Asmusssen, Hald & Larsen (1948) observed that the infusion of acetaldehyde

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1 234 J. Physiol. (1963), 168, pp With 2 plates and 1 text-figure Printed in Great Britain THE ACTION OF ACETALDEHYDE ON THE CHEMO- RECEPTORS OF THE CAROTID GLOMUS BY N. JOELS AND E. NEIL From the Department of Physiology, Middlesex Hospital Medical School, London, W. 1 (Received 28 January 1963) Asmusssen, Hald & Larsen (1948) observed that the infusion of acetaldehyde in man causes hyperpnoea. This hyperpnoeic response was abolished by the simultaneous inhalation of oxygen, and Asmussen et al. attributed the effects of acetaldehyde to stimulation of the arterial chemoreceptors. Handovsky (1934) had previously reported that in dogs the injection of acetaldehyde led to increased respiration and a rise in blood pressure which were no longer obtained after chemoreceptor denervation by section of the sinus and aortic nerves. We have examined the role of the chemoreceptors in the response to the injection of acetaldehyde in the cat. The action of acetaldehyde on the carotid body was studied by recording the impulse activity in chemoreceptor fibres of the sinus nerve (a) following the local intra-arterial injection of acetaldehyde and (b) during the perfusion of the vascularly isolated carotid body by solutions containing known concentrations of acetaldehyde. METHODS Cats were used, anaesthetized by the intraperitoneal injection of sodium thiopentone (45 mg/kg body weight). Two main groups of experiments were performed: (1) Local intra-arterial injections of a 1 % solution of acetaldehyde were made through a cannula in the lingual artery. The reaction of the solution was previously adjusted to ph 7-4 by the addition of sodium bicarbonate. The external carotid artery was clipped cranial to the origin of the lingual artery, to minimize any central actions of the drug. Femoral artery blood pressure was registered on a kymograph by a mercury manometer. The trachea was cannulated and a side tube from the cannula led to a tambour. This operated a lever which recorded respiration on the kymograph. In some animals few-fibre chemoreceptor preparations of the sinus nerve were made (Heymans & Neil, 1958). Action potentials were led off by saline-wick electrodes and displayed, after amplification, on one beam of a Cossor double-beam oscilloscope from which they were photographed. (2) In a second group of cats one carotid body was vascularly isolated by ligating all the arterial branches arising from the carotid bifurcation with the exception of the supply to the carotid body. The venous drainage of the glomus was carefully preserved. The carotid

2 ACETALDEHYDE AND CHEMORECEPTORS 235 body was perfused through a cannula in the common carotid artery with modified Krebs- Henseleit solutions (Joels, Neil & Vaughan Hudson, 1961). The arrangement was such as to allow Krebs-Henseleit solutions containing known concentrations of acetaldehyde to be substituted for the control perfusate. Chemoreceptor activity was again sampled by the discharge in few-fibre preparations of the sinus nerve. RESULTS Responses to the local intra-arterial injection of acetaldehyde The injection of acetaldehyde 2 mg (0.2 ml. of a 1 % solution) through the lingual cannula caused hyperpnoea (Text-fig. la). This response was abolished by cutting the corresponding sinus nerve, proving that it was of reflex origin (Text-fig. 1 b). An electroneurogram of the sinus nerve preparation (P1. 1, fig. 1) showed obvious chemoreceptor activity in response to such an intra-lingual injection of acetaldehyde. Respir-ation a_ co es "I F 100 L sec d(b,al Text-fig. 1. Cat, 2-7 kg, anaesthetized with sodium thiopentone; spontaneous respiration. Records from above downwards: respiration; femoral blood pressure; signal marker; time marker, 10 sec intervals. In both a and b signal denotes injection of acetaldehyde 1-5 mg in 0-15 ml. through cannula in right lingual artery. Right sinus nerve cut between a and b.

3 236 N. JOELS AND E. NEIL The action of acetaldehyde on the perfused carotid body During perfusion of the carotid body with Krebs-Henseleit solution there was only a sporadic discharge of chemoreceptor impulses (P1. 2, fig. 1 a). Krebs-Henseleit solution containing acetaldehyde 3 x 10-3 M was then substituted for this control perfusate and evoked a very brisk impulse traffic (P1. 2, fig. 1 b) as was to be expected from the results of intra-arterial injection already described. In such experiments the perfusates were equilibrated with a PO2 of 150 mm Hg. However, when the PO2 of the perfusing solution was raised the stimulant effect of the acetaldehyde was considerably decreased or even abolished (P1. 2, fig. 2b, c). P1. 2, fig. 2d shows that the stimulant effect of acetaldehyde compares in intensity with that of hypoxic hypoxia. The action of other aldehydes on the chemoreceptors As aldehydes are reducing substances we examined the effects of formaldehyde in similar concentration, using the electroneurogram of a chemoreceptor preparation of sinus nerve. Formaldehyde did not stimulate the chemoreceptors (P1. 2, fig. 3b), whereas a similar concentration of acetaldehyde provoked an intense discharge (P1. 2, fig. 3d). DISCUSSION Lubin & Westerfeld (1945) showed that acetaldehyde is metabolized in the body to acetic acid. They concluded that the principal enzyme responsible for this oxidation is aldehyde mutase. Diphosphopyridine nucleotide (co-enzyme I) acts as hydrogen carrier in this reaction, which probably utilizes pyruvate as the hydrogen acceptor. Thus the oxidation of acetic acid would be coupled with the reduction of pyruvate to lactate. Molecular oxygen is then required to reoxidize DPNH2 to DPN, and such oxygen usage presumably lowers the intracellular PO2. One might expect therefore that the provision of a high local oxygen tension by the perfusion fluid would offset the stimulant action of acetaldehyde. This is indeed borne out by the perfusion of such solutions and our results prove that the suppositions of Asmussen et al. (1948) are correct. If acetaldehyde excites the chemoreceptors by the metabolic changes considered above, one might suppose that other aldehydes exert a similar stimulant action. However, formaldehyde is quite ineffective as a chemoreceptor excitant, indicating that the action of acetaldehyde cannot simply be attributed to its possession of the CHO grouping.

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6 ACETALDEHYDE AND CHEMORECEPTORS 237 SUMMARY 1. The local injection of acetaldehyde via the lingual artery stimulates the carotid chemoreceptors and provokes reflex hyperpnoea which is abolished by section of the carotid sinus nerve. 2. If the vascularly isolated carotid body is perfused by Krebs- Henseleit solution equilibrated at P02 of 150 mm Hg and containing 3 x 10-3 M acetaldehyde, chemoreceptor discharge results. This response is virtually abolished by raising the P02 of the perfusing fluid. 3. Formaldehyde fails to excite the chemoreceptors when perfused through the carotid body in similar concentrations. REFERENCES ASMUSSEN, E., HALD, J. & LARSEN, V. (1948). The pharmacological action of acetaldehyde on the human organism. Acta pharmacol. 4, HANDOVSKY, H. (1934). Au sujet des propri6t6s biologiques et pharmacodynamiques de l'acetaldehyde. C.R. Soc. Biol., Paris, 117, HEYMANS, C. & NEIL, E. (1958). Reflexogeric Areas of the Cardiovascular System. London: Churchill. JOELS, N., NEIL, E. & VAUGHAN HUDSON, B. (1961). The investigation of chemoreceptor responses from the perfused carotid body in the cat. J. Physiol. 155, 30-32P. LUBIN, M. & WESTERFELD, W. W. (1945). The metabolism of acetaldehyde. J. biol. Chem. 161, EXPLANATION OF PLATES PLATE 1 Fig. 1. Cat, 4-2 kg, anaesthetized with sodium thiopentone; spontaneous respiration. Record from slip of right sinus nerve containing several chemoreceptor fibres and two or three baroreceptor fibres. Time marker 1/50 sec; between signals (interruption of time marker) acetaldehyde 2 mg in 0-2 ml. injected through cannula in right lingual artery. Records a, b and c are continuous; gap of 5 sec between records c and d. Note that though the chemoreceptor impulse activity is increased by the drug the baroreceptor discharge is not affected. PLATE 2 Fig. 1. Cat. Action potentials in chemoreceptor preparation of sinus nerve. Carotid body perfused with Krebs-Henseleit solution. a, control perfusate; b, perfusate containing acetaldehyde 3 x 10-3 M. Time marker 1/50 sec. Fig. 2. Cat. Action potentials in chemoreceptor preparation of sinus nerve; carotid body perfused with Krebs-Henseleit solutions. a, Control perfusate (PO2 = 150 mm Hg); b, perfusate eontaining acetaldehyde 3 x 10-3 M and normal tension of oxygen, PO2= 150 mm Hg; c, perfusate containing acetaldehyde 3 x 10-3 M and high tension of oxygen, P02 = 500 mm Hg; d, hypoxic perfusate, PO2 = 30 mm Hg. Time marker 1/50 sec. Fig. 3. Cat. Action potentials in chemoreceptor preparation of sinus nerve; carotid body perfused with Krebs-Henseleit solutions. a and c, control perfusate; b, perfusate containing formaldehyde 65 x 103 M; d, perfusate containing acetaldehyde 3 x 10-8 M. Time marker 1/50 see.