Veijo Saano

Characterization of the selectivity, specificity and potency of medetomidine as an α2-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.

Peripheral benzodiazepine binding sites

Article de synthese sur les sites de fixation peripheriques des benzodiazepines: distribution, fixation biologique, action au niveau du systeme nerveux central, regulation par le GABA et le stress, regulation endocrine, relation avec les canaux calcium, autres ligands, role physiologique

Correlation Between Ciliary Beat Frequency and the Structure of Ciliated Epithelia in Pathologic Human Nasal Mucosa

The structure and function of ciliated epithelium were studied in 44 human nasal mucosa samples using a photoelectric method and scanning electron microscopy (SEM). The ciliary beat frequency (CBF) of cases with recurrent or chronic sinusitis was 9.1 ± 5.4 Hz. In eight of the samples (18.2%) no ciliary activity was detected. The amount of ciliated cells, the orientation of cilia, epithelial metaplasia, and secretion were found to be explanatory factors accounting for the decreased ciliary activity. Ciliary disorientation and a lack of ciliated cells in SEM correlated with low ciliary activity. In cases where sinusitis secretion was not seen, the CBF was slower than in cases with mucus or mucopurulent secretion. Sinusitis with disoriented cilia, a loss of ciliated cells, and a lack of mucosal secretion is associated with a decreased CBF. This may lead to impaired mucociliary clearance and increase the risk of recurrent and chronic sinusitis.

CILIARY BEAT FREQUENCY AT SIX LEVELS OF THE RABBIT AND RAT RESPIRATORY TRACT IN COW, DOG, GUINEA‐PIG, PIG

1. The ciliary beat frequency (CBF) of six animal species from six regions of the respiratory tract were measured: inferior turbinate, nasopharynx, the upper part of trachea from first to second cartilage, the lower part of trachea, main bronchus and subsegmental bronchi. Cow, pig, dog, rabbit, guinea‐pig and rat were studied.

Effects of Some Preservative Agents on Rat and Guinea Pig Tracheal and Human Nasal Ciliary Beat Frequency

Many preservatives commonly included in nasal drops and sprays are known to impair mucociliary clearance. We studied the effects of four frequently used preservatives on ciliary beat frequency (CBF) in respiratory tissue. Sodium metabisulfite and chlorbutol did not change the CBF at concentrations up to 50 mg/L in rat tracheal mucosa. Chlorocresol 25 mg/L and 50 mg/mL reversibly decreased CBF (by 33% and 68%, respectively) in 60 minutes. Benzalkonium chloride impaired CBF irreversibly already at a relatively low concentration (12.5 mg/L). To further clarify these results, we studied the effects of the most ciliotoxic (benzalkonium chloride) and nonciliotoxic (chlorbutol) preservative on guinea pig tracheal epithelium and human nasal mucosa. Although chlorbutol had no effect on the CBF, a dose-dependent decrease on CBF was seen in guinea pig and human ciliated epithelium during their immersion in benzalkonium chloride. At a concentration of 50 mg/L it stopped the ciliary activity in 40 minutes in guinea pig trachea, and in human nasal mucosa, benzalkonium chloride concentrations of 25 and 50 mg/L, decreased the CBF irreversibly (by 28% and 60%, respectively) in 60 minutes. These results suggest that chlorbutol is a safe and well tolerated preservative. Banzalkonium chloride is ciliostatic in vitro to rat, guinea pig, and human respiratory mucosa. Therefore, prolonged clinical use of benzalkonium chloride may impair mucociliary clearance, a major defense respiratory mechanism.

Binding of strychnocarpine and related β-carbolines to brain receptors in vitro

Abstract The affinity of strychnocarpine and related β-carbolines for serotonin, benzodiazepine, tryptamine, opiate and GABA receptors in rat brain was studied. Strychnocarpine showed a low to very low affinity for all the receptors tested. The weak binding to tryptamine receptors might explain part of the tremorigenic effects found earlier in the in vivo studies.

The effect of chronic treatment with peripheral benzodiazepine receptor ligands on behavior and GABAA/benzodiazepine receptors in rat.

SummaryRats were twice daily (2 × 10 mg/kg, i.p.) treated for three weeks with the peripheral benzodiazepine (BZ) receptor ligands Ro 5-4864 (4′-chlorodiazepam) and PK 11 195 (1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxamide). After the first injection there were no differences between the drug-treated and control animals in behavioral tests. After 10 days treatment, the number of sniffings was increased in Ro 5-4864-treated rats. After the last injection, sniffings and ambulations were decreased in PK 11 195-treated animals. The number of rearings and groomings remained unchanged throughout the treatment, and there were no changes in the results in the elevated plus-maze test. Apparently these compounds are devoid of anxiolytic and anxiogenic effects at moderate doses.The effect of 72 a h withdrawal from the above mentioned chronic treatment on peripheral and central BZ receptors as well as on GABAA receptors was studied with receptor binding techniques using 3H-Ro 5-4864, 3H-flumazenil and 3H-muscimol, respectively, as ligands. The number of GABAA and central BZ receptors was lower after Ro 5-4864 treatment, as was the effect of progesterone-induced stimulation of 3H-muscimol binding. The number of peripheral BZ receptors was decreased after Ro 5-4864 and PK 11 195 treatments in the olfactory bulb but not in the cerebral cortex.The chronic treatment with peripheral BZ receptor ligands ] Ro 5-4864 and PK 11 195 produced only little behavioral effects. Ro 5-4864, often presented as an agonist of peripheral BZ receptors, was behaviorally inactive. PK 11 195, often considered to be an antagonist of Ro 5-4864 developed a small sedative action during chronic treatment. The withdrawal from chronic treatment with these ligands similarly affected peripheral BZ receptors but only Ro 5-4864 affected GABAA/BZ receptor complex in the CNS.The present data support the idea that Ro 5-4864 has independent of peripheral BZ receptors effects on GABA, receptors while PK 11 195 is rather a partial agonist than antagonist of peripheral BZ receptors.

INFLUENCE OF AGEING ON CILIARY BEAT FREQUENCY AND ON CILIARY RESPONSE TO LEUKOTRIENE D4 IN GUINEA-PIG TRACHEAL EPITHELIUM

1. In the present study on guinea‐pig tracheal epithelium, the influence of age on ciliary beat frequency (CBF) was investigated.

Influence of Chinoin-170, a novel antitussive, on the mucociliary activity in respiratory airways of rats, rabbits, guinea-pigs and man

Abstract— Chinoin‐170 (Ch‐170; 3,7‐dihydro‐1,3‐dimethyl‐7‐[(5‐methyl‐1,2,4‐oxadiazol‐3‐yl)methyl]1H‐purine‐2,6‐dione) is a new antitussive with bronchodilating activity. Its effects on the ciliary beating frequency (CBF) and mucociliary clearance were studied. In tracheal explants of rats, Ch‐170 dose‐dependently at concentrations 2 and 5 mg mL−1 depressed CBF by 24 and 33%, respectively. In human mucosal explants, however, no effects were seen at concentrations up to 5 mg mL−1. In anaesthetized guinea‐pigs, an intravenous 50 mg kg−1 dose of Ch‐170 caused no changes, and 100 mg kg−1 increased the CBF by 15%. Intravenous Ch‐170 dose‐dependently increased by 93 (50 mg kg−1), 179 (70 mg kg−1) and 253% (100 mg kg−1) the tracheobronchial mucociliary clearance in rabbits. The effect, studied using 99mTc‐labelled red blood cells as a marker, was of similar quantity to that brought about by administering 16, 25 and 40 mg kg−1 doses of bromhexine. It is concluded that unlike many older antitussives, Ch‐170 in‐vitro only slightly decreases the CBF in rats and has no adverse effects on the CBF in human mucosal explants at concentrations up to 5 mg mL−1. In‐vivo, Ch‐170 does not significantly alter the CBF in guinea‐pigs, but dose‐dependently increases the mucociliary clearance in rabbits. The increase is most probably a result of changes in the production and the properties of respiratory mucus.

CILIARY ULTRASTRUCTURE AND BEATING ACTIVITY IN RAT AND GUINEA-PIG RESPIRATORY MUCOSA

1. The rat and the guinea‐pig are commonly used animals when the effects of drugs on ciliary activity in respiratory airways are studied. There are few data concerning the possible differences in ciliary function between these two animals.