Oral, transdermal and vaginal combined contraceptives induce an increase in markers of chronic inflammation and impair insulin sensitivity in young healthy normal-weight women: a randomized study.

STUDY QUESTION: What is the effect of alternative administration routes of combined contraceptives (CCs) on androgen secretion, chronic inflammation, glucose tolerance and lipid profile? SUMMARY ANSWER: The use of oral, transdermal and vaginal CCs impairs glucose tolerance and induces chronic inflammation. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Oral CCs worsen insulin sensitivity and are associated with increased levels of circulating inflammatory markers, whereas the metabolic effects of transdermal and vaginal CCs have been reported to be minimal. This is the first study comparing three different administration routes of CCs on metabolic variables. STUDY DESIGN, SIZE AND DURATION: This randomized (computer-generated) open-label 9-week follow-up study was conducted at the Oulu University Hospital, Finland. Fasting blood samples were collected at baseline and thereafter at 5 and 9 weeks of treatment, and serum levels of 17-hydroxyprogesterone, androstenedione, testosterone, C-reactive protein (CRP), sex hormone-binding globulin (SHBG), glucose, insulin, C-peptide, total, low-density lipoprotein and high-density lipoprotein cholesterol and triglycerides were measured. Oral glucose tolerance tests were performed and plasma levels of pentraxin 3 (PTX-3) were measured at 0 and 9 weeks. The randomization list, with an allocation ratio of 1:1:1 and block size of six, was computer generated and constructed by a pharmacist at the Oulu University Hospital. The research nurse controlled the randomization list and assigned participants to their groups at the first visit. PARTICIPANTS AND SETTING: Forty-two of 54 healthy women who entered the study used oral contraceptive pills (n = 13), transdermal contraceptive patches (n = 15) or contraceptive vaginal rings (n = 14) continuously for 9 weeks. Inclusion criteria were regular menstrual cycles, at least a 2-month washout as regards hormonal contraceptives and no medication. MAIN RESULTS AND THE ROLE OF CHANCE: Serum levels of SHBG increased and consequently the free androgen index (FAI) decreased in all study groups from baseline to 9 weeks of treatment [FAI, oral: 1.3 (95% confidence interval, CI: 0.94; 1.62) to 0.40 (0.25; 0.54); transdermal: 1.2 (0.96; 1.4) to 0.36 (0.30; 0.43); vaginal: 1.6 (1.1; 2.1) to 0.43 (0.29; 0.58), P < 0.001 in all groups]. Insulin sensitivity was reduced at 9 weeks in all three groups according to the Matsuda index [oral: 7.3 (5.5; 9.0) to 5.6 (3.9; 7.3); transdermal: 9.1 (6.7; 11.4) to 6.6 (4.5; 8.8); vaginal: 7.7 (5.9; 9.5) to 5.4 (3.9; 7.0), P= 0.004-0.024]. Levels of HDL cholesterol, triglycerides and CRP rose in all three groups [CRP, oral: 0.70 (0.38; 1.0) to 5.4 (1.0; 9.9) mg/l; transdermal: 0.77 (0.45; 1.1) to 2.9 (1.4;4.4) mg/l; vaginal: 0.98 (0.52; 1.4) to 3.7 (-0.25; 7.7, a negative value due to skewed distribution to right) mg/l, P≤ 0.002 in all groups] and PTX-3 levels increased in the oral and transdermal study groups (P = 0.007 and P = 0.002). WIDER IMPLICATIONS OF THE FINDINGS: Although the long-term consequences of the present results remain undetermined, these findings emphasize the importance of monitoring glucose metabolism during the use of CCs, especially in women with known risks of type 2 diabetes or cardiovascular diseases. BIAS, LIMITATIONS, GENERALIZABILITY: The number of subjects was relatively low. Moreover, the 9-week exposure to CCs is too short to draw conclusions about the long-term health consequences. However, as the subjects were healthy, normal-weight young women, the possible alterations in the glucose and inflammatory profiles among women with known metabolic risks might be even greater. STUDY FUNDING/COMPETING INTERESTS: This work was supported by grants from the Academy of Finland, the Sigrid Jusélius Foundation, the Finnish Medical Foundation, the Research Foundation of Obstetrics and Gynecology, Oulu University Scholarship Foundation, the North Ostrobothnia Regional Fund of the Finnish Cultural Foundation, the Tyyni Tani Foundation of the University of Oulu and the Finnish-Norwegian Medical Foundation. No competing interests. TRIAL REGISTRATION NUMBER: NCT01087879.

Comparative effects of medetomidine enantiomers on in vitro and in vivo microsomal drug metabolism.

The effects of dexmedetomidine, a selective alpha 2-adrenoceptor agonist, and its levo enantiomer (MPV-1441), on in vitro microsomal P450-dependent drug-metabolizing activities as well as on in vivo aminopyrine elimination and hexobarbital sleeping time were studied. Both enantiomers inhibited the oxidative metabolism of several model substrates and testosterone in rat liver microsomal incubations. Microsomal activities derived from control animals or rats pretreated with phenobarbital were more sensitive to inhibitory effects of dexmedetomidine than those from rats treated with 3-methylcholanthrene. Enzyme activities in human liver microsomes were also inhibited by dexmedetomidine. Retardation of the elimination of aminopyrine was dose-dependent; elimination was marginally retarded with doses up to 100 micrograms/kg (from 17 to 23 min.; both enantiomers). Higher doses of the levo enantiomer prolonged aminopyrine half-life to 78 (1 mg/kg) and 162 min. (10 mg/kg). The hexobarbital sleeping time was prolonged by the dose of 1 mg/kg of the levo enantiomer (128 min. versus 20 min. in controls), while the dose of 0.1 mg/kg had no effect (23 versus 20 min.). These studies indicate that both enantiomers of medetomidine are inhibitors of microsomal drug metabolism in vitro, but significant effects on aminopyrine elimination or hexobarbital sleeping time are apparent only at doses, which do not allow the use of dexmedetomidine because of excessive sedative effect.

Alpha 2-adrenoceptor-mediated inhibition of gastric acid secretion by medetomidine is efficiently antagonized by atipamezole in rats.

The effect of a novel highly selective alpha 2-adrenoceptor agonist, medetomidine (4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole), was studied on gastric secretion in conscious and anaesthetized rats. Medetomidine (3-30 micrograms/kg s.c.) inhibited basal gastric acid and fluid output in conscious rats in a dose-dependent manner, while in anaesthetized rats no effect was observed when administered i.v. at the doses of 1-1000 micrograms/kg. Furthermore, medetomidine did not modify gastric acid output stimulated by infusion of histamine i.v. in anaesthetized rats, suggesting also that a medetomidine-induced change in gastric secretion does not involve any action on histamine H2-receptors. Furthermore, evidence was given indicating that alpha 2-adrenoceptors mediate the antisecretory action of medetomidine, since a low dose (0.1 mg/kg s.c., -30 min) of a selective alpha 2-adrenoceptor antagonist, atipamezole [MPV 1248, 4-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole] efficiently antagonized the effects of medetomidine (30 micrograms/kg s.c.) in conscious rats. In summary, medetomidine inhibits gastric secretion in the rat via alpha 2-adrenoceptor activation, the antisecretory action being blocked by atipamezole. Probably due to its high specificity for alpha 2-adrenoceptors, medetomidine did not show a stimulatory effect on gastric acid secretion in anaesthetized rats.

Stimulatory effect of prostaglandin F2 alpha on gastric acid secretion in rats.

The effect of intravenously administered prostaglandin F2 alpha on gastric acid secretion was investigated in anaesthetized rats. Doses of 0.03-0.3 mg/kg PGF2 alpha stimulated gastric acid output in rats with intact vagi, whereas an inhibitory effect was observed in vagotomized animals. Treatment with 5 mg/kg of Na-meclofenamate intravenously attenuated the secretory response to PGF2 alpha, while 10 mg/kg of indomethacin intravenously and 3 mg/kg of 8-phenyltheophylline intraperitoneally were without any effect. The results indicate that intravenously administered PGF2 alpha stimulates gastric acid secretion in anaesthetized rats via activation of the vagus nerve. The effects of Na-meclofenamate and indomethacin suggest that PGF2 alpha may exert its secretagogue action via specific receptors. The lack of the effect of 8-phenyltheophylline indicates that adenosine which reportedly had a similar effect on gastric secretion after intravenous injection seems not to be involved here.

Centrally applied histamine increases gastric acid secretion in rats.

Administration of 10-100 micrograms of histamine into the lateral cerebral ventricle of anaesthetized rats stimulated gastric acid secretion in a dose-dependent manner, while subcutaneous (s.c.) injections of the same doses produced clearly less pronounced increases in the acid output. In vagotomized rats only a marginal response to histamine given into the lateral ventricle was observed. When injected into the third cerebral ventricle the doses of histamine needed for the stimulation of gastric acid secretion were 1-10 micrograms, the effect being totally abolished by vagotomy. The results indicate that histamine is capable of stimulating gastric acid secretion by a central, vagal-dependent mechanism.

Atrial natriuretic peptide (ANP) in rat gastrointestinal tract.

Acid extracts of rat stomach and small intestine contained 8.6 +/- 3.7 and 39 +/- 15 ng/g of immunoreactive atrial natriuretic peptide (ANP). When studied by gel filtration and reverse-phase high-performance liquid chromatography, the stomach immunoreactivity consisted of multiple components, whereas the small intestine contained mostly proANP and ANP 1-28-like material. These findings indicate that ANP may have a role in the physiology of the gastrointestinal tract, e.g. in the regulation of water and electrolyte absorption.

Alpha-1 adrenoceptor-mediated positive inotropic effect and inositol trisphosphate increase in mammalian heart.

The positive inotropic effect of the alpha-1 adrenoceptor agonist phenylephrine was accompanied by a concentration-dependent increase in inositol trisphosphate (IP3) in electrically driven left auricles isolated from rat hearts. Further analysis of the myocardial phosphoinositide pathway revealed an additional increase in inositol phosphate and inositol bisphosphate with a concomitant decrease in phosphatidylinositol phosphate and phosphatidylinositol bisphosphate. The decrease in phosphatidylinositol bisphosphate and increase in IP3 preceded the increase in force of contraction. All effects were antagonized by the alpha-1 adrenoceptor antagonist prazosin. For comparison the effects of the beta adrenoceptor agonist isoprenaline were studied. Isoprenaline produced a positive inotropic effect similar to that of phenylephrine but all phosphoinositide products remained unaffected. The influence of lithium and calcium ions were studied systematically. The stimulatory effect of phenylephrine on inositol phosphates was lithium-dependent. Without lithium phenylephrine did not detectably affect the phosphoinositide turnover. Phenylephrine caused a maximal increase in inositol phosphate, inositol bisphospate and IP3 at 10 mmol/l of lithium. Lithium itself had a concentration-dependent positive inotropic effect. However, lithium did not enhance the positive inotropic effect of phenylephrine. Variation of the extracellular concentration of calcium did not influence the stimulatory effect of phenylephrine on inositol phosphates indicating that inositol phosphate turnover does not require the presence of extracellular calcium. It is concluded that the stimulation of myocardial phosphoinositide breakdown generating an increased IP3 turnover may be involved in the mechanism(s) whereby alpha-1 adrenoceptor stimulation exerts an increase in myocardial force of contraction.

Central gastric antisecretory action of adenosine in the rat.

The effects of intracerebroventricularly (i.c.v.) administered adenosine and some of its analogues on gastric secretion were studied in rats. The compounds inhibited the gastric output of acid, pepsin and fluid in pylorus-ligated rats in a dose-dependent manner with an order of potency: 5'-N-ethylcarboxamidoadenosine (NECA) greater than (-)N6-phenylisopropyladenosine (R-PIA) greater than (+)N6-phenylisopropyladenosine (S-PIA) greater than adenosine. Pretreatment with 10 and 30 mg/kg of theophylline i.v. or 5 mg/kg of 8-phenyltheophylline s.c. did not modify the antisecretory effect of 0.1 microgram of NECA i.c.v. NECA injected i.c.v. did not affect the secretion induced by carbachol in awake rats subjected to vagotomy or in anaesthetized rats with intact vagi. NECA i.c.v. had no effect on the serum concentration of gastrin. The depletion of brain monoamines (noradrenaline, dopamine and serotonin) with 6-OHDA i.c.v. significantly attenuated the inhibitory action of NECA. Pretreatment with 10 mg/kg of naloxone i.v. or indomethacin s.c. did not modify the antisecretory effect of NECA. The results indicate that adenosine inhibits gastric secretion in rats by a decrease in the stimulatory vagal impulses to the stomach, and that it acts in the brain via receptors insensitive to xanthines. Brain biogenic monoamines, but not opioid peptides or prostaglandins seem to be involved in the central gastric antisecretory action of adenosine.

Stimulation of central alpha-2 adrenoceptors inhibits gastric secretion in rats by releasing vasopressin.

The mechanism of the gastric antisecretory action of the stimulation of central alpha-2 adrenoceptors were studied in conscious, pylorus-ligated rats using intracerebroventricularly (i.c.v.) administered oxymetazoline as the model substance. I.c.v. administration of 10 micrograms of oxymetazoline strongly inhibited the secretion of acid, pepsin and fluid, whereas upon s.c. injection this dose was without any effect. Pretreatment with idazoxan abolished the antisecretory effect of i.c.v. administered oxymetazoline. I.c.v. injected oxymetazoline inhibited gastric secretion induced by carbachol in vagotomized rats, but the inhibitory effect was less pronounced than on the spontaneous secretion in rats with intact vagi. Hypophysectomy abolished the antisecretory effect of i.c.v. oxymetazoline, and pretreatment with the vasopressin antagonist, d(CH2)5Tyr(Me)AVP, significantly attenuated it. The results suggest that the inhibition of gastric secretion by the stimulation of central alpha-2 adrenoceptors in rats is mediated in part by vasopressin released from the pituitary gland.

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)

Interactions between intracellular cyclic AMP and agonist-induced inositol phospholipid breakdown in isolated gastric mucosal cells of the rat.

The interactions between putative second effector mechanisms for hydrogen ion secretion were studied in isolated gastric cell preparations of the rat containing 60-70% parietal cells. Dibutyryl-cAMP and the compounds which increased the level of cAMP (histamine plus rolipram and forskolin plus rolipram) inhibited the carbachol-induced accumulation of [3H]inositol tris-, bis- and monophosphate. There was both a temporal and quantitative correlation between the increase in cAMP and the inhibition of the accumulation of [3H]inositol phosphates. Cimetidine attenuated the inhibitory effect of histamine on the formation of [3H]inositol phosphates. The enhancement of the accumulation of [3H]inositol phosphates by various concentrations of carbachol affected neither the basal nor the histamine-stimulated cAMP levels. In contrast to dibutyryl-cAMP, dibutyryl-cGMP did not modify the carbachol-induced formation of [3H]inositol phosphates. The biologically active phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), which activates protein kinase C, inhibited both the basal and carbachol-induced accumulation of [3H]inositol phosphates. We suggest that the inhibition of the formation of inositol trisphosphate by the increase in the intracellular level of cAMP and by the activation of protein kinase C might be intracellular negative feedback systems which prevent the overreaction of the acid-secreting parietal cells under the simultaneous influence of the physiological gastric secretagogues.

Vagal-dependent stimulation of gastric acid secretion by intracerebroventricularly administered atrial natriuretic peptide in anaesthetized rats.

The intracerebroventricular (i.c.v.) administration of 10 micrograms of atrial natriuretic peptide (ANP) stimulated spontaneous gastric acid secretion in anaesthetized rats, whereas this dose of ANP was without any effect after i.v. injection. The secretagogue action of i.c.v. administered ANP was totally abolished by truncal vagotomy. The findings indicate that i.c.v. administration of ANP stimulates gastric acid secretion in anaesthetized rats by a central, vagal-dependent mechanism.

Effect of gastric secretagogues on the formation of inositol phosphates in isolated gastric cells of the rat.

The effects of compounds affecting gastric acid secretion were studied on the formation of inositol phosphates after prelabelling with [3H]-inositol in enriched gastric parietal cells of the rat, prepared by isopycnic centrifugation with Percoll. In cell preparations with 60 to 70% parietal cells, carbachol (10(-6)-10(-2) M) enhanced the accumulation of [3H]-inositol monophosphate ([3H]-IP1), [3H]-inositol bisphosphate ([3H]-IP2) and [3H]-inositol trisphosphate ([3H]-IP3) in a concentration-dependent manner, an effect which was antagonized by 10(-8) M atropine. Li+ (0.5-30 mM) enhanced the basal and carbachol-induced accumulation of all three [3H]-inositol phosphates, the formation of [3H]-IP1 being more sensitive to Li+ than those of [3H]-IP2 and [3H]-IP3. The concentration of Ca2+ in the incubation medium did not affect the relative stimulation of the accumulation of [3H]-inositol phosphates by carbachol, although the basal formation was higher in the presence of Ca2+ in the medium. In the absence of added Ca2+, the incorporation of [3H]-inositol into phospholipids was increased--an effect which was further enhanced by the addition of EGTA to the medium. Gastrin and pentagastrin (10(-8)-10(-5) M) enhanced the formation of [3H]-inositol phosphates, although they were clearly less effective than carbachol. Histamine (10(-6)-10(-3) M) had no effect of its own, but slightly attenuated the effect of carbachol. Cholecystokinin octapeptide (10(-9)-10(-6) M) slightly increased the formation of [3H]-inositol phosphates. Indomethacin (10(-4) M) had no consistent effect on the basal and carbachol-induced accumulation of [3H]-inositol phosphates, nor did prostaglandin E2 (10(-5) M) modify it. Adrenaline (10(-3) M), 5-hydroxytryptamine (10(-3) M), forskolin (10(-5) M), vasopressin (10(-5) M), angiotensin II (10(-5) M) and bombesin (10(-9)-10(-6) M) were all without effect. We suggest that the hydrolysis of inositol phospholipids may be involved in the signal transduction mechanism by which the activation of the muscarinic and gastrin receptors on the parietal cells leads to Ca2+ mobilization and the stimulation of hydrogen ion secretion.

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.

Vagally mediated stimulation of gastric acid secretion by intravenously administered adenosine derivatives in anaesthetized rats.

The effects of adenosine and some of its analogues on gastric acid secretion were investigated in rats. These compounds increased gastric acid secretion in anaesthetized rats after intravenous injection, the order of potency being 5'-N-ethylcarboxamidoadenosine (NECA) greater than (-)N6-phenylisopropyladenosine (L-PIA), N6-cyclohexyladenosine (CHA) greater than (+)N6-phenylisopropyladenosine (D-PIA) greater than 2-chloroadenosine (2-CADO) greater than adenosine (ADO). The stimulation of acid secretion by L-PIA in anaesthetized rats was antagonized by theophylline and 8-phenyltheophylline and totally prevented by vagotomy and atropine. Intracerebroventricular administration of L-PIA had no effect on gastric acid secretion in anaesthetized rats, whereas in conscious rats it inhibited the output of acid, pepsin and fluid. These results indicate that adenosine derivatives stimulate gastric acid secretion in anaesthetized rats by activating the vagus nerve via adenosine receptors in afferent pathways.

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.

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.