William C. Bowman

Adrenoreceptors in the cardiovascular system of the domestic fowl

Abstract Reversal of adrenaline pressor responses was obtained inconsistently following α-receptor blockade, but isoprenaline produced depressor responses. Intra-arterial injections of isoprenaline were without effect or produced only weak vasodilation when the blood flow from skin, intestine, or the lower leg was recorded, and intra-arterially injected adrenaline failed to produce vasodilation even after α-receptor blockade. β-Adrenoreceptors were demonstrated in helical strips of both the aorta and visceral veins, but not in other veins. The maximum responses of fowl aortic strips to noradrenaline and to dopamine, but not to tyramine, were significantly greater than the maximum responses to adrenaline. Cocaine potentiated the responses of vascular muscle and of the blood pressure to noradrenaline, and cocaine or reserpine pretreatment reduced the responses to tyramine. Reserpine pretreatment did not abolish the responses of perfused hearts to tyramine but hastened the development of tachyphylaxis, while cocaine increased the duration but reduced the intensity of adrenaline responses.

Effects of tremorine and harmine in the chick

Abstract Tremorine produced pronounced tremor, akinesia, hypothermia and parasympathetic effects in young chicks. Tremor was recorded quantitatively and the tremor response to tremorine was found to diminish with increasing age and with repeated dosage. The optimal age of the chicks for obtaining a tremor response to tremorine was 3 to 4 days. Harmine also produced tremor, and some akinesia and hypothermia. The harmine effect did not diminish with age or with repeated dosage. Tremorine produced a significant increase in the brain levels of acetylcholine, and a decrease in the brain levels of noradrenaline. It did not affect the levels of tyramine, dopamine or ergothioneine. Harmine produced an increase in the brain levels of noradrenaline but did not affect the levels of acetylcholine, tyramine or ergothioneine.

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

Abstract 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.

A comparison of the neuromuscular and autonomic blocking activities of (+)-tubocurarine and its N-methyl and O,O,N-trimethyl analogues.

(+)-Tubocurarine was compared to its methyl analogues (+)-N-methyltubocurarine and (+)-O,O,N-trimethyltubocurarine for differences in neuromuscular and autonomic blocking activities. On the cat soleus muscle O,O,N-trimethyltubocurarine had the highest neuromuscular blocking activity, tubocurarine the lowest and N-methyltubocurarine was intermediate. The ganglion blocking activities of tubocurarine and N-methyltubocurarine were equal, but O,O,N-trimethyltubocurarine was less active. Vagolytic activity was determined in the cat and all three compounds were equipotent, but only O,O,N-trimethyltubocurarine blocked the bradycardial response of acetyl-β-methylcholine. It is suggested that tubocurarine and N-methyltubocurarine block parasympathetic vagal ganglia and only O,O,N-trimethyltubocurarine blocks cardiac muscarinic receptors. The neuromuscular blocking activities were also compared by determination of pA2 values, against carbachol, on the isolated chick biventer cervicis muscle. These results indicated competitive antagonism by all three antagonists and showed that activities were different in different species. It is concluded that previous workers overestimated the increased neuromuscular blocking activity due to O-methylation of tubocurarine.

Interaction between the effects of tremorine and harmine and of other drugs in chicks

Abstract Responses to tremorine and harmine were recorded in conscious chicks. The tremor response to tremorine was depressed by atropine, hyoscine, propantheline, orphenadrine, benzhexol, chlorpromazine, morphine, hemicholinium, α-methyldopa, 5-hydroxytryptamine and 5-hydroxytryptophan, and was potentiated by amphetamine, dopamine, dopa and physostigmine. Small doses of deaner potentiated and large doses depressed the response. Acute administration of reserpine or tetrabenazine depressed whereas chronic administration potentiated the response. Chlorpromazine, 5-hydroxytryptamine, 5-hydroxytryptophan, amphetamine, dopamine dopa, reserpine and tetrabenazine affected the tremor response to harmine in a similar way to that of tremorine.

Effects of catecholamines on the gastrocnemius muscle of the domestic fowl.

Abstract The effects of adrenaline, noradrenaline and isoprenaline on contractions of the nonfatigued gastrocnemius muscle have been studied in anaesthetized fowls. The amines did not appear to affect the muscle by a direct action on the contractile elements, but both facilitatory and inhibitory effects on neuromuscular transmission were evident. Facilitation of transmission, as evidenced by an initial reversal of the blockade produced by tubocurarine and a slight increase in the twitch tension of the indirectly stimulated muscle, was mediated through α -adrenoreceptors. Hyperpolarization of the muscle fibres, mediated through β -adrenoreceptors, accounted for the depressant effect on contractures produced by depolarizing drugs, for the secondary potentiation of blockade produced by tubocurarine, and for the small decrease in twitch tension produced in the indirectly stimulated muscle. The results are discussed with reference to the action of the amines in amphibian and mammalian muscles.

Neuromuscular transmission: prejunctional events

Transmission from nerve to muscle is mediated by acetylcholine, which is synthesized and stored in the axon terminals. The transmission process involves acetylcholine synthesis, acetylcholine storage, acetylcholine release, acetylcholine function, and acetylcholine inactivation. Each process is capable of modification by drugs. This chapter discusses the events in the process that take place in the nerve endings. Acetylcholine is synthesized from choline and acetylcoenzyme A in the axoplasm of cholinergic axon terminals, the reaction being catalysed by the enzyme choline-O-acetyltransferase. The chapter discusses some experimental work carried out on cholinergic nerves in mammalian brain rather than on somatic motor nerves. In the synthetic reaction, the two substrates combine with the enzyme, and the two products leave it in a set order. In cholinergic neurons, acetylcholine is present throughout the axoplasm and probably in the cytosol of the cell body. Its concentration in the axoplasm of main axons is estimated to be about 0.3 mmol/1. Its concentration within axon terminals is considerably higher.

Neuromuscular transmission: postjunctional events

This chapter discusses the development of the receptor concept and explains the postjunctional acetylcholine receptors. Acetylcholine molecules, released in response to a nerve impulse, bind with their receptors and open ion channels that allow brief rectangular pulses of inward ionic current to flow. Many elementary current pulses summate to produce the endplate current (epc), which is recorded by a voltage clamp system. The convention is to record currents as downward deflections and voltages as upward deflections on the oscilloscope. The epc depolarizes the endplate membrane to produce the epp. The falling phase of the epp is determined by the time course of the passive decay of charge on the fiber membrane. It is prolonged compared with the time course of action of acetylcholine and the epc. The epp is the important biological event because once it reaches a critical threshold, it triggers off an all-or-nothing propagating action potential that passes around the sarcolemma to activate the contractile mechanism via the T tubules, the sarcoplasmic reticulum, and the contractile proteins.

Pharmacological manipulation of prejunctional events

The various steps in the transmission process that occur in the nerve endings may be modified by the actions of drugs and toxins. This chapter discusses the various types of these drugs and toxins: (1) drugs that inhibit acetylcholine synthesis, (2) drugs that inhibit vesicular loading, and (3) agents and factors that modify acetylcholine release. The chapter presents evidence for the existence of nicotinic and muscarinic receptors on the motor nerve endings and discusses the possible role of physiological feedback control mechanisms that modulate transmitter release. The actions of vesamicol and similarly acting drugs are best explained in terms of the vesicular theory of acetylchohne release. However, the fact that vesamicol is capable of inhibiting spontaneous molecular leakage indicates that other explanations may be possible. The most important and usually interrelated factors that modify the release of acetylchohne by nerve impulses are changes in resting membrane polarization, changes in the terminal action potential size or shape, and changes in the [Ca 2+ ] : [Mg 2+ ] ratio.

Chapter 1 – Striated muscle

Publisher Summary This chapter focuses on striated muscles, which are innervated by somatic efferent nerve fibers that are fast-conducting myelinated group A axons with cell bodies in the motor nuclei of the cranial nerves in the brain stem or in the anterior horns of grey matter in the spinal cord. These peripheral neurons are known as the lower motoneurons to distinguish them from the upper motoneurons involved in the central control of striated muscle movement. Muscle fibers that receive their innervation at a focal point on their membranes are described as focally innervated. Most mammalian muscle fibers are of this type. The focal motor endplates of muscle fibers innervated by spinal nerves are usually midway between the origin and the insertion of the muscle fibers. Some very long muscle fibers may possess two or three foci of innervation; such muscle fibers are still regarded as focally innervated. Multiply innervated fibers receive a dense innervation all over their membranes from many nerve endings. These fibers are common in certain muscles of birds, some snakes, amphibians, and fish. Fibers with a Fibrillenstruktur have a distinct fibrillar appearance owing to the regular arrangement and uniform width of their myofibrils, which are distinctly separated one from another by sarcoplasm.