Journal of Theoretical Biology 249 (2007) 737–748 Can carotid body perfusion act as a respiratory controller? Arho Virkki a,b,Ã , Olli Polo d,e , Mats Gyllenberg c , Tero Aittokallio a,b,d,f a Biomathematics Research Group, Department of Mathematics, University of Turku, FIN-20014 Turku, Finland b Turku Centre for Computer Science, Joukahaisenkatu 3-5 B 6th Floor, FIN-20520 Turku, Finland c Department of Mathematics and Statistics, Rolf Nevanlinna Institute, University of Helsinki, FIN-00014 Helsinki, Finland d Department of Physiology, Sleep Research Unit, University of Turku, FIN-20014 Turku, Finland e Department of Pulmonary Medicine, Tampere University Hospital, FIN-33521 Tampere, Finland f Systems Biology Unit, Institut Pasteur, FR-75724 Paris, France Received 22 March 2007; received in revised form 5 September 2007; accepted 7 September 2007 Available online 15 September 2007 Abstract The carotid bodies contain chemoreceptor cells that respond to hypoxia and hypercapnia/acidosis of the arterial blood. Since the carotid bodies receive exceptionally high blood perfusion through branches of the external carotid artery, their impulse activity to the respiratory center is thought to be determined mainly by the arterial partial pressures of oxygen (O 2 ) and carbon dioxide (CO 2 ). However, this paradigm explains the observed increase in ventilation neither during mentally agitated states nor physical exercise. The objective of the work was to test whether physiologically feasible reductions in carotid body perfusion could explain such respiratory overdrive using a flow-sensitive mathematical model of the carotid body chemoreception. The model is based on the law of mass balance and on the description of the chemical reactions in the arterial blood and inside the receptor cells. The neural response to the arterial O 2 and CO 2 levels is assumed to be mediated via the controller’s intracellular O 2 partial pressure and pH. The model predicts that the O 2 response is affected even by moderate changes in blood flow, whereas the CO 2 response is not altered until blood flow is severely limited. Reducing blood flow increases neural stimulus but decreases sensitivity to changes in the partial pressures of arterial O 2 and CO 2 . An example is given in which relatively small changes in blood flow significantly modify the carotid body sensitivity to CO 2 . These results suggest that limiting perfusion of the carotid bodies through vasoconstriction can offer a powerful mechanism to drive breathing beyond metabolic needs. This observation may provide important insight into the control of ventilation, e.g., during transition from wakefulness to sleep, before physical exercise or during panic attack. r 2007 Elsevier Ltd. All rights reserved. Keywords: Mathematical model; Respiratory system; Gas exchange 1. Introduction Careful adjustment of ventilation to meet the metabolic needs is essential for optimal energy production and physical performance. Chemoreceptors in various locations of the body respond to changes in pH or partial pressures of carbon dioxide (P CO 2 Þ or oxygen ðP O 2 Þ, and determine the chemical drive for breathing during sleep. CO 2 concentration is monitored both at the central and peripheral chemoreceptors, whereas low O 2 levels are detected mainly by the peripheral chemoreceptors in carotid and aortic bodies. Carotid bodies are highly perfused as compared to other organs in the body, which is in line with their principal function of monitoring and responding to changes in P O 2 , P CO 2 and pH occurring in the arterial blood (Marshall, 1994; Ganong, 2005). While the response to increased CO 2 levels is believed to be due to the corresponding increase in the hydrogen ion concentra- tion ð½H þ Þ, the precise mechanism of how O 2 is sensed remains unknown (Lahiria et al., 2006). Even though carotid bodies have been extensively studied since they were first shown to monitor the arterial blood gases in the late 1920s (Zapata and Larraı´n, 2005), ARTICLE IN PRESS www.elsevier.com/locate/yjtbi 0022-5193/$ - see front matter r 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.jtbi.2007.09.010 Ã Corresponding author. Biomathematics Research Group, Department of Mathematics, University of Turku, FIN-20014 Turku, Finland. Tel.: +358 2 333 5686; fax: +358 2 333 6595. E-mail address: arho.virkki@utu.fi (A. Virkki).