: To avoid the modifying influence of general anesthesia on vagal control of respiration, we investigated the effect of phenyldiguanide (PDG), a drug known to stimulate juxta-pulmonary capillary ("J") receptors, in the non-anesthetized, unrestrained cat and recorded EEG, eye movements, neck muscle EMG, EKG and respiratory movements. The response to bolus injection of PDG into the right atrium was qualitatively similar to the one seen in cats under anesthesia, consisting of bradycardia and apnea followed by rapid shallow breathing (RSB). The injection-response latencies ranged from 1.5 to 3 s, indicating that the effect originated on the venous side of the cardiopulmonary region. Vagal block with lidocaine, which was applied via external tubings feeding into implanted vagal "sleeves", abolished the responses to PDG, demonstrating their dependence on vagal mediation. Atropine blocked the bradycardia but did not affect the apnea. All doses of PDG which affected respiration uniformly produced initial apnea, whose duration, in any given animal and trial session, exhibited a consistent dose-response relationship. Slow injections also produced apnea. RSB following the apnea was variable in frequency and amplitude of excursions and in its overall duration, and failed to reveal a dose-response relationship. Apnea lasted significantly longer when injections were made during slow wave sleep or REM sleep as compared to injections given during wakefulness or drowsiness. Arousal from all states of sleep occurred simultaneously with the onset of apnea and bradycardia and was also dependent on the vagi. Spontaneous awakening from sleep, by contrast, was always associated with an increase in breathing.(ABSTRACT TRUNCATED AT 250 WORDS)

Afferent vagal endings with non-myelinated axons are widely distributed in the lungs, where they are considerably more umerous than the endings of myelinated fibers. Until recently this group of C-fibers has been thought of as a single, functionally homogeneous afferent input. Action potential studies in both dogsl and cats2 indicated that chemicals injected into the bloodstream gained access to the endings through the pulmonary circulation, and Paintal2 obtained good evidence that they were situated near the pulmonary capillaires; he, therefore, named them "juxtapulmonary capillary receptors (type J receptors)". When stimulated by chemicals, these endings give rise to the pulmonary chemoreflex triad of bradycardia, systemic vasodilatation and apnea.

Two cyclic ether (CE) analogues of the prostaglandin endoperoxide PGH2, CE I and CE II, have been found to exert powerful stimulant effects on lung ‘irritant’ receptors and bronchial C-fiber endings after intravascular or aerosol administration in open-chest dogs under Dial-pentobarbital anesthesia. ‘Irritant’ receptors responded to a dose as small as 0.1 μg/kg CE II, injected into the right atrium. CE II was twice as effective as CE I and 10–20 times more potent than PGF2α. As an aerosol, it exceeded histamine in potency by more than 800 times. ‘Irritant’ receptor stimulation was always associated with decrease in lung compliance and increase in lung resistance. Isoproterenol which reduced the latter effects also diminished the response of ‘irritant’ receptors. Left atrial injection of GES had only weak and delayed effects. CE-induced ‘irritant’ receptor firing declined or ceased during ventilatory arrest in expiration and following hyperinflation of the lungs. In contrast to ‘irritant’ receptors, C-fibers responded more effectively and more rapidly, and in the absence of mechanical changes, when the drugs were injected into the left atrium as compared to right atrial injection. These findings suggest that CE-induced ‘irritant’ receptor stimulation is secondary to changes in lung mechanics, whereas C-fiber stimulation is a direct effect upon the nerve ending.

THE lungs are among the many organs that generate, release and destroy prostaglandins (PGs)1. It has been suggested that PCs act as ‘local hormones’2, so that prostaglandins E1 and E2, which relax the smooth muscle of bronchi and pulmonary blood vessels in many species, and F2α, which contracts it, may be implicated in normal regulation of airway and pulmonary vascular calibre3. PGF2α has been proposed as a causal factor in asthma4. The bronchoconstrictor effect of PGF2α is reduced by atropine, hence a reflex component may be involved5. Cough and airway irritation have been reported in clinical trials of PGE1 and PGE2 as bronchodilators in the treatment of asthma6,7. Thus PGs may stimulate afferent nerve endings in the lungs, and there has been speculation as to which endings are involved. We have recorded impulse activity from rapidly-adapting pulmonary stretch (’irritant‘) receptors8,9 and afferent C-fibre endings10,11 in the lungs of anaesthetised dogs. When PGF2α was injected into the right atrium, lung ‘irritant’ receptors were strongly stimulated. Injection of PGEs, by contrast, caused marked and prolonged stimulation of lung C-fibres.

The role that sensory nerve endings can play in drug action and the strategy used for its experimental analysis and proof is first exemplified by three effects of nicotine which are seen when the lowest effective doses of the drug are given intravenously in the cat: (1) a vasopressor effect due to arterial chemoreceptor stimulation; (2) a triad of bradycardia, hypotension and apnea, and (3) a depressant effect upon somatic motor activity, both of which are traced to vagal afferent endings in the pulmonary circulation. While receptors in the lung are responsible at least for the initial phase of the reflex responses listed in (2) and (3), sensory endings in heart, aorta, and carotid sinus region may be recruited into action as the drug reaches them. Several of these reflex effects can also be elicited by other sensory stimulant agents such as phenyldiguanide, 5-hydroxytryptamine, and veratrum alkaloids.

The effects of nicotine on the stretch reflex and on electrically induced monosynaptic and cutaneous polysynaptic reflex responses at a lumbosacral level were studied in lightly anesthetized (chloralose‐urethane) cats in which the regional fusimotor‐spindle loops had been interrupted by ventral rhizotomy. Doses of 15–40 μg/kg injected into the superior vena cava or the right atrium produced depression of the reflex responses in extensor and flexor α motoneurons after latent periods of 1–3 sec, while γ activity was initially accelerated. The early phase of this α depression was abolished by bilateral vagotomy. Sebacylcholine (a nicotinic agent) and acetylcholine also caused depression of evoked α activity in the absence of spindle feedback. It is concluded that nicotine activates a viscerosomatic reflex by exciting sensory receptors in the cardiopulmonary region and that α motor depression results independent of the changes in γ activity. However, α depression with delayed onset can still be elicited by nicotine after vagotomy and Renshaw blockade, and this effect is also duplicated by sebacylcholine and aboilshed by hexamethonium. In the doses used, spindle or skin afferents were not excited by nicotine. Thus, two more mechanisms are described by which nicotine can depress α activity. Both are reflex in nature, one implicating vagal, the other nonvagal peripheral receptors.

Nicotine, given by i.v. or right intra-atrial injection in doses of 10–40 μg/kg, depressed the “spontaneous” electrical activity and tone in both extensor and flexor muscles of cats rendered rigid by intercollicular decerebration and in intact preparations under light chloraloseurethane anaesthesia. The latent periods of this action following intra-atrial injection varied from 1 to 2 sec, indicating that it must have originated from receptors located between the right atrium and the pulmonary capillary bed. The onset of the reflex motor depression frequently coincided with the onset of the vagovagal cardiodecelerator-hypotensive response, suggesting that both effects arose from the same type of receptor. These brief latency effects were dependent on vagal afferents. After vagotomy a motor depressant effect with delayed onset was seen. Instances of differential abolition, or absence, of the effect of nicotine and phenyldiguanide under varying conditions of decerebration and anesthesia suggest that the motor depressant effect of nicotine does not arise from the pulmonary deflation receptors, responsible for the effect of phenyldiguanide, but is initiated at the pulmonary arterial baroreceptors which have earlier been implicated in the hypotensive reflex response to nicotine.

Phenyldiguanide and veratridine, given to cats i.v. or into the right atrium in doses of 25–100 and 6–25 μg/kg, were found to depress “spontaneous” EMG activity and muscle tone in “gamma-type” decerebrate preparations and in animals under light chloralose-urethane anaesthesia. The depression of motor activity involved both extensor and flexor muscles and was abolished by bilateral mid-cervical vagotomy. The effect was less consistent and more often preceded by initial increases in activity in the decerebrate cat than in experiments under anaesthesia, and also required doses in the upper portion of the ranges shown. Protoveratrine and veratrine also produced vagus-dependent depression of spontaneous motor activity.

The effect of vagal afferent firing, evoked by veratridine and phenyldiguanide, on the reflex responses of lumbosacral a motoneurons to muscle stretch (stretch reflex) and to electrical stimulation of muscle (monosynaptic reflex) and skin nerves (polysynaptic reflex) was investigated in cats under light chloralose-urethane anesthesia in the absence of fusimotor spindle feedback. It was found that α activity in ventral root filaments to both extensor and flexor muscles was depressed and that this depression was not only independent of the previously described γ effects but differed from them in various respects. Unlike the γ depression, α depression was infrequently preceded by an initial increase in activity. Thus, α depression often was already present when γ firing went through its early phase of acceleration. Furthermore, α depression was sometimes seen in the absence of γ effects. 5HT which had predominantly increased γ firing, produced a depression of α activity. Determination of the latent periods of the α depression and correlation of these with the latencies of the autonomic reflex responses, whose sites of initiation have provisionally been identified, prompt the conclusion that the viscerosomatic reflex elicited by phenyldiguanide arises from the pulmonary deflation receptors, while that elicited by veratridine originates in ventricular pressure and/or lung stretch receptors. The 5HT-induced α motor depression is of both vagal and non-vagal origin. It is proposed that these viscero-skeletomotor reflex effects constitute a mechanism which protects heart and lung from excessive demands of the body musculature.