). These correlations suggest that there are common regulatory factors for AHH inducibility in different tissues. No significant difference in any drug metabolism parameter measured was observed between the lung cancer patients and the controls.

Animals↗
PubMed1987

The metabolism of 2,5-diphenyloxazole (PPO) in human lymphocytes and rat liver microsomes.

The oxidative metabolism of 2,5-diphenyloxazole (PPO) is associated with 3-methylcholanthrene inducible cytochrome P-450. The major metabolite formed has m/z of 237, corresponding to hydroxylated PPO. All the possible hydroxylated metabolites of PPO were synthesized and characterized, enabling the assignment of a structure for the major metabolite and two minor metabolites. The metabolites are easily extracted and their fluorescence is quantifiable in alkaline medium with a sample fluorescence to blank fluorescence ratio of 400:1. A sensitive HPLC assay of PPO metabolism was also developed. PPO metabolism is readily catalyzed by 3-methylcholanthrene-induced rat liver microsomes and strongly inhibited by alpha-naphthoflavone, but poorly inhibited by metyrapone or SKF 525A, indicating the involvement of cytochrome P-448 or P1-450 in the metabolism of PPO. With human lymphocytes the method has proven to be a good indicator of "aryl hydrocarbon hydroxylase" (AHH) activity, correlating well with AHH assays using benzo(alpha)pyrene (BP) as a substrate. Both the induced BP and PPO metabolism by human lymphocytes is inhibited by alpha-naphthoflavone, but not by metyrapone.

Animals↗
PubMed1987

Hepatic drug metabolism and the activities of NADPH generating enzymes and glucose-6-phosphatase in phenobarbital treated genetically obese (ob/ob) mice.

We aim to evaluate the effects of phenobarbital (PB) on the liver drug metabolism, NADPH production capacity and terminal gluconeogenic enzyme, glucose-6-phosphatase (G6Pase) activity in the diabetic state associated with genetic obesity in mice. The results showed that PB treatment increased the amount of liver total cytochrome P450 (cytP450), a drug metabolizing monooxygenase enzyme in genetically obese, hyperglycemic (ob/ob) mice 6-fold and the total activities of other monooxygenase enzymes NADPH cytP450 reductase and 7-ethoxyresorufin O-deethylase (ERDE) 2- and 6.5-fold, respectively. In addition, the regimen increased the liver total activities of two NADPH generating enzymes, 6-phosphogluconate dehydrogenase (6PGDH) and malic enzyme (ME) in obese mice suggesting that the regimen enhanced liver NADPH production capacity in the animals. The data further showed that PB treatment decreased the high hepatic G6Pase activity in obese mice. Both enhanced NADPH generating enzyme activities and lowered G6Pase activity may suppress hepatic glucose output. Since NADPH is required for drug oxidation reactions as a reducing cofactor, high NADPH generating capacity may facilitate liver drug metabolism in vivo. Although the diabetic state in obese mice differs somewhat from that seen in non-insulin dependent diabetic subjects (NIDDs), these findings provide some knowledge about the possible biochemical mechanisms whereby PB treatment normalizes drug metabolism and glycemic control in NIDDs, as has been noted in previous studies.

Animals↗
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↗
PubMed1986

Increased sister-chromatid exchange rate and its regression during prolonged incubation in lymphocyte cultures from patients with multiple sclerosis.

Peripheral venous blood lymphocytes from multiple sclerosis patients, cultured for 72 h in the presence of phytohemagglutinin, appeared to have a higher sister-chromatid exchange (SCE) rate than cells from matched controls. Prolongation of the incubation time to 9 days by adding interleukin-2 to the cultures, caused the cells from the MS patients to lose their increased SCE frequency, so that the mean rate no longer differed from that of the controls. The SCE rate of the controls did not change significantly on prolonged incubation.

Adult↗
PubMed1986

Evidence for medetomidine as a selective and potent agonist at alpha 2-adrenoreceptors.

The activity on alpha-adrenoreceptors of medetomidine ((+/-)-4-(alpha,2,3-trimethylbenzyl)imidazole), an alpha-methyl derivative of detomidine, has been characterized in vivo and in vitro using detomidine, MPV 207, MPV 295, azepexole, clonidine and xylazine for reference purposes. Medetomidine (1-100 micrograms/kg i.v.) was a hypotensive and bradycardic compound in anaesthetized rats. Furthermore, it induced vasopressor (PD50 1.7 microgram/kg) and sympatho-inhibitory (ID50 1.6 microgram/kg) actions in pithed rats, the effects being antagonized by idazoxan (0.3 mg/kg i.v.) but not by prazosin (0.1 mg/kg i.v.). Medetomidine (30-300 micrograms/kg i.m.) had an alpha 2-adrenoreceptor mediated sedative effect on chicks. Medetomidine was, overall, more potent than detomidine, MPV 207, clonidine, xylazine, MPV 295 or azepexole in central (sedation in the chick) and peripheral (cardiac presynaptic in the pithed rat) actions on alpha 2-adrenoreceptors. Clonidine had, however, about an equal potency to medetomidine in the vascular smooth muscle of the pithed rat. Like detomidine and MPV 295, medetomidine had no agonistic activity in the rat aortic ring, but high concentrations antagonized methoxamine-induced contractions, giving a pA2 value of 5.68 for alpha 1-adrenoreceptor antagonism. The overall lipophilicity (log P') of medetomidine in the octanol/buffer (pH 7.4, 24-26 degrees C, HPLC technique) was 2.80. In summary, the experimental data suggest that medetomidine is a lipophilic compound with selective alpha 2-adrenoreceptor-stimulating properties and high potency. It may, therefore, prove to be a suitable pharmacologic tool for interventions in alpha 2-adrenoreceptor mediated effects in the autonomic nervous system.

Adrenergic alpha-Agonists↗
PubMed1985

Cardiovascular action of detomidine, a sedative and analgesic imidazole derivative with alpha-agonistic properties.

The cardiovascular effects of detomidine, a new veterinary sedative and analgesic imidazole derivative were studied in rats and cats using as reference compound xylazine, a widely employed veterinary antinociceptive and sedative drug with alpha-agonistic potency. Detomidine (1-30 micrograms/kg i.v.) and xylazine (10-1000 micrograms/kg i.v.) had both dose-dependent hypotensive and bradycardiac effects in anaesthetized rats. After i.v. administration of 3-100 micrograms/kg detomidine and 0.1-3 mg/kg xylazine to conscious rats, detomidine was more active in reducing the heart rate than in lowering the blood pressure. In anaesthetized cats, detomidine (1-30 micrograms/kg i.v.) was hypotensive and bradycardiac in a dose-dependent manner. A low dose of detomidine into the vertebral artery was more effective than i.v. application in reducing blood pressure. Idazoxan (0.3 mg/kg i.v. and 0.03 mg/kg into the vertebral artery) antagonized the hypotensive and bradycardiac effects of detomidine injected into the femoral vein or vertebral artery, respectively. In pithed rats, detomidine and xylazine stimulated presynaptic and postsynaptic alpha 2-adrenoceptors, and to a lesser extent postsynaptic alpha 1-adrenoceptors. The results indicate that detomidine is an agonist of central and peripheral alpha 2-adrenoceptors which exerts its hypotensive and bradycardiac effects via activation of the central alpha 2-adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1985

Peripheral cardiovascular alpha- and beta-adrenergic effects of some hypotensive and bradycardic arylalkyl imidazole derivatives in the rat.

In pithed rats, a series of four alkyl bridge analogues of 4(5)-substituted arylalkyl imidazole induced alpha-adrenoceptor-mediated vasoconstriction and inhibition of electrically stimulated tachycardia. These effects were induced in the order of potency clonidine = MPV 207 greater than MPV 295 greater than MPV 304 greater than MPV 390, correlating with the length of the alkyl bridge between the phenyl and imidazole moieties. The peripheral postsynaptic actions of MPV 207 and MPV 304 were attenuated by prazosin (0.1 mg kg-1 i.v.) and yohimbine (1 mg kg-1 i.v.). The pressor responses induced by MPV 295 were antagonized only by yohimbine (0.3 and 1 mg kg-1 i.v.). The peripheral sympathoinhibitory action of these compounds was antagonized by yohimbine (1 mg kg-1 i.v.). In spontaneously beating rat atria, the MPV compounds showed neither agonistic nor antagonistic activity at cardiac postsynaptic alpha- and beta-adrenoceptors. The results indicate that the hypotensive and bradycardic MPV compounds are agonists at peripheral cardiovascular alpha-adrenoceptors. The extension of the alkyl bridge between the phenyl and imidazole moieties reduces their activity at alpha-adrenoceptors. Finally, MPV 295 seems to be a selective agonist of peripheral alpha 2-adrenoceptors in the cardiovascular system of the pithed rat.

Animals↗
PubMed1985

Medroxyprogesterone acetate and phenobarbital induce NADPH producing enzyme activities in rats with a chemical liver injury.

The administration of medroxyprogesterone acetate (MPA) and phenobarbital (PB) improves liver function in rats with liver damage. This was seen here as increased aryl hydrocarbon hydroxylase (AHH) activity after therapy with MPA or PB in rats with a chemical liver injury, produced by dimethylnitrosamine (DMN). Hepatic glucose-6-phosphatase (G6Pase) activity, an index of glucose metabolism was also normalized in the MPA treated rats. The present study further shows that MPA induced hepatic malic enzyme (ME) and isocitrate dehydrogenase (ICDH) activities and PB enhanced glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconate dehydrogenase (6PGDH) and ME activities in the DMN pretreated rats. This suggests that MPA and PB enhanced the capacity of altered liver tissue to generate NADPH, a cofactor in the monooxygenase system, which may, in part, enhance the restoration of drug hydroxylation in the rats. Since G6PDH, 6PGDH and ME participate in glucose metabolism, the finding that the compounds influenced these enzymes in distinct ways, may explain the different effects of MPA and PB on the restoration of glucose metabolism.

Animals↗
PubMed1985

Metabolism of medroxyprogesterone acetate and hepatic drug metabolism activity.

The effect of microsomal enzyme activity on the hepatic metabolism of medroxyprogesterone acetate (MPA), measured in vitro, and the MPA concentrations in liver and plasma were investigated in rats with intact and injured livers before and after MPA therapy. The amount of total MPA metabolites and the activity of drug-metabolizing enzyme system changed in a parallel manner in the livers. The ratio of liver/plasma concentration of MPA was decreased in the liver injury. The hepatic metabolism of MPA is accelerated during MPA treatment in rat.

Animals↗
PubMed1984

Genetic and environmental regulation of aryl hydrocarbon hydroxylase in man: studies with liver, lung, placenta, and lymphocytes.

Properties and response smoking of aryl hydrocarbon hydroxylase (AHH) activity in various human tissues are reviewed. In the placenta, induction of AHH by smoking can be demonstrated unequivocally. AHH activity in lung samples is variable, but the relation to current or past smoking is unclear. The effect of cigarette smoking can be readily shown in the rate of antipyrine elimination, although there is no change in AHH activity in liver biopsy samples. The reason for this discrepancy is not known. In peripheral lymphocytes a sort of "memory-effect" of cigarette smoking is retained even after culturing, the nature of this phenomenon remaining unclear. Furthermore, there seem to be many factors affecting AHH induction in peripheral lymphocytes in culture. These data suggest that regulation of AHH activity and induction is tissue-specific, i.e. no systemic regulation is discernible. It is also possible that the P-450 isozyme composition in some tissues masks the induction. Reasons for discrepancies between animal and human data are not clear; however, genuine biological differences and technical difficulties in human studies can be postulated.

Animals↗
PubMed1983

Medroxyprogesterone acetate improvement of the hepatic drug-metabolizing enzyme system in rats after chemical liver injury.

Medroxyprogesterone acetate (MPA) has an inducing effect on the hepatic drug-metabolizing enzyme system in the rat. The effect of MPA on the liver metabolism was further evaluated here by investigating the restoration of hepatic function after chemical liver injury in female rats. The hepatic injury was induced by pretreating the animals with CCl4 and dimethylnitrosamine for 4 weeks, after which rats treated with MPA for a week were compared with rats showing spontaneous regeneration upon treatment with the MPA vehicle only. Changes in various parameters of the drug-metabolizing enzyme system were used as indices of hepatic function together with liver protein content. The results showed that MPA therapy increased the cytochrome P-450 content and the activity of NADPH-cytochrome c reductase, the monooxygenase enzymes benzo[a]pyrene hydroxylase and aminopyrine N-demethylase, epoxide hydrolase and glutathione S-transferase. MPA increased the relative values in the rats with liver injury almost equally to, or even more than, that seen in the intact animals in comparison to the corresponding vehicle-treated rats. MPA seemed to enhance protein synthesis during liver regeneration, as indicated by changes in total liver protein and in the gel electrophoresis pattern of the microsomal proteins. The hepatic enzyme induction and enhancement of protein synthesis achieved by MPA after liver injury may be of value in the treatment of liver diseases.

Animals↗
PubMed1983

Disposition of medroxyprogesterone acetate and drug metabolism activity.

The role of drug-metabolizing enzyme activity on the disposition of medroxyprogesterone acetate (MPA) was investigated in male rats. The metabolizing enzyme system was induced by phenobarbital (PB) or inhibited by SKF 525A. Plasma concentrations of unmetabolized MPA and the amounts of MPA-related residues in various tissues were higher in the SKF 525A and slightly lower in the PB treated animals than in the controls. The disappearance of MPA-related substances from the lung, skeletal muscle and brain was slow, and in the lung there was even an increase in the amount of radioactivity in the PB and saline treated rats at 24 hr. Almost equal amounts of radioactivity were excreted in the urine and intestine in the control rats, while the induction of drug metabolism enhanced the excretion in the urine and its reduction enhanced elimination in the intestinal tract within 24 hours. The findings demonstrate that plasma and tissue levels of MPA and its elimination route are influenced by the drug metabolism activity.

Animals↗
PubMed1983

A comparative study on hypotensive and bradycardic effects of some new imidazole derivatives with possible central mechanism of action.

Cardiovascular actions of 4(5)-(2,6-dimethylbenzyl)imidazole (MPV-207) and its three alkyl bridge analogues were investigated in urethane-anaesthetized normotensive rats. Intravenous (i.v.) injections of 0.001-0.1 mg/kg of MPV-207 lowered mean arterial pressure (MAP) and heart rate (HR) in a dose-dependent manner. The compound was effective also upon intracerebroventricular (i.c.v.) administration. The hypotensive effect of i.v. injected MPV-207 (5 micrograms/kg) was attenuated by i.c.v. administered yohimbine (100 micrograms/kg), an alpha 2-adrenoceptor antagonist. MPV-295 having an ethano group between the phenyl and imidazole moieties decreased MAP and HR at i.v. doses of 0.03-3 mg/kg, being active also after i.c.v. injection. Extension of the alkyl bridge to the propano group further decreased the hypotensive and bradycardic activity, and the compound having a butano bridge was practically inactive. The results indicate that the extension of the alkyl bridge between the phenyl and imidazole rings reduces the hypotensive and bradycardic activities of the MPV compounds. Furthermore, the hypotensive action of these compounds may be mediated by a central mechanism involving a stimulation of alpha-adrenoceptors.

Animals↗
PubMed1982

Aryl hydrocarbon hydroxylase activity in cultured lymphocytes of psoriatic patients.

To evaluate further the metabolic capacity of psoriatics, the activities and inducibility of aryl hydrocarbon hydroxylase (AHH) were measured in cultured mitogen-stimulated lymphocytes from the peripheral blood of 68 psoriatic and 39 control patients. There was no significant difference in the mean basal and induced AHH activities between the psoriatics and the controls, although the former showed a slight tendency towards a higher inducibility ratio. In both, the basal and induced AHH values decreased significantly with increasing age. The cigarette smokers in both groups had significantly higher AHH activities than the nonsmokers. Antipsoriatic treatment (Anthralin, PUVA) did not seem to influence the lymphocyte AHH activities. No association was demonstrable between the AHH activities and the duration of the disease.

Adult↗
PubMed1982

Is aryl hydrocarbon hydroxylase induction 'systemically' regulated in man?

We demonstrated recently that, in smokers, placental activity of aryl hydrocarbon hydroxylase (AHH) is statistically significantly correlated with cord-blood lymphocyte AHH inducibility, whereas the correlation between maternal lymphocyte AHH inducibility and placental AHH activity is poor. These findings suggest that AHH induction in man may be 'systemically' regulated. In hospital patients, however, correlations among lymphocyte-AHH induction, hepatic mono-oxygenase activities and antipyrine elimination were poor, even in groups with no indication of liver injury. It seems that the 'systemic' regulation of AHH induction in man can be demonstrated only in special, favourable situations.

Aryl Hydrocarbon Hydroxylases↗