Afferent neural pathway in the regulation of cardiopulmonary responses to tissue hypermetabolism.

Abstract

SUMMARY We studied the role of neural transmission from hypermetabolic peripheral tissues in the regulation of cardiac output and pulmonary ventilation in chloralose-anesthetized dogs. Cross-circulation techniques with femoral-femoral or femoral-aortic anastomoses were used to produce a vascularly isolated, but normally innervated, hindlimb or lower half-body. 2,4-Dinitrophenol (DNP) was infused into the arterial side of the perfusion circuit to triple oxygen consumption and to increase lactate production by the cross-perfused area. After infusion of DNP, cardiac output and mean systemic arterial blood pressure increased, but neither heart rate nor pulmonary artery wedge pressure changed significantly. Pulmonary minute ventilation and arterial pH also increased, while arterial Pco 2 fell. These changes were abolished when the nerve connections between the perfused limb and its parent body were severed. Normal saline, when administered in a similar manner, did not increase either ventilation or cardiac output, and simple denervation without previous infusions of DNP also had no effect. These results indicate that there are receptors sensitive to metabolic changes in the tissue, and that neural transmission is an important afferent link in regulating the cardiopulmonary responses to increased tissue metabolism.BOTH CARDIAC output and pulmonary ventilation are increased during tissue hypermetabolism induced by 2,4-dinitrophenol (DNP). 1 -2 Levine and Huckabee 3 showed that the respiratory stimulation which follows DNP infusion is not a result of direct action of DNP on the brain or carotid chemoreceptors, hence the primary stimulus for these responses probably occurs in the peripheral hypermetabolic tissue from which it is transmitted to the central nervous system, heart, and lungs via neural or humoral pathways.Earlier, Ramsay 4 infused DNP into the normally innervated hindlimb of a dog (recipient dog), which was separated vascularly from its own central circulation and perfused by a second dog. He found that ventilation of the recipient dog was stimulated after DNP infusion and that this response was abolished when the nerve connections between the limb and the body were severed. These findings suggest that a neural pathway is involved in the regulation of pulmonary ventilation during tissue hypermetabolism. These findings, however, were not confirmed by Bailen and Horvath, 5 who also used a hindlimb preparation but administered a smaller dose of DNP than did Ramsay. This difference in doses might explain in part the discrepancies between their experimental results. In addition, the mass of tissue that could be rendered hypermetabolic in the hindlimb preparations is small, and the magnitude of stimulus generated in such areas by the small dose of DNP used in the experiments of Bailen and Horvath might not have been sufficient to produce a significant increase in pulmonary ventilation.In our present experiments, we attempted to study the role of neural transmission in the regulation of pulmonary ventilation and ca...

Metabolic Control of the Circulation

“…These results suggest that the stimulus that increases cardiac output and myocardial contractility during intravenous infusion of acetate in intact dogs probably originates in peripheral tissues. A neural afferent pathway is involved in the hemodynamic and ventilatory responses to increases in oxygen consumption produced by 2,4-dinitrophenol (11). Whether such a mechanism is also involved in the changes that occur during acetate infusion warrants further study.…”

“…Adenine nucleotides are also vasodilators (9,10), but it is probable that they act by being broken down to adenosine. Our recent finding (11) that cardiac output increases after administration of an uncoupling agent, 2,4-dinitrophenol, into vascularly isolated cross-perfused peripheral areas indicates that depletion of ATP in the peripheral tissue may be responsible, at least in part, for the increase in cardiac output that occurs during hypoxia and exercise.…”

Exercise intolerance, lactic acidosis, and abnormal cardiopulmonary regulation in exercise associated with adult skeletal muscle cytochrome c oxidase deficiency.

“…Regulation probably involves central command (55) as well as the action of bloodborne muscle metabolites such as CO2 or H' ions. There also may be a reflex ventilatory drive originating in metabolically sensitive neural afferents in working muscle (56). In patients with muscle oxidative defects and exaggerated oxygen transport in exercise, a parallel disturbance of ventilation is typical, marked by normal ventilation at rest but a larger than normal hyperpnea relative to the increase in metabolic rate in exercise.…”

Skeletal muscle chemoreflex and pHiin exercise ventilatory control

“…One such pathway is the muscle chemo-or metaboreflex where by-products of exercising muscle metabolism are believed to stimulate group IV unmyelinated nerves communicating with regions of the central nervous system important in cardiorespiratory regulation. Evidence for such a reflex is strongest for cardiovascular function (1,14), but a growing body of literature suggests it may be important for control of ventilation as well (5,12,16,29,32,35,42,46,52,53). The presence of neural afferents that stimulate respiration has been established from several animal studies (5,29,32,35,42,46,52).…”

“…The presence of neural afferents that stimulate respiration has been established from several animal studies (5,29,32,35,42,46,52). The most compelling evidence comes from experiments involving crosscirculation of a neurally intact isolated hindlimb (29,32,52).…”