The sections in this article are: Reflex Cardiovascular Responses to Muscular Contraction in Anesthetized and Decerebrate Animals Sensory Innervation of Skeletal Muscle Reflex Autonomic Responses to Stimulation of Muscle Afferents in Anesthetized Animals Discharge Properties of Group III and IV Muscle Afferents The Site of the First Synapse—The Dorsal Horn Role of Spinal Neurotransmitters and Neuromodulators in the Exercise Pressor Reflex Pathways Ascending from the Dorsal Horn The Ventrolateral Medulla Other Central Neural Structures Final Common Pathways Interaction Between the Arterial Baroreflex and the Exercise Pressor Reflex in Anesthetized and Decerebrate Animals Evidence for the Exercise Pressor Reflex in Humans and Conscious Animals Feedback from Contracting Limb Skeletal Muscle in Humans and Conscious Animals The Nature of the Stimulus Evoking the Exercise Pressor Reflex Contribution of Peripheral Afferents to the Exercise Hyperpnea Afferents from the Exercising limbs The Carotid Chemoreceptor Afferents Role in Hyperventilation During Heavy Exercise The Pulmonary Afferents Cardiac Afferents Respiratory Muscle Afferents Mediation of the Exercise Hyperpnea by Multiple Mechanisms Summary and Conclusions Peripheral Afferent Contribution to Circulatory Responses to Exercise Peripheral Afferent Contribution to Ventilatory Responses to Exercise

During exercise by healthy mammals, alveolar ventilation and alveolar-capillary diffusion increase in proportion to the increase in metabolic rate to prevent PaCO2 from increasing and PaO2 from decreasing. There is no known mechanism capable of directly sensing the rate of gas exchange in the muscles or the lungs; thus, for over a century there has been intense interest in elucidating how respiratory neurons adjust their output to variables which can not be directly monitored. Several hypotheses have been tested and supportive data were obtained, but for each hypothesis, there are contradictory data or reasons to question the validity of each hypothesis. Herein, we report a critique of the major hypotheses which has led to the following conclusions. First, a single stimulus or combination of stimuli that convincingly and entirely explains the hyperpnea has not been identified. Second, the coupling of the hyperpnea to metabolic rate is not causal but is due to of these variables each resulting from a common factor which link the circulatory and ventilatory responses to exercise. Third, stimuli postulated to act at pulmonary or cardiac receptors or carotid and intracranial chemoreceptors are not primary mediators of the hyperpnea. Fourth, stimuli originating in exercising limbs and conveyed to the brain by spinal afferents contribute to the exercise hyperpnea. Fifth, the hyperventilation during heavy exercise is not primarily due to lactacidosis stimulation of carotid chemoreceptors. Finally, since volitional exercise requires activation of the CNS, neural feed-forward (central command) mediation of the exercise hyperpnea seems intuitive and is supported by data from several studies. However, there is no compelling evidence to accept this concept as an indisputable fact.

No abstract

No abstract

The purpose of the present study was to determine the effect on breathing in the awake state of carotid body denervation (CBD) over 1-2 wk after denervation. Studies were completed on adult goats repeatedly before and 1) for 15 days after bilateral CBD (n = 8), 2) for 7 days after unilateral CBD (n = 5), and 3) for 15 days after sham CBD (n = 3). Absence of ventilatory stimulation when NaCN was injected directly into a common carotid artery confirmed CBD. There was a significant (P < 0.01) hypoventilation during the breathing of room air after unilateral and bilateral CBD. The maximum PaCO2 increase (8 Torr for unilateral and 11 Torr for bilateral) occurred approximately 4 days after CBD. This maximum was transient because by 7 (unilateral) to 15 (bilateral) days after CBD, PaCO2 was only 3-4 Torr above control. CO2 sensitivity was attenuated from control by 60% on day 4 after bilateral CBD and by 35% on day 4 after unilateral CBD. This attenuation was transient, because CO2 sensitivity returned to control temporally similar to the return of PaCO2 during the breathing of room air. During mild and moderate treadmill exercise 1-8 days after bilateral CBD, PaCO2 was unchanged from its elevated level at rest, but, 10-15 days after CBD, PaCO2 decreased slightly from rest during exercise. These data indicate that 1) carotid afferents are an important determinant of rest and exercise breathing and ventilatory CO2 sensitivity, and 2) apparent plasticity within the ventilatory control system eventually provides compensation for chronic loss of these afferents.

.-In awake goats, 29% bilateral destruction of neurokinin-1 receptorexpressing neurons in the pre-Bötzinger complex (pre-BötzC) area with saporin conjugated to substance P results in transient disruptions of the normal pattern of eupneic respiratory muscle activation (Wenninger JM, Pan LG, Klum L, Leekley T, Bastastic J, Hodges MR, Feroah T, Davis S, and Forster HV. J Appl Physiol 97: 1620 -1628, 2004). Therefore, the purpose of these studies was to determine whether large or total lesioning in the pre-BötzC area of goats would eliminate phasic diaphragm activity and the eupneic breathing pattern. In awake goats that already had 29% bilateral destruction of neurokinin-1 receptor-expressing neurons in the pre-BötzC area, bilateral ibotenic acid (10 l, 50 mM) injection into the pre-BötzC area resulted in a tachypneic hyperpnea that reached a maximum (132 Ϯ 10.1 breaths/min) ϳ30 -90 min after bilateral injection. Thereafter, breathing frequency declined, central apneas resulted in arterial hypoxemia (arterial PO 2 ϳ40 Torr) and hypercapnia (arterial PCO2 ϳ60 Torr), and, 11 Ϯ 3 min after the peak tachypnea, respiratory failure was followed by cardiac arrest in three airway-intact goats. However, after the peak tachypnea in four tracheostomized goats, mechanical ventilation was initiated to maintain arterial blood gases at control levels, during which there was no phasic diaphragm or abdominal muscle activity. When briefly removed from the ventilator (ϳ90 s), these goats became hypoxemic and hypercapnic. During this time, minimal, passive inspiratory flow resulted from phasic abdominal muscle activity. We estimate that 70% of the neurons within the pre-BötzC area were lesioned in these goats. We conclude that, in the awake state, the pre-BötzC is critical for generating a diaphragm, eupneic respiratory rhythm, and that, in the absence of the pre-BötzC, spontaneous breathing reflects the activity of an expiratory rhythm generator. respiratory rhythm generator; terminal apnea; inspiratory and preinspiratory neurons SMITH ET AL. (21) DEMONSTRATED in the in vitro neonatal rat brain stem preparation that elimination of the pre-Bötzinger complex (pre-BötzC) caused cessation of respiratory rhythm. Since then, results from many in vitro studies support the pre-BötzC as the site or "kernel" of respiratory rhythm generation (9,19,20,21). Furthermore, in in vivo studies on anesthetized cats and rats, injection of the glutamate receptor agonist DL-homocysteic acid into the pre-BötzC area increases tonic and/or phasic phrenic nerve output, whereas injections into other proximal or distal nuclei do not increase respiratory rhythm (1,15,22), thus providing a physiological definition of the preBötzC. In addition, in vivo studies in anesthetized or decerebrate cats or rats demonstrate that lesioning of the pre-BötzC results in transient (24) or irreversible (7, 10, 18) elimination of eupneic respiratory activity. Further demonstrating the importance of the pre-BötzC in control of breathing was a study showing that Ͼ80% destruction o...

Key points• Carbon dioxide (CO 2 ) provides a major chemical stimulus to breathe, primarily through the activity of CO 2 /pH sensors called chemoreceptors in the brainstem and in the carotid body.• Carotid body denervation (CBD) causes hypoventilation at rest and reduces ventilatory sensitivity to CO 2 in multiple mammalian species, suggesting an important role of the carotid bodies in determining levels of ventilation relative to the CO 2 drive to breathe.• CBD in three strains of adult rats with large inherent differences in CO 2 sensitivity causes hypoventilation at rest but has no effect on CO 2 sensitivity.• These data from rats reinforce the concept that the carotid bodies provide a tonic facilitatory drive to breathe, but differ from other species suggesting a minimal contribution of the carotid bodies to CO 2 sensitivity in rats.Abstract Brown Norway (BN) rats have a relatively specific deficit in CO 2 sensitivity. This deficit could be due to an abnormally weak carotid body contribution to CO 2 sensitivity. Accordingly, we tested the hypothesis that CBD would have less of an effect on eupnoeic breathing and CO 2 sensitivity in the BN rats compared to other rat strains. We measured ventilation and blood gases at rest (eupnoea) and during hypoxia (F IO 2 = 0.12) or hypercapnia (F ICO 2 = 0.07) before and up to 23 days after bilateral or Sham CBD in BN, Sprague-Dawley (SD) and Dahl Salt-Sensitive (SS) rats. In all three rat strains, CBD elicited eupnoeic hypoventilation ( P aCO 2 +8.7-11.0 mmHg) 1-2 days post-CBD (P < 0.05), and attenuated ventilatory responses to hypoxia (P < 0.05) and venous sodium cyanide (NaCN; P < 0.05), while sham CBD had no effect on resting breathing, blood gases or chemoreflexes (P > 0.05). In contrast, CBD had no effect on CO 2 sensitivity ( V E / P aCO 2 ) in all strains (P > 0.05). Eupnoeic P aCO 2 returned to pre-CBD values within 15-23 days post-CBD. Thus, the effects of CBD in rats (1) further support an important role for the carotid bodies in eupnoeic blood gas regulation, (2) suggest that the carotid bodies are not a major determinant of CO 2 sensitivity in rats, and (3) may not support the concept of an interaction among the peripheral and central chemoreceptors in rats.

In this review we discuss the implications for ventilatory control of newer evidence suggesting that central and peripheral chemoreceptors are not functionally separate but rather that they are dependent upon one another such that the sensitivity of the medullary chemoreceptors is critically determined by input from the carotid body chemoreceptors and vice versa i.e., they are interdependent. We examine potential interactions of the interdependent central and carotid body (CB) chemoreceptors with other ventilatory-related inputs such as central hypoxia, lung stretch, and exercise. The limitations of current approaches addressing this question are discussed and future studies are suggested.