THE EFFECTS OF THYROXINE TREATMENT ON SLOW- AND FAST-CONTRACTING SKELETAL MUSCLE CONTRACTIONS OF THE CAT AND THEIR CYCLIC AMP LEVEL

1. The effects of thyroxine treatment on soleus and extensor digitorum longus (EDL) muscle contractions and their cyclic adenosine 3',5'-monophosphate (cyclic AMP) levels were examined in anaesthetized cats. 2. Thyroxine treatment decreased the tension of incomplete tetanic contractions of the soleus as well as the EDL muscles. The effect on tension of these muscles was not associated with an increase in the cyclic AMP level of the muscle as is the case with a beta 2-adrenoceptor agonist effect. 3. The results do not support the involvement of cyclic AMP in the tension depressant effect of thyroxine on contractions of skeletal muscle. 4. It is suggested that the muscle weakness and tremor observed in thyrotoxicosis and during administration of beta 2-adrenoceptor agonists are mediated by different mechanisms.     

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.     

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.     

EFFECTS OF ISOPRENALINE, LEVODOPA AND A PHOSPHODIESTERASE INHIBITOR (ICI 63,197) ON CYCLIC AMP LEVELS AND CONTRACTIONS OF SOLEUS MUSCLES IN ANAESTHETIZED CATS

1. Cyclic AMP levels have been determined in the soleus muscles of anaesthetized cats in the absence of drugs, and during depression of incomplete tetanic contractions produced by (-)-isoprenaline, ICI 63,197 (a phosphodiesterase inhibitor) or levodopa. 2. Cyclic AMP levels were elevated at the peak of tension depression produced by isoprenaline. Effects of isoprenaline on cyclic AMP and on contractions were dose dependent and statistically significantly related one to the other. Both effects were blocked by propranolol. 3. ICI 63,197 and levodopa produced isoprenaline-like effects on contractions but times to peak effect and recovery were longer. Cyclic AMP levels estimated during the depressant action were elevated. 4. The results support the involvement of cyclic AMP in the depressant effect of beta-adrenoreceptor agonists on slow-contracting mammalian skeletal muscle.     

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 effect of nipradilol on the isoproterenol-induced depression of contractions in the cat soleus muscle

The effect of nipradilol on the isoproterelol-induced depression of contractions of the soleus muscle of the anesthetized cats was studied. Isoproterenol (0.3 microg/kg) injected intravenously decreased the tension and degree of fusion of incomplete tetanic contractions of the soleus muscle of the anesthetized cats. The effect of isoproterenol was blocked by nipradilol (> or = 3 microg/kg), desnitro-nipradilol (> or = 10 microg/kg) and propranolol (> or = 10 microg/kg), but not by nitroglycerin (10-100 microg/kg). Nipradilol (30 microg/kg) and desnitronipradilol (300 microg/kg) almost completely antagonized the depressor effects of isoproterenol. These results coupled with evidence that nipradilol does not penetrate the blood-brain barrier indicate that nipradilol exerts an anti-tremor action by blocking peripheral beta2-adrenoceptors.     

Effects of isoetharine on airways resistance, heart rate, and contractions of the soleus muscle of the anaesthetised cat

The actions of the sympathomimetic bronchodilator, isoetharine, were compared with those of laevoisoprenaline, racemic isoprenaline and salbutamol, on the heart and lungs and on contractions of the soleus muscle of cats under chloralose anaesthesia. Isoetharine and salbutamol injected i.v. were approximately equipotent in all tests, and were about 8 times less potent than laevoisoprenaline both in decreasing the tension and degree of fusion of incomplete tetanic contractions of the cat soleus muscle, and in opposing the bronchoconstrictor action of 5-hydroxytryptamine. They were about 22 times less potent than laevoisoprenaline in increasing heart rate. In all tests, racemic isoprenaline was about 2 times less potent than laevoisoprenaline. The results suggest that the configuration of soleus β-receptors is closely similar to that of β-receptors in the lungs, and that the systemic administration of isoetharine might produce muscle tremor as a side-effect in man.     

DIRECT ACTION OF 4-AMINOPYRIDINE ON THE CONTRACTILITY OF A FAST-CONTRACTING MUSCLE IN THE CAT

The effects of 4-aminopyridine on the contractility of the fast-contracting tibialis anterior and the slow-contracting soleus muscles of cats under chloralose anaesthesia have been studied. 2. 4-Aminopyridine, in doses of 0.5 mg/kg and above, produced a slowly developing increase in the twitch tension of directly stimulated chronically denervated and of indirectly stimulated innervated tibialis anterior muscles, but had little or no effect on twitches of soleus muscles. The effect on innervated tibialis anterior muscles was more pronounced than that on chronically denervated muscles, but it was nevertheless concluded that the whole effect on innervated muscles was the result of a direct action on the muscle fibres. The simultaneously occurring facilitatory action on neuromuscular transmission, which is manifested in the anti-curare action of 4-aminopyridine, had a faster time-course and occurred in both the tibialis anterior and the soleus muscles. 3. 4-Aminopyridine antagonized dantrolene sodium on the tibialis anterior muscle but not on the soleus muscle. The antagonism could be described as physiological antagonism since it simply reflected the opposing actions on contractility of the two drugs. 4. 4-Aminopyridine was without effect on maximal tetanic tension of either the tibialis anterior or the soleus muscle. 5. It seems clear from the literature that a species difference exists with regard to the ability of 4-aminopyridine to increase muscle contractility. The results described in this paper show that muscle differences within the same species also exist.     

The effects of physostigmine on the mechanical and electrical responses of the cat nictitating membrane

The effects of physostigmine on the electrical and mechanical responses of the nictitating membrane elicited by single nerve shocks have been studied in cats anaesthetized with a mixture of chloralose and pentobarbitone. The results were variable but the most consistent effect, observed with large doses of physostigmine, was a depression and prolongation of the contractions which was sometimes associated with augmentation of the characteristic rhythmic electrical activity of the smooth muscle. Although the amplitude of single responses was depressed, incomplete tetanic contractions were sometimes increased in tension because of the greater fusion which occurred as a result of prolongation of the units of contraction. Possible mechanisms underlying the effect of physostigmine are discussed.     

Actions of the sympathomimetic bronchodilator, rimiterol (R798), on the cardiovascular, respiratory and skeletal muscle systems of the anaesthetized cat

1. The actions of rimiterol [erythro(3,4-dihydroxyphenyl, 2-piperidyl methanol hydrobromide)], a new sympathomimetic bronchodilator, have been compared with those of salbutamol and laevoisoprenaline on the heart and lungs, and on contractions of the soleus muscle of cats under chloralose anaesthesia.2. Rimiterol and salbutamol injected intravenously were about equipotent in all tests, and were about 8 times less potent than laevoisoprenaline both in opposing the bronchoconstrictor action of 5-hydroxytryptamine, and in decreasing the tension and degree of fusion of incomplete tetanic contractions of the cat soleus muscle. They were about 19 times less potent than laevoisoprenaline in increasing heart rate.3. The effect on the soleus muscle is considered to be analogous to the muscle tremor that often occurs in man, and the results therefore suggest that systemic administration of bronchodilator doses of rimiterol, like salbutamol, may produce muscle tremor as an unwanted side-effect.4. When equipotent doses to oppose 5-hydroxytryptamine-induced bronchospasm were compared, rimiterol and salbutamol produced less tachycardia than did laevoisoprenaline. In order to match the tachycardia produced by laevoisoprenaline, the doses of rimiterol or salbutamol had to be increased about two and a half times. This safety margin for salbutamol in the cat is considerably less than that reported by others for different species, which suggests that beta(1)- and beta(2)-adrenoceptors may be less clearly differentiated in the cat than they are in other laboratory animals.     

Use of cumulative dose-response curves in potency comparisons of sympathomimetic amines on the cat soleus muscle

The ability of beta-adrenoceptor agonists to reduce the fusion of incomplete tetanic contractions of the soleus muscle of the cat has been used previously as a model to assess the potential tremor producing effect of sympathomimetic bronchodilators. The ability of (-)-isoprenaline, (-)-adrenaline, (+/-)-soterenol and (+/-)-quinterenol to depress incomplete tetanic contractions of the soleus has now been assessed using cumulative administration of the amines. The method quickly produced accurate and reproducible dose-response curves. It is particularly useful for evaluating the potency of long-acting compounds.     

Actions of procaterol (OPC-2009), a new β2-adrenoceptor stimulant,on pulmonary resistance,contractions of the soleus muscle,and cardiovascular system of the anaesthetized cat

The β-adrenoceptor stimulant actions of procaterol hydrochloride [5-(1-hydroxy-2-iso-propylaminobutyl)-8-hydroxycarbostyril hydrochloride hemihydrate] were compared with those of isoprenaline, orciprenaline and salbutamol on pulmonary resistance, contractions of the soleus muscle, heart rate and diastolic blood pressure in the anaesthetized cat. All four drugs reduced the 5-HT-induced increase in pulmonary resistance, decreased the tension of incomplete tetanic contractions of the soleus muscle and the diastolic blood pressure, and increased the heart rate in a dose-related manner. The duration of the bronchodilator action of procaterol was far longer than that of orciprenaline or salbutamol while isoprenaline had the shortest duration. Procaterol was about 1·5 times more potent, and orciprenaline and salbutamol about 80 and 10 times less potent than isoprenaline in reducing the 5-HT-induced increase in pulmonary resistance and in decreasing the tension of incomplete tetanic contractions of the soleus muscle. Procaterol, orciprenaline and salbutamol were 3·5, 91·9 and 43·9 times less potent than isoprenaline in increasing the heart rate. Procaterol, orciprenaline and salbutamol were 3·4, 130·2 and 12·9 times less potent than isoprenaline in decreasing the diastolic blood pressure. Calculation of selectivity for bronchial vs cardiac β-adrenoceptors indicates that procaterol and salbutamol have a similar degree of selectivity for β₂-adrenoceptors mediating the bronchodilation, and that orciprenaline was an essentially unselective stimulant. Furthermore, the results support the suggestion that at present it is not possible to separate the bronchodilating and tremor-enhancing properties of β-adrenoceptor stimulants.     

Effects of dantrolene sodium on respiratory and other muscles and on respiratory parameters in the anaesthetised cat.

The effects of intravenous dantrolene sodium on contractions of the tibialis anterior, the flexor digitorum longus, the soleus and the diaphragm muscles, and on respiratory parameters, blood pressure and heart rate were recorded in cats under chloralose anaesthesia. Dantrolene maximally depressed twitches of the tibialis anterior and flexor digitorum loncles to a significantly greater extent (ca. 90%) than it depressed those of the soleus and diaphragm muscles (ca. 72%). When the muscles were indirectly stimulated at frequencies high enough to produce complete fusion of responses, the depressant action of dantrolene was largely masked. The onset of this “break through” effect was evident with paired stimuli, and was maximal with trains of about 6 stimuli. Dantrolene was without effect on blood pressure and heart rate in all experiments; the slight effects that accompanied each injection were entirely attributable to the solvent (propylene glycol). In 8 out of 12 experiments, dantrolene was without any detectable effect on breathing. In one cat, however, which happened to be unusually deeply anaesthetised, dantrolene produced a decrease in the frequency of breathing and the animal tended to hold each breath for longer than usual. In 3 out of the 12 cats, dantrolene produced a slight increase in transpulmonary pressure, a slight reduction in tidal volume and a slight shortening of the duration of each respiratory cycle with no alteration in the frequency of breathing. It is proposed that the lack of effect of dantrolene on the respiratory parameters in most experiments was the result of a reflex increase in the frequency of discharge from the respiratory centre to the extent that resistant tetanic contractions of the respiratory muscles were evoked.     

TETANIC FADE DURING PARTIAL TRANSMISSION FAILURE PRODUCED BY NON-DEPOLARIZING NEUROMUSCULAR BLOCKING DRUGS IN THE CAT

1. A comparison has been made of the effects of three acetylcholine antagonists—hexamethonium, tubocurarine and pancuronium—on maximal tetani of limb muscles of cats under chloralose anaesthesia. In most experiments, the indirectly stimulated soleus muscle was studied, but observations were also made on the tibialis anterior and flexor digitorum longus muscles. 2. When neuromuscular block was produced by intra-arterial injections of the acetylcholine antagonists, tetanic tension, though depressed in amplitude, did not wane and there was little or no post-tetanic relief of the block as judged by the amplitude of subsequent twitches. On the other hand, during similar degrees of block produced by intravenous injections, tetanic tension rapidly waned, and, after the tetanus, transmission was temporarily facilitated, as evidenced by an increase in the amplitude of post-tetanic twitches. 3. Intravenously injected hexamethonium caused complete waning of tetanic tension in doses too small to depress twitch amplitude and which caused only a small depression of peak tetanic tension. In contrast, pancuronium caused only partial tetanic fade even in doses that produced pronounced depressions of twitch and tetanic tensions. The effects of tubocurarine fell between these extremes. 4. The results suggest that depression of peak tension and tetanic fade are independent effects of acetylcholine antagonists. It is postulated that the former is a consequence of block of post-junctional cholinoceptors, whereas the latter arises from an action at pre-junctional cholinoceptors. 5. The results obtained, together with those of other workers, led to the suggestion that transmitter acetylcholine, in addition to evoking the endplate potential, acts on the nonmyelinated nerve terminals in a positive feed-back mechanism that mobilizes transmitter to keep pace with release during high frequencies of stimulation.     

Pharmacological actions of a new β-adrenoceptor agonist, MJ-9184-1, in anaesthetized cats

1. The effects of (-)-isoprenaline and the new beta-adrenoceptor agonist, MJ-9184-1, on the lungs, on the cardiovascular system, and on slow contracting skeletal muscle have been compared in cats under chloralose anaesthesia.2. Both amines reduced the increases in airways resistance produced by 5-HT, depressed incomplete tetanic contractions of the soleus muscle, lowered the blood pressure and produced an increase in heart rate. In comparison with (-)-isoprenaline, MJ-9184-1 had a long duration of action.3. The effects of MJ-9184-1 and (-)-isoprenaline were antagonized by the beta-adrenoceptor antagonist, propranolol.4. MJ-9184-1 was approximately half as potent as (-)-isoprenaline in its effects on pulmonary resistance and soleus muscle contractility, and one seventh as potent in producing chronotropic effects in the heart.5. These results suggest that MJ-9184-1 possesses some specificity as a beta(2) receptor stimulant.     

The effects of beta-adrenoceptor activation on contraction in isolated fast- and slow-twitch skeletal muscle fibres of the rat.

1. The aim of the experiments was to examined the effects of beta-adrenoceptor activation on twitch and tetanic contractions in fast- and slow-twitch mammalian skeletal muscle fibres. Isometric force was recorded from bundles of intact fibres isolated from the normal and denervated slow-twitch soleus and normal fast-twitch sternomastoid muscles of the rat. 2. Terbutaline (10 microM), a beta 2-adrenoceptor agonist, induced an average 15% potentiation of peak twitch and peak tetanic force in normal soleus fibres and abbreviated twitch and tetanic relaxation. In white- and red-sternomastoid fibres, 10 microM terbutaline potentiated peak twitch force by about 7% and slowed twitch relaxation. 3. The potentiation of twitches and tetani by terbutaline was quantitatively similar in normal and denervated soleus fibres. However, in contrast to the normal soleus, terbutaline slowed twitch relaxation and had no effect on tetanic relaxation in denervated soleus fibres. 4. Adrenaline (10 microM) increased peak tetanic force by about 7% in both normal and denervated soleus fibres. 5. Exposure to (+/-)-propranolol (0.1 microM), a general beta-adrenoceptor blocker, completely abolished the tetanus potentiation by terbutaline. 6. Dibutyryl-cyclic AMP (2 mM) mimicked the effects of 10 microM terbutaline on peak tetanic force and tetanic relaxation in normal and denervated soleus fibres. Dibutyryl-cyclic AMP also potentiated peak twitch force in denervated soleus fibres but only after a brief period of twitch depression: the twitch depression might be due to butyrate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Actions of some sympathomimetic bronchodilator and beta-adrenoceptor blocking drugs on contractions of the cat soleus muscle

1. (-)-Isoprenaline, salbutamol, orciprenaline and quinterenol injected intravenously decreased the tension and degree of fusion of incomplete tetanic contractions of the soleus muscle of the anaesthetized cat.2. Under the most sensitive conditions, the smallest effective dose of (-)-isoprenaline was of the order of 0.01 mug/kg intravenously. Salbutamol was usually 6-10 times, orciprenaline 20-30 times and quinterenol about 35 times less potent than isoprenaline. The effects of salbutamol were about 1.6 times, of orciprenaline about 1.8 times and of quinterenol more than 20 times as long lasting as those of (-)-isoprenaline.3. The effects of the sympathomimetic amines were blocked by propranolol, H56/28, H35/25 and butoxamine but not by ICI 50172. The combined results with agonists and antagonists indicate that the receptors involved can be classified as of the beta(2) type.4. The effect of the amines on the cat soleus muscle appears to be analogous to that causing enhancement of physiological tremor in man, which suggests that skeletal muscle tremor may be an occasional unwanted side effect of the use of these bronchodilators.     

SELECTIVE DEVELOPMENT OF TOLERANCE TO β-ADRENOCEPTOR AGONISTS IN SKELETAL MUSCLE AS COMPARED WITH AIRWAY SMOOTH MUSCLE FROM THE GUINEA-PIG

1. Guinea-pig were fed with a diet containing terbutaline or placebo for 4--5 days. The trachea, soleus muscle and the extensor digitorum longus (EDL) from these animals were prepared for recording of isometric contractions in vitro. 2. After treatment with terbutaline in vivo, the response of the pilocarpine-contracted trachea to terbutaline and isoprenaline was slightly suppressed with no change in maximum relaxation. 3. After treatment with terbutaline in vivo the maximum depression of the incomplete tetanic contractions of the soleus muscle brought about by terbutaline or isoprenaline was diminished by about 70%. The response of the EDL was also attenuated after previous treatment with terbutaline in vivo. 4. These data indicate a selective development of tolerance to the effects of beta-adrenoceptor agonists in skeletal muscle as compared with tracheal smooth muscle. 5. The present results provide an experimental analogue to the clinical observation that patients being treated with beta-adrenoceptor agonists become tolerant to the tremorogenic rather than to the bronchodilating effect.     

A comparison between the effects of a tetanus and the effects of sympathomimetic amines on fast- and slow-contracting mammalian muscles

The effects of adrenaline and isoprenaline on the tension and time-course of the contractions of the tibialis anterior and soleus muscles of cats and rabbits have been compared with the effects of previous high-frequency stimulation. Like a tetanus, adrenaline possessed a facilitating action on neuromuscular transmission and an action exerted directly on the muscle fibres. Isoprenaline possessed only the second of these two actions. The effect of adrenaline and isoprenaline on the muscle fibres was blocked by dichloroisoprenaline and by 1-(2 naphthyl)-2-isopropylaminoethanol, whereas the effect of adrenaline on neuromuscular transmission was blocked by phentolamine and by phenoxybenzamine. In the soleus muscle, both the catechol amines and a previous tetanus caused similar decreases in maximal twitch tension and in the times to peak tension and to half-relaxation. The muscle action potentials were unaltered or slightly increased in amplitude. In the tibialis anterior muscle, a previous tetanus and the catechol amines caused an increase in twitch tension and an increase in the overall duration of the twitch. The muscle action potentials were either unchanged or were slightly decreased in amplitude. In this muscle the effect of a tetanus differed from that of the catechol amines in that the large post-tetanic change was associated with a marked increase in the rate of rise of twitch tension.     

Correlation between the effects of salbutamol on contractions and cyclic AMP content of isolated fast — and slow — contracting muscles of the guinea pig

Summary The effects of isoprenaline and salbutamol on incomplete tetanic contractions of the isolated soleus (slow contracting) and extensor digitorum longus (EDL-fast-contracting) muscles of the guinea pig were studied and an attempt made to correlate these effects on contractility with changes in cyclic AMP concentrations. Salbutamol was 10–12 times less potent than (±)isoprenaline in decreasing the force of subtetanic contractions in the soleus and between 5–6 times less potent in increasing the force of subtetanic contractions in the EDL.This observation plus the lack of activity of both the selective ₁-adrenoceptor antagonist (atenolol) and the selective ₁ agonist (H 133/22) in the EDL implies involvement of ₂-adrenoceptors in these responses of the muscles to isoprenaline and salbutamol. The soleus muscle was about 6–12 times more sensitive to effects of -adrenoceptor agonists than the EDL. In concentrations which produced effects on muscle contractility, salbutamol significantly elevated cyclic AMP concentrations in both types of muscle. These effects were antagonised by propranolol. It seems clear that the contrasting effects of sympathomimetic amines on slow — and fast contracting muscle are mediated through a common mechanism — elevation of cyclic AMP. Possible explanations of this apparent paradox are discussed.