The Humoral Regulation of Breathing

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Abstract
The clasic concept that breathing is regulated only by chemoreceptor mechanisms in the arterial blood stream— the respiratory center, the carotid and aortic bodies—has been modified in two ways. It has been expanded by postulating another chemoreceptor which reacts to the composition of mixed venous blood. It has been qualified by questioning the assumption that the respiratory center has physiologically significant chemosensitivity. (The respiratory center is considered to be, on the contrary, primarily a computing mechanism that integrates information received from chemoreceptors responding to both arterial and mixed venous blood.) By postulating a chemoreceptor mechanism which reacts to the composition of mixed venous blood, a variety of ventilatory responses can be accounted for with a unified and semiquantitative concept based on the ventilatory response to exercise. For the quantitative description of exercise, data obtained from normal men at rest and during exercise have been used to develop several equations which describe the ventilatory response to exercise in terms of Pco2 and H+ of arterial and mixed venous blood. The simplest of these equations, yet a useful one, is the following: V = 1.1 H+a + 2.3 Pvco2 - 135 (5a) which states that the volume of breathing is determined by the algebraic summation of influences in arterial and mixed venous blood. Ventilatory responses, as measured in several experimental and clinical situations characterized by acid-base imbalance and associated hyperpnea, have been compared with the ventilation predicted by this equation and by the equation which quantifies Gray's multiple-factor theory. Equation 5a estimated the various ventilatory responses as closely as the multiple-factor theory equation did. Equation 5a was also able to predict ventilation during exercise. It is concluded, therefore, that the hyperpnea of muscular exercise may be a generally applicable expression of the ventilatory response to alterations of the composition of both arterial and mixed venous blood. When applied to the ventilatory responses of cross-perfused animals during exercise, the concept gives a satisfactory qualitative explanation of the various observations. Although there is strong indirect evidence that a chemoreceptor mechanism exists which reacts to the composition of mixed venous blood and whose activity can be quantified, the equations that have been developed are not definitive expressions of the stimuli which regulate breathing. That the equations apply as well as they do, in view of the known errors of fact in their development, is probably the best evidence yet adduced for the essential validity of the present concept.