Comroe's study of aortic chemoreceptors: a path well chosen.

AS EARLY AS 1868, Pflüger (8) recognized that hypoxia stimulated ventilation, which spurred a search for the location of oxygen-sensitive receptors both within the brain and at various sites in the peripheral circulation. When Corneille Heymans and his colleagues (4) observed that ventilation increased when the oxygen content of the blood flowing through the bifurcation of the common carotid artery was reduced (winning him the Nobel Prize in 1938), the search for the oxygen chemosensor responsible for the ventilatory response to hypoxia was largely considered accomplished. The focus of research then shifted toward a search for the exact nature of the stimulus and the transduction process. However, the persistence of stimulatory effects of hypoxia in the absence of the carotid chemoreceptors led other investigators, among them Julius Comroe, to ascribe hypoxic chemosensitivity to other sites, including both peripheral sites (e.g., aortic bodies) and central sites (e.g., hypothalamus, pons and rostral ventrolateral medulla; see Ref. 7). At the time this classic paper (1) was published in 1939, Comroe was a junior faculty member at the University of Pennsylvania, having recently been appointed in 1936 as an Instructor in the Department of Pharmacology (6). Working with Carl Schmidt, Comroe was interested in hypoxic chemosensors both in terms of their transduction mechanisms and the location of the extracarotid chemoreceptors. One of the first of his many major contributions was to show that the carotid body responded to reductions in PO2 and increases in PCO2 and did not respond to changes in oxygen concentration (3). However, he was struck by the fact that hypoxia, in the absence of intact carotid bodies, still produced an increase in ventilation, suggesting to him (and others) that an alternative receptor with hypoxic chemosensitivity must exist. Comroe was intrigued by the fact that, before their identification of the carotid site, Heymans and Heymans (5) had also reported that the aortic arch was chemosensitive, although this work was subsequently challenged. However, the observation that within the aortic arch there existed cells that greatly resembled carotid body cells supported the hypothesis and led many to propose that their structure was consistent with a chemosensitive function. The challenge, then, was to prove that these structures functioned physiologically as oxygen chemosensors and to characterize their specific responses. The problem consisted of designing an experiment to first show that hypoxia excited respiratory and cardiovascular parameters in a “physiological” preparation without any influence from the carotid chemoreceptors and then to show that these responses could be induced by discretely stimulating cell bodies along the aortic arch. Important to the experimental design was an intimate understanding of the local anatomy with regard to both the location of the afferent nerves and the blood supply to the cell bodies. Comroe, a surgeon by training, undertook the daunting task of defining both the physiological responses to hypoxia and the neural and circulatory anatomy of aortic bodies in both dogs and cats. The “sophisticated tech-