FURTHER EVIDENCE OF THE ROLE OF CYCLIC AMP AS A MEDIATOR OF THE DEPRESSANT EFFECTS OF β-ADRENOCEPTOR AGONISTS AND PHOSPHODIESTERASE INHIBITORS ON SLOW-CONTRACTING MAMMALIAN SKELETAL MUSCLES

The depressant effects of beta-adrenoceptor agonists and phosphodiesterase inhibitors on contractions of slow-contracting mammalian skeletal muscles are associated with increased muscular cyclic AMP levels. A strong correlation was found to exist between the percentage depression of contraction and the percentage increase in cyclic AMP level, irrespective of the drug used and regardless of the mechanism of cyclic AMP production. The results strongly support the mediatory role of cyclic AMP in the depressant effects of beta-adrenoceptor agonists and phosphodiesterase inhibitors on slow-contracting mammalian skeletal muscle contractions.     

EFFECTS OF CATECHOLAMINES, CYCLIC NUCLEOTIDES AND PHOSPHODI-ESTERASE INHIBITORS ON CONTRACTIONS OF SKELETAL MUSCLES IN ANAESTHETIZED CATS

SUMMARY 1. The actions and interactions of compounds with phosphodiesterase-in-hibiting activity and of sympathomimetic amines have been studied on contractions of skeletal muscles in chloralose-anaesthetized cats treated with bethanidine and in which the adrenals were excluded from the circulation.
2. Compounds with phosphodiesterase-inhibiting activity, ICI 63,197, ICI 58,301, papaverine, theophylline, and dipyridamole, potentiated isoprenaline in its depressant effect on tension and fusion of incomplete tetanic contractions of the slow-contracting soleus muscle, the order of potency being as listed. ICI 63,197 and theophylline also potentiated adrenaline and salbutamol in depressing contractions.
3. ICI 63,197 potentiated isoprenaline in its enhancing effect on tension and degree of fusion of incomplete tetanic contractions of the fast-contracting tibialis anterior and flexor digitorum longus muscles.
4. The results are compatible with the hypothesis that the effects of sympathomimetic amines on muscle contractility are mediated by cyclic adenosine-3',5'-monophosphate, although this nucleotide and its dibutyryl analogue, injected intra-arterially, were themselves without any consistent effect.
5. High doses of ICI 63,197, ICI 58,301, papaverine and dipyridamole, themselves produced isoprenaline-like effects on the soleus muscle. These effects were partially antagonized by (±)-propranolol, (+)-propranolol, or sotalol. The (+)-isomer of propranolol was only about ten times less potent than racemic propranolol in this respect. This antagonistic action of propranolol and sotalol appeared to be independent of β-adrenoceptor blockade.     

EFFECTS OF THYROXINE TREATMENT ON CONTRACTIONS OF SOLEUS MUSCLES OF ANAESTHETIZED CATS

The effects of chronic thyroxine treatment on cat soleus muscle contractions were studied. Maximum twitch tension, contraction time, half relaxation time and tension-time integral of maximal twitches of the soleus muscles of thyroxine treated cats were significantly decreased. Consequently, there was a decrease in tension and degree of fusion of incomplete tetanic contractions of the soleus muscle. The maximum tetanic tension was not statistically significantly changed, suggesting that the effects may be due to a decrease in the duration of the active state of the muscle. Isoprenaline given intravenously during incomplete tetanic contractions of the soleus muscle caused a statistically significant depression of tension in the control group but not in the thyroxine treated group. This further suggests reduction in the duration of the active state of soleus muscles of thyroxine treated cats. Propranolol injected chronically with thyroxine reversed or prevented the depression of tension caused by thyroxine treatment, suggesting the involvement of beta-adrenoceptors in these effects. The decrease in tension and degree of fusion during incomplete tetanic contractions of the thyroxine treated soleus could be responsible, at least partly, for the muscle weakness and tremor of thyrotoxicosis. Cyclic AMP may possibly be the mediator of these effects.     

EFFECTS OF α- AND β-ADRENOCEPTOR AGONISTS AND A PHOSPHODIESTERASE INHIBITOR (ICI 63 197) ON CYCLIC AMP AND GMP LEVELS IN BOVINE SPLENIC NERVE

1. Cyclic AMP and cyclic GMP levels were determined in bovine splenic nerve segments in the absence and presence of (±) - isoprenaline, (-)-phenylephrine, clonidine and ICI 63 197 (a phosphodiesterase inhibitor). The chosen concentrations of adrenoceptor agonists were those which are known to affect stimulation-induced overflow of noradrenaline from nerve terminals. 2. The mean levels of cyclic AMP ranged from 229 to 555 pmol/g of microwave irradiated tissue. Mean cyclic GMP levels ranged from 27.9 to 42.2 pmol/g. 3.Isoprenaline enhanced cyclic AMP levels but did not affect cyclic GMP levels. The effect was blocked with (±)-propranolol. ICI 63 197 increased cyclic AMP levels but did not change cyclic GMP. Phenylephrine and clonidine caused no consistent changes in cyclic AMP or cyclic GMP levels or in the concentration ratio between these two nucleotides. 4.The results support the involvement of cyclic AMP in the enhancing effect of β-adrenoceptor agonists and phosphodiesterase inhibitors on stimulation-induced release of noradrenaline from sympathetic nerves.     

PERIPHERAL MUSCLE EFFECTS OF LEVODOPA IN THE ANAESTHETIZED CAT

1. Levodopa, dopamine, noradrenaline and adrenaline (in increasing order of potency) depressed the tension and degree of fusion of incomplete tetanic contractions of the slow-contracting soleus muscle in chloralose-anaesthetized cats. 2. The effects of all compounds were antagonized by propranolol (50-20 μg/kg), but not practolol (1.0-5.0 mg/kg). This indicates that effects are mediated by β₂-adrenoceptor stimulation. 3. The effect of levodopa, but not of the catecholamines, was antagonized by prior administration of the dopa decarboxylase inhibitor benserazide. This indicates that levodopa itself is inactive, whereas its decarboxylated metabolites are active. 4. The depressant action of β-adrenoceptor agonists on incomplete tetanic contractions of the cat soleus muscle, which are exerted directly on the muscle fibres, is a model for effects exerted on slow-contracting units of human muscles; the latter effects probably underlie the tremor observed after β-adrenoceptor agonist administration. 5. These results therefore suggest that levodopa, via its decarboxylated metabolites, dopamine, noradrenaline and adrenaline, may produce or exacerbate tremor in man. Thus in Parkinsonian patients, any centrally induced relief of tremor that levodopa may produce may be masked by tremorogenic effects of such metabolites exerted in the periphery.     

ACTIONS OF DANTROLENE SODIUM ON CONTRACTIONS OF THE TIBIALIS ANTERIOR AND SOLEUS MUSCLES OF CATS UNDER CHLORALOSE ANAESTHESIA

SUMMARY 1. Dantrolene depresses the tension of directly or indirectly elicited twitches and tetaní of the tíbíalís anteríor and soleus muscles of cats under chloralose anaesthesia, without affecting the gross muscle action potentials.
2. The decrease in twitch tension is associated with slowed rates of rise of tension and of relaxation, but there is no change in the time to peak tension. The decrease in maximal tetanic tension is associated with a slowed rate of rise of tension, but there is no change in the rate of relaxation. It is concluded that dantrolene decreases the intensity of the active state, possibly by impairing the release of Ca²⁺ from the sarcoplasmic reticulum.
3. The soleus muscle is slightly more resistant than the tibialis anterior muscle to the action of dantrolene, and maximal tetani of both muscles are much more resistant than twitches.
4. Adrenaline, theophylline and quazodine produce effects on the dantrolene-depressed twitches that are proportionately the same as those produced on the control twitches; there is no evidence of a specific antagonistic effect of any of these drugs.
5. Tetanic stimulation of the tibialis anterior muscle but not the soleus muscle causes a temporary relief of the twitch depression produced by dantrolene.     

THE EFFECTS OF IMIDAZOLE ON CONTRACTILITY AND CYCLIC AMP LEVELS OF GUINEA-PIG TRACHEAL SMOOTH MUSCLE

1. Imidazole contracted guinea-pig isolated tracheal smooth muscle, and at low concentrations (50 mumol/l to 2 mmol/l) also enhanced contractions induced by histamine. 2. Imidazole had no effect on contractile responses to potassium chloride, acetylcholine, prostaglandin F2 alpha, or the ionophore A23187; nor did it affect anaphylactic contractions in tracheal strips from guniea-pigs sensitized to ovalbumin. 3. Imidazole had no effect on the content on cyclic AMP in guinea-pig tracheal smooth muscle, nor did it affect the accumulation of cyclic AMP induced by histamine, isoprenaline, theophylline plus isoprenaline, or prostaglandin E1. 4. Imidazole-induced contractions were partially antagonized by atropine, mepyramine maleate and the omission of extracellular calcium ions. 5. Imidazole-induced hyperreactivity to histamine was not affected by atropine or indomethacin, and was more pronounced in the absence of extracellular calcium ions. 6. It is concluded that imidazole does not affect cyclic nucleotide phosphodiesterase activity in guinea-pig trachea, and its effects on contractile responses of the smooth muscle are unrelated to any action of cyclic AMP metabolism. The potentiating effect of imidazole may involve inhibition of histaminase, or the facilitation of calcium ion release from intracellular storage sites.     

THE ANTAGONISM BY PROPRANOLOL AND α-METHYLPROPRANOLOL (ICI 77602) OF VASCULAR AND CARDIAC RESPONSES TO ISOPRENALINE IN ANAESTHETIZED DOGS

1. In anaesthetized dogs, α-methylpropranolol was less potent than propranolol in antagonizing both vascular (hind limb perfusion pressure) and cardiac heart rate) responses to isoprenaline. 2. α-Methylpropranolol was more potent in antagonizing vascular than cardiac responses to isoprenaline, but this selectivity was no greater than that seen also with propranolol. 3. Isoprenaline sensitivity was greater in the hind limb than the heart and vascular-selective antagonism was more pronounced in those dogs in which this differential sensitivity was the greatest. 4. Introduction of an a-methyl group into propranolol decreases its 0-adrenoceptor antagonist potency but does not enhance vascular selectivity.     

人参皂甙对血小板聚集性、cAMP和cGMP含量的影响

本文报告了人参皂甙对家兔血小板聚集性,cAMP和cGMP含量的影响。结果表明,人参皂甙在体内外均抑制由花生四烯酸、ADP和凝血酶诱导的血小板聚集。同时,人参皂甙明显升高血小板中cAMP含量,但是不影响血小板中cGMP含量。提示人参皂甙对血小板聚集的抑制作用与其升高血小板中cAMP含量有关。     

EFFECTS OF CYCLIC NUCLEOTIDE PHOSPHODIESTERASE IV INHIBITOR, Ro20,1724, ON PANCREATIC EXOCRINE SECRETION IN DOG

1. The effects of the cyclic nucleotide phosphodiesterase (PDE) inhibitors, Ro20,1724, 3-isobutyl-1-methylxanthine (IBMX), trifluoperazine (TFP) and amrinone on pancreatic exocrine secretion were investigated in anaesthetized dogs in comparison with those of secretin and cholecystokinin octapeptide (CCK-8). 2. Ro20,1724 (1–30 nmol/kg), IBMX (3–30 nmol/kg), secretin (0.01–0.1 pmol/kg) or CCK-8 (0.1–1 pmol/kg) injected i.a. elicited a dose-dependent increase in the secretion of pancreatic juice, but TFP and amrinone (up to 1 μmol/ kg) did not. 3. The bicarbonate concentration in pancreatic juice was increased and the protein concentration was decreased by Ro20,1724, IBMX and secretin. Cholecystokinin octapeptide increased the protein concentration but did not alter the bicarbonate concentration. 4. Ro20,1724 and IBMX elicited more than the respective additive secretory response when added together with secretin, although the stimulatory effects of CCK-8 with Ro20,1724 and IBMX were additive. 5. Ro20,1724 and IBMX increased cyclic AMP concentration but did not affect cyclic GMP concentration. 6. These results suggest that Ro20,1724 and IBMX have secretory properties on pancreatic exocrine glands of the dog, which may be mediated through an increase in cyclic AMP subsequent to inhibition of PDE activity. Furthermore, pancreatic PDE enzymes in the dog may be mainly type IV.     

EFFECT OF DIPYRIDAMOLE ON BLOOD GLUCOSE AND LIVER CYCLIC AMP LEVELS AND PLATELET COUNT DURING ENDOTOXAEMIA IN MICE

1. Blood glucose, liver cyclic AMP (cAMP) levels, and platelet count were studied at different times during a 12 h interval after intravenous (i.v.) endotoxin injection (40 mg/kg) in mice. 2. Blood glucose and liver cAMP levels showed a progressive decrease in endotoxic mice and the decrease was significant after 8 and 12 h. 3. Dipyridamole (50 mg/kg) administered intraperitoneally (i.p.) 7 h post-endotoxin improved blood glucose and liver cAMP levels. 4. Platelet counts were decreased after 1 h in endotoxic mice and remained decreased up to 8 h. Dipyridamole administered soon after endotoxin improved platelet counts in endotoxic mice and increased survival rate to 100%.     

VASORELAXANT EFFECTS OF SCA40 (A PHOSPHODIESTERASE III INHIBITOR) IN PULMONARY VASCULAR PREPARATIONS IN RATS

1. The novel phosphodiesterase (PDE) inhibitor SCA40 (6-bromo-8(methylamino)imidazo[1,2-α]pyrazine-2-carbo-nitrile) was examined for its vasorelaxant activity on isolated pulmonary vascular preparations from rats. 2. SCA40 relaxed ring preparations of main and intralobar pulmonary artery precontracted submaximally with either phenylephrine or U46619 (thromboxane-mimetic). Based on negative log EC50 values, SCA40 was six- to 14-fold more potent than the PDE III inhibitor milrinone or the non-selective PDE inhibitor 3-isobutyl-1-methyI xanthine (IBMX). The potency of SCA40 corresponded to its reported potency as a PDE III inhibitor. 3. In isolated perfused lungs, SCA40 reversed the vasoconstriction induced by alveolar hypoxia. It was 49-fold more potent than IBMX. 4. In main pulmonary artery the vasorelaxation induced by SCA40 was not blocked by the large-conductance calcium-activated potassium channel (BKca) inhibitors iberiotoxin (50 and 100nmoI/L) or charybdotoxin (100 and 300nmol/L). This was in contrast to data on guinea-pig trachea, where responses to SCA40 were significantly inhibited by charybdotoxin (100nmol/L). 5. It is concluded that opening of BKca channels does not contribute to the pulmonary vasorelaxant effects of SCA40 in main pulmonary artery and it is likely that responses reflect the PDE III inhibitory properties of the drug. 6. It is postulated that SCA40 may be useful as a pulmonary vasodilator in disorders such as pulmonary hypertension.     

BETA-ADRENOCEPTOR-MEDIATED EFFECTS OF CLENBUTEROL (NAB 365) ON TRACHEA, HEART AND SKELETAL MUSCLE IN ANAESTHETIZED GUINEA-PIGS

1. Intravenous injection of clenbuterol (NAB 365) in anaesthetized guinea-pigs produced decreases in tracheal segment pressure and in soleus muscle contractions and a slight increase in heart rate. These responses were reduced by propranolol. 2. Clenbuterol was less potent than isoprenaline on the trachea and soleus muscle and even less potent on the heart. The maximum response to clenbuterol was the same as that to isoprenaline on the trachea and the soleus muscle but it was not more than 30% of that to isoprenaline on the heart. There was no significant difference between the potencies of clenbuterol on the trachea and the soleus muscle. 3. The onset of the responses to clenbuterol were slower and the duration of action longer than those to isoprenaline. 4. High doses of clenbuterol blocked isoprenaline responses on heart rate. 5. Clenbuterol showed selectivity for the trachea and the soleus muscle (β₂-adrenoceptors) as compared with the heart (β₁-adrenoceptors). This could result, at least in part, from its partial agonist activity on the heart.     

MECHANISMS OF ADAPTIVE SUPERSENSITIVITY IN SMOOTH MUSCLES VS CARDIAC MUSCLE: A BRIEF REVIEW

1. Depending upon the type of cell being studied, adaptive supersensitivity has been traced to molecular changes in receptors, the Na+/K+ pump or the G-protein/adenylate cyclase system. 2. Evidence is reviewed that indicates that adaptive supersensitivity in guinea-pig atria is the result of changes in the G-protein/adenylate cyclase system.     

EFFECTS OF PROPRANOLOL ON DEVELOPMENT AND MAINTENANCE OF SEVERE RENAL HYPERTENSION IN RATS

1. The effect of chronic administration of propranolol on the development and maintenance of severe renal hypertension in rats subjected to unilateral renal artery constriction was studied in relation to possible changes in peripheral PRA and the blood and tissue levels of propranolol. Propranolol was administered s.c. twice daily in doses of 1, 10 and 25 mg/kg, starting 2 days before operation. 2. Contrary to expectations, not only did the initial rise in systolic blood pressure become accelerated, but the established level of hypertension attained in the propranolol treated rats was of the same severity as that attained in placebo treated rats. Moreover, the progressive rise in peripheral plasma renin activity following unilateral renal artery constriction was not affected by propranolol administration. 3. The same doses of propranolol were also administered daily for 8 days to rats with established severe hypertension. A slight further rise in blood pressure occurred initially, followed by a moderate decrease of 15–25 mmHg. Propranolol failed to exert this minor hypotensive effect in hypertensive rats treated concomitantly with furosemide. No suppressive effect on the markedly increased levels of plasma renin activity was observed in these severely hypertensive rats in the presence or absence of furosemide administration. 4. These results indicate that in severely renal hypertensive rats propranolol has only a minor hypotensive effect and no blocking action on renin release under the conditions of study.     

THE EFFECTS OF PROPRANOLOL, PRACTOLOL AND METOPROLOL ON EXERCISE-INDUCED TACHYCARDIA IN RELATION TO PLASMA LEVELS IN MAN

1. The effects of single oral doses of propranolol, practolol and a new cardio-selective β-adrenoceptor blocking drug, metoprolol, on exercise-induced tachycardia in relation to plasma levels were studied in six normal volunteers. 2. Exercise undertaken on treadmill was submaximal which, under control conditions, increased the heart rate from 74·3 (s.e.m. = 6·8) to 153·8 (s.e.m. = 9·8) beats/min. 3. Plasma concentrations of propranolol and practolol were assayed fluoro-metrically and of metoprolol by electron-capture gas liquid chromatography, the details of which are described. 4. Between 1·5 and 2 h after drug ingestion 80 mg of propranolol associated with plasma level of 50–60 ng/ml (half-life 2·75 h), reduced the exercise-induced tachycardia by 27%, 250 mg of practolol with plasma levels of 1050–1100 ng/ml reduced it by 28% and 100 mg of metoprolol with plasma concentrations of 140–150 ng/ml (half-life 1·7 h), reduced it by 30%. 5. The resting heart rates were reduced significantly by propranolol and metoprolol but not by practolol. 6. Metoprolol is a potent short-acting β-adrenoceptor antagonist; its advantages as a cardioselective agent over practolol in therapeutic use are discussed.     

COMPARISON OF THE EFFECTS OF (—)-ISOPRENALINE, ORCIPRENALINE TERBUTALINE, AND ME506 ON HEART RATE, SOLEUS MUSCLE CONTRACTILITY AND PULMONARY RESISTANCE OF ANAESTHETIZED CATS

1. Three resorcinol derivatives with N-isopropyl (orciprenaline), N-t-butyl (terbutaline) and N-p-hydroxypheny-t-butyl (Me506) amine substituents have been compared with (—)-isoprenaline for their ability to produce β-receptor mediated reductions in serotonin-induced increases in pulmonary resistance, decreases in soleus muscle contractility and increases in heart rate in anaesthetized cats. 2. For all parameters studied the four compounds produced similar maximal responses and dose-response curves were close to parallel. From the graphs doses of the compounds producing 50% of the maximal response (ED50) were interpolated, and from these dose-ratios with respect to (—)-isoprenaline [drug ED₅₀: (—)-isoprenaline ED₅₀] were calculated on a molar basis. 3. Increasing the size of the amine substituent from N-isopropyl to N-t-butyl led to an increase in β-receptor stimulant activity in bronchial and skeletal muscle, but not in the heart. The change from N-t-butyl to N-p-hydroxyphenyl-t-butyl did not further affect stimulant activity in any of the parameters studied. 4. Calculation of selectivity ratios [molar dose-ratio (heart): molar dose-ratio (pulmonary resistance)] showed that orciprenaline was non-selective, and that terbutaline and Me506 showed a similar degree of selectivity for β₂- as opposed to β₁-receptor mediated actions.     

EFFECTS OF THROMBOXANE SYNTHETASE INHIBITOR (UK 38,485) AND THROMBOXANE RECEPTOR ANTAGONIST (ICI 185,282) ON DIGOXIN-INDUCED ARRHYTHMIAS IN ANAESTHETIZED GUINEA-PIGS

1. Increased local thromboxane (Tx) formation has been considered to be a contributing factor in digitalis-induced arrhythmias. 2. A potent Tx synthetase inhibitor (TxSI), UK 38,485 (0.1, 1.0 or 10.0 mg/kg per h, administered intravenously) and a Tx receptor antagonist (TxRA), ICI 185,282 (1, 2 or 10 mg/kg bolus and 1, 2 or 10 mg/kg per h, administered intravenously) were tested for their ability to reduce digoxin-induced arrhythmias in anaesthetized guinea-pigs. 3. Electrocardiograms, mean blood pressure, heart rate and arrhythmias were recorded, starting 30 min before digoxin administration and continued for 60 min afterwards. 4. ICI 185,282, at the doses used, significantly delayed the time of onset of arrhythmias, and reduced the incidence of ventricular fibrillation, mortality and arrhythmia score. In contrast, UK 38,485 was found to be effective on all measured variables only at the dose rate of 1.0 mg/kg per h, except for time required for the development of arrhythmias. These protective effects of both TxSI and TxRA were not found to be dose-dependent. 5. Arterial blood pressure and heart rate changes caused by either UK 38,485 or ICI 185,282 infusions did not have any marked effects on digoxin-induced arrhythmias. 6. These data suggest that endogenously released TxA2 and prostaglandin endoperoxides may play an important role in digoxin-induced arrhythmias in guinea-pigs.     

THE EFFECTS OF INTRACISTERNAL ADMINISTRATION OF α-ADRENORECEPTOR AGONISTS ON THE SYSTEMIC BLOOD PRESSURE AND ITS RESPONSE TO HEAD-UP TILTING IN ANAESTHETIZED CATS

1. The effects of intracisternal injections of the α-adrenoreceptor agonists clonidine (0.2, 0.63 and 2.0μg/kg), xylazine (0.5, 8.0 and 50μg/kg), oxymetazoline (2.0 and 8.0μg/kg), noradrenaline (12.5, 50 and 100μg/kg) and α-methylnoradrenaline (5.0 and 25;μ/kg) on mean arterial pressure and the reflex pressure responses to bilateral carotid occlusion and 45° vertical head-up tilting have been investigated in chloralose-urethane-anaesthetized cats. 2. All the a-adrenoreceptor agonists tested caused dose-dependent reductions in mean arterial pressure (P<0.05, Anova, d.f. = 1,58) and the reflex pressor response to bilateral carotid occlusion (P < 0.05, Anova, d.f. = 1,58). 3. Only xylazine (50μg/kg) and noradrenaline (100μg/kg) produced a significant depression of the magnitude of the pressure compensatory response to tilting (P<0.05, Anova, d.f. = 1, 58) whilst all the agonists tested caused an increase in the period required for pressure compensation to occur (P<0.05, Anova, d.f. = 1,58). The action of the a-adrenoreceptor agonists to depress mean arterial pressure and the reflex responses to bilateral carotid occlusion and tilting could be reversed by the subsequent intracisternal injection of the a-adrenoreceptor antagonist piperoxane (50 or 100μg/kg). 5.Clonidine (0.63 μg/kg) decreased the perfusion pressure of the vascularly isolated autoperfused hindquarters (P<0.05, Anova, d.f. = 1,19), but had no significant effect on the reflex rises in perfusion pressure evoked by bilateral carotid occlusion or tilting. Noradrenaline (50 jug/kg) significantly reduced the reflex response to tilting (P<0.05, Anova, d.f. = 1,19), but had no effect on the other hindquarter parameters. Oxymetazoline (8.0 μg/kg) caused no significant change in any of these parameters. 6. It is concluded that intracisternally administered a-adrenoreceptor agonists may cause some depression of orthostatic cardiovascular reflexes via a central interaction with adrenergic mechanisms.     

ACTIONS OF THE SYMPATHOMIMETIC BRONCHODILATOR, TRIMETOQUINOL (AQL 208) ON THE CARDIAC, RESPIRATORY AND SKELETAL MUSCLE SYSTEMS IN THE ANAESTHETIZED CAT, AND ON CAT ISOLATED ATRIAL AND TRACHEAL PREPARATIONS

SUMMARY 1. The actions of the sympathomimetic bronchodilator trimetoquinol (AQL 208) have been compared with those of laevoisoprenaline on the cardiac, respiratory and skeletal muscle systems of the cat under chloralose anaesthesia, and on cat isolated atrial and tracheal preparations.
2. Trimetoquinol injected intravenously ranged in potency from two to four times less potent to about four times more potent than laevoisoprenaline in different in vivo experiments. Despite such wide variations in absolute potency the mean effective doses of trimetoquinol in both in vitro and in vivo studies were not significantly different ( P >0.05) from those of laevoisoprenaline.
3. The effect on the soleus muscle is considered to be analogous to the muscle tremor that often occurs in man, and the results suggest that systemic administration of trimetoquinol may produce muscle tremor as an unwanted side effect in some patients.
4. Trimetoquinol, in the cat, shows no evidence of the selectivity for β-adreno-receptors in different tissues reported for it in other species. It is suggested that β-receptors in the cat are less clearly differentiated and that they resemble those in man more closely than do those in other species.