Hans Loeschcke, Robert Mitchell and the medullary CO2 chemoreceptors: a brief historical review
Section snippets
The ‘reaction theory’ and cerebro–spinal fluid
The relationship between spinal fluid acid–base balance and respiratory center sensitivity to CO2 (and acid) begins with Winterstein (1911) who described a ‘reaction’ theory of ventilation in which he proposed that both CO2 and hypoxia operated through hydrogen ions (H+). The peripheral chemoreceptors, discovered by Heymans (1929), were subsequently shown to separately account for the hypoxic and the arterial H+ responses, but only a small fraction of the response to increased PCO2. Leusen
The Cardiovascular Research Institute
In 1958, Julius Comroe came to head the new Cardiovascular Research Institute (CVRI) at the University of California in San Francisco (UCSF), and provided a lab for Mitchell and Carman. Mitchell presented the studies of these two patients at one of the first weekly CVRI conferences. Comroe ordered a stop to the tests, because some years earlier he and Carl Schmidt at the University of Pennsylvania had injected saline into the lumbar CSF of a patient and produced a grand mal convulsion. Comroe
Background work in Göttingen
Stimulated by the same papers of Leusen and Winterstein, Hans Loeschcke, with Koepchen and Gertz in 1958, had published animal studies of the ventilatory responses to fourth ventricular CSF pH and PCO2 changes. Solutions with normal pH containing high PCO2 and equally high HCO3− depressed ventilation while high H+ with low HCO3− and normal PCO2 stimulated. Loeschcke had concluded that the most sensitive place for micro-injections was the lateral recessus of the fourth ventricle.
Collaboration in San Francisco
During a visit in Göttingen, in 1959, I described Mitchell’s work to Loeschcke and his group. Loeschcke agreed to spend 3 months with Mitchell in San Francisco looking for the acid-sensing site. Almost 2 months went by without any cats from the animal supplier. Rabbits were tried without success. During the last 4 weeks, when the supply line problem was solved, they studied 31 animals, sometimes two per day, working late into the night. Mitchell recalls that the Grass pen recording had sections
Discovery of chemosensitivity on the ventral medullary surfaces
Mitchell proceeded to develop a new surgical approach to the ventral surface of the cat medulla which was difficult, bloody, and, at first, unsuccessful. By late 1961, he was able to apply acid pledgets to the ventral surface, where he soon located the now classical CO2 chemosensitive areas. He showed that topical solutions with low bicarbonate were far more stimulating than those with high PCO2 and normal bicarbonate, because extra dissolved CO2 in the perfusate rapidly diffuses away into
Ondine’s curse
Mitchell and I had studied three patients who had lost all response to CO2, and stopped breathing when asleep. We coined the name ‘Ondine’s curse’ for central nervous system failure of automatic ventilatory drive (Severinghaus and Mitchell, 1962). I had recently seen the play ‘Ondine’ by Jean Girardoux (1939) based on the 15th century Germanic legend reported by Paracelsus, in which a 3-year-old child was found coming out of a lake by a fisherman and his wife who had lost their own daughter,
Progesterone and pregnancy effects on ventilation
One of Loeschcke’s earliest interests in the early 1940s had been the variation of resting end tidal PCO2 with menstrual cycles and pregnancy in females including his wife and a technician (Loeschcke and Sommer, 1944, Heerhaber et al., 1948, Loeschcke, 1950, Koepchen et al., 1954). He established that this periodic hyperventilation was causally related to progesterone but he was unable to determine whether it was mediated by acidification of CSF or by up-regulation of peripheral chemoreceptor
Acclimatization to high altitude
A mystery about high altitude effects on respiration persisted from the work for the US Navy of Houston and Riley (1947) during World War II. In their study, called ‘Operation Everest’, they noted that men who had been living in a low pressure chamber simulating extreme altitude, had continued to hyperventilate when removed from the chamber, despite alkaline blood, low PCO2 and high oxygen saturation. The source of this ventilatory drive was still unknown in 1960. Mitchell and Loeschcke now
Subsequent work in Germany
Meanwhile, in Göttingen, and later in Bochum, Loeschcke and colleagues, especially Marianne Schläfke, mounted a thorough investigation of the ventral medullary surface, locating the second, caudal acid-sensitive region and an intermediate area responding to electrical stimulation but not acid (Schläfke et al., 1970). They then suggested names for these three areas, M for the rostral (Mitchell), S for the intermediate (Schläfke) and L for the caudal (Loeschcke).
Fukuda and Loeschcke (Fukuda and
Later chemoreceptor studies in California
In San Francisco, studies of the medullary ventral superficial chemosensitive regions continued for some 30 years as Robert Mitchell guided the research of many pre- and post-doctoral students. He guided fellows working with me on the effects of hypoxia and altitude. Early on it was apparent that hypoxia not only failed to stimulate breathing in animals with denervated carotid chemoreceptors, but often depressed breathing centrally. This hypoxic ventilatory depression, HVD, could be shown in
Remaining questions
There remain several questions about CO2 chemosensors. Are they truly widespread throughout the brainstem as the Dartmouth group (Coates et al., 1993) alleges? How does the micro-injection in regions far from the MVS of either acetazolamide or CO2 gas (Li and Nattie, 1997) so profoundly stimulate CO2 chemosensors and result in hyperventilation? How can these observations be compatible with the demonstration by Schläfke et al. (1979) of ablation of CO2 response by focal MVS lesions of area S? In
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2010, Respiratory Physiology and NeurobiologyCitation Excerpt :The solitary complex of the caudal dorsomedial medulla occupies a unique position in the history of debate on locations of central chemoreceptors and their relative importance in cardiorespiratory chemoreception: the caudal NTS region was the first area outside of the VLM that was proposed as an additional site of CO2 chemosensitivity during the Loeschcke era (Miles, 1983; Dean et al., 1989, 1990; Dean and Millhorn, 1992). The “Loeschcke era” began in 1958–1963 with the first VLM studies of Mitchell, Loeschcke and colleagues (Loeschcke et al., 1958; Mitchell et al., 1963) and dominated the chemoreceptor field for the next three decades (Severinghaus, 1998). Pioneering studies during the 1930s–50s in whole animals (Section 2.1.1) demonstrated that CO2/H+ chemosensitivity resided in medullary regions outside the VLM (Sobin and Nicholson, 1938; Pitts et al., 1939; Comroe, 1943; Liljestrand, 1953) and included the dorsal medulla (Sobin and Nicholson, 1938).
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