Inhibitory actions of amoxapine, a tricyclic antidepressant agent, on electrophysiological properties of mammalian isolated cardiac preparations.
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1. The electrophysiological effects of amoxapine were examined in guinea-pig isolated papillary muscles and rabbit sinoatrial nodes using a conventional microelectrode technique. 2. In papillary muscles, amoxapine above 10 microM caused a dose-dependent decrease in the maximum upstroke velocity (Vmax) of the action potential and in the action potential amplitude (APA), whereas the action potential duration at 90% repolarization (APD90) was significantly prolonged. For a decrease in Vmax, amoxapine produced a negative shift of the curve relating Vmax to the resting potential (Em) along the voltage axis to more negative membrane potentials. 3. Amoxapine also decreased Vmax and the overshoot potential of K+-depolarized slow action potentials of papillary muscle preparations. 4. In spontaneously beating sinoatrial node preparations, amoxapine above 3 microM reduced the heart rate, Vmax, APA and the slope of phase 4 depolarization in a dose-dependent manner. 5. It was concluded that amoxapine exerts inhibitory actions on fast- and slow-response fibres of the heart and these actions can be mainly explained by inhibition of both fast Na+ and slow Ca2+ channels. (+info)
Electrophysiological effects of amoxapine in untreated and in amoxapine-pretreated rat atria.
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The effects of amoxapine (10(-7)-10(-4) M) have been studied in rat atrial fibres obtained from untreated animals and animals pretreated for 28 days with amoxapine (10 mg kg-1, i.p.). In untreated atria amoxapine reduced atrial rate, contractile force and df/dtmax, prolonged the sinus node recovery time and decreased atrial excitability. Amoxapine also decreased amplitude and Vmax of the upstroke, prolonged the duration of the action potential (APD) and effective refractory period (ERP) and reduced the resting membrane potential. During the treatment with amoxapine behavioural and cardiovascular adverse effects, including hypotension, tachycardia and prolongation of the Q-Tc, were observed. However, with the exception of the ERP which was significantly prolonged in pretreated atria, pretreatment with amoxapine did not modify the control values of the measured parameters compared to those obtained in untreated atria. Further addition of amoxapine produced similar changes in both pretreated and untreated atria. However, in contrast to untreated atria, in pretreated atria the prolongation of the ERP produced by amoxapine exceeded the prolongation of the APD and thus, the ERP/APD ratio increased. The decrease in atrial excitability was also more marked in pretreated than in untreated atria. Amoxapine inhibited the slow action potentials and contractions induced by isoprenaline in K-depolarized atria. It is concluded that the electrophysiological effects of amoxapine on rat atrial fibres are similar to those described for other tricyclic antidepressants. Possible explanations for the lower cardiodepressant activity of amoxapine are discussed. (+info)
Ultrastructure of rat lungs following exposure to aerosols of dibenzoxazepine (CR).
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Three groups of 18 animals were exposed respectively to the following large doses of dibenz (b.f)-1:4 oxazepine (CR) aerosols, 78,200,140,900 and 161,300 mg/min/m3. Animals were killed at intervals from 15 min to 2 days, and the lungs examined macroscopically, by electron microscopy and conventional histology. There were no deaths during or after exposure. Macroscopically the lungs from all rats appeared normal. Microscopically there were a few areas of mild congestion, haemorrhage and emphysema, but there was little variation between the different groups. Electron micrographs revealed some morphological alteration of the epithelium and endothelium but only occasional changes in the interstitium. The alterations took the form of "ballooning" of the endothelium with isolated foci of swelling and thickening of the epithelium. Interstitial oedema was observed in one animal only which was exposed to the highest concentration. The effects appeared similar in all groups, and are thought to be transient. The results of this investigation suggest that even high doses of CR aerosols cause minimal damage to the lung, and the structural alterations which do occur are believed to be due to the stress to which the animals were subjected during the exposure period. (+info)
Antagonism of tone and prostaglandin-mediated responses in a tracheal preparation by indomethacin and SC-19220.
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1 The effects of the prostaglandin synthetase inhibitor, indomethacin and the prostaglandin antagonist SC-19220 (1-acetyl-2-[8-chloro-10,11-dihydrodibenz (b,f) (1,4)oxazepine-10-carbonyl] hydrazine), were examined on the tone of the guinea-pig isolated tracheal preparation and on the responses of the preparation to prostaglandin F(2alpha), arachidonic acid and methacholine.2 Indomethacin (0.05-1.6 mug/ml) produced a long-lasting inhibition of the intrinsic tone of the tracheal preparation and of the contractile responses to arachidonic acid. Much higher concentrations of indomethacin also reduced the responses of the preparation to methacholine. This effect was readily reversible and appeared to be unrelated to the action on tone.3 The contractile responses of the preparation to prostaglandin F(2alpha) were enhanced by low concentrations of indomethacin (1-5 mug/ml) and inhibited by higher concentrations (2.5-80 mug/ml).4 SC-19220 was shown to inhibit responses of the preparation to prostaglandin F(2alpha) in concentrations (0.1-1 mug/ml) which had no effect on responses to methacholine. Similar concentrations also inhibited the intrinsic tone of the preparation and the responses to arachidonic acid.5 The evidence suggests that prostaglandins may be involved in the maintenance of tone of the guinea-pig isolated tracheal preparation. (+info)
Prostaglandin E2 and the bovine sphincter pupillae.
(5/12)
1. The bovine isolated sphincter pupillae incubated in Krebs solution releases a biologically active substance tentatively identified as prostaglandin E(2).2. The prostaglandin did not appear to be of neural origin or to result merely from tissue degeneration.3. The spontaneous release of prostaglandin E(2)-like material was related to the tone of the sphincter. Output increased as tone was acquired after setting up the tissue and fell when various procedures were used to reduce the tone.4. Low concentrations of E and F-type prostaglandins produced slow, well-sustained contractions of the atonic sphincter, prostaglandin E(2) being the most potent of those tested. The responses to prostaglandin E(2) were antagonized selectively by a prostaglandin antagonist SC-19220 (a dibenzoxazepine derivative) which in higher concentrations caused dose-dependent relaxations of the preparation.5. Prostaglandins did not appear to modulate transmission from nerve to muscle in the sphincter.6. The hypothesis that prostaglandin E(2) might be produced to act as a local hormone causing tonic contraction of the sphincter pupillae is discussed. (+info)
Studies on prostaglandin antagonists.
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1. Three prostaglandin antagonists have been examined for their ability to block PGE(2) and PGF(2alpha) on human, guinea-pig and isolated rat gastrointestinal muscle.2. 7-oxa-13-Prostynoic acid was either a non-selective antagonist, or was ineffective on the tissues studied; it had marked spasmogenic activity on the rat fundus.3. 1-Acetyl-2-(8-chloro-10,11-dihydrodibenz (b,f)(1,4) oxazepine-10-carbonyl) hydrazine selectively antagonized the excitatory effects of PGE(2) and PGF(2alpha) in guinea-pig and rat tissues, but not in human muscle.4. Polyphloretin phosphate selectively antagonized the excitatory effects of prostaglandins in both human and guinea-pig muscle preparations, but it caused stimulation of the rat fundus.5. All the antagonists lowered the tone in many tissues. They also reduced contractions caused by potassium.6. None of the compounds blocked the inhibitory effect of PGE(2) on intestinal circular muscle.7. The implication of these results on the nature of prostaglandin receptors, and the value of each compound as a prostaglandin antagonist are discussed. (+info)
Prostaglandin-induced inhibition of acetylcholine release from neuronal elements of dog tracheal tissue.
(7/12)
In an attempt to elucidate the possible roles of endogenous prostaglandins on the neuro-effector transmission in the dog trachea, effects of a prostaglandin antagonist (1-acetyl-2-[8-chloro-10, 11- dihydrobenz (b.f) (1.4) oxazepine-10-carbonyl]hydrazine (SC-19220] on the electrical and mechanical properties of smooth muscle cells and on neuro-effector transmission in the smooth muscle layer were studied by means of micro-electrode, double sucrose-gap, and tension recording methods. The levels of prostaglandins in the perfusate from the dog tracheal tissue were also determined using radioimmunoassay. Excitatory junction potentials (e.j.p.s) and twitch tension evoked by electrical field stimulation with short pulse duration (50-100 microseconds), which were abolished by tetrodotoxin (10(-7) M) or atropine (5 X 10(-6) M), showed gradual and continuous reduction in amplitude during superfusion with normal Krebs solution. Reduction in the amplitude of e.j.p.s occurred with no change in the membrane potential or membrane input resistance. SC-19220 (3.1 X 10(-5) M) did not modify the membrane potential, membrane input resistance or the sensitivity to acetylcholine of the smooth muscle cells. Yet, with application of SC-19220 (3.1 X 10(-6) M), gradual and continuous reductions in the amplitude of e.j.p.s and twitch contractions were no longer observed. With an increased concentration (3.1 X 10(-5) M), e.j.p.s and twitch contractions with a constant amplitude were obtained after the initial increase in the amplitude. When the amplitude of twitch contractions was stabilized by treatment with indomethacin (10(-5) M), low concentrations (10(-12) to 10(-10) M) of prostaglandin E2 (PGE2) or prostaglandin F2 alpha (10(-8) to 10(-6) M) markedly suppressed the amplitude of the twitch contractions. In some muscle preparations (ten out of twenty-two preparations examined), SC-19220 (3.1 X 10(-6) to 3.1 X 10(-5) M) produced a sustained contraction of the muscle, which was suppressed by atropine (5 X 10(-6) M) or PGE2 (10(-8) M). Following pre-treatment of the tissue with atropine (5 X 10(-6) M), SC-19220 did not evoke contracture. In the resting condition, 10-40 ng g-1 wet wt. tissue min-1 PGE or PGF was released into the perfusate from the tracheal muscle tissue of the control dog.(ABSTRACT TRUNCATED AT 400 WORDS) (+info)
Mitochondrial lamellated bodies and surfactant depots in the Type II cells of the lung compared by bimetallic staining and X-ray analysis.
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After heavy dosages of sensory irritants osmiophilic whorls (mitochondrial lamellated bodies) are found in the mitochondria of the Type II cells of the lung. To obtain evidence of their nature, the lead/osmium (Pb/Os) ratio in these and other bodies after bimetallic staining was studied by electron probe X-ray analysis during transmission electron microscopy. To allow for inter-specimen variation the Pb/Os ratio was divided by the Pb/Os ratio for chromatin in the same cell, to give a "relative ratio". The values of the latter ranged from 1.4 for granules in an eosinophil leucocyte to 0.60-0.77 for lamellated osmiophilic bodies of Type II cells, 0.4 for nerve myelin, and 0.05 for fat globules. The Pb/Os ratio for mitochondrial lamellated bodies did not differ significantly from that for lamellated osmiophilic bodies (which are depots of lung surfactant) in the same cell. This is compatible with the mitochondrial lamellated bodies consisting of excess surfactant produced in response to stress. the method is capable of extension. (+info)