The ventilatory ( E) response to electrically induced rhythmic muscle contractions (ERC) was studied in six urethane-chloralose anaesthetised sheep, while PaO2, PaCO2 and perfusion pressure were maintained constant at the known chemoreception sites. With cephalic PaCO2 held constant, the response to inhaled CO2 was virtually abolished (0.03 ± 0.04 l min-1 Torr-1). During low current ERC, which doubled the metabolic rate ( CO2 increased from 192 ± 23 to 317 ± 84 ml min-1, p<0.01), E followed the change in CO2 closely (from 5.24 ± 1.81 to 9.27± 3.60 l min-1, p<0.01) in the absence of any chemical error signal occurring at carotid and central chemoreceptor level (? Cephalic PaCO2 = -0.75 ± 1 Torr). Systemic PaCO2 decreased by -2.47 + 1.9 Torr (p<0.01). Both HR and systemic BP increased significantly by 18.6 ± 5.5 b min-1 and 7.0 ± 9.3 mmHg respectively. When the CO2 flow to the central circulation was reduced during ERC by blocking venous return ( CO2 decreased by 102 ± 45 l min-1, p<0.01), ventilation was stimulated (from 11.99± 4.11 to 13.01 ± 4.63 l min-1, p<0.05). The opposite effect was observed by blocking the arterial supply. Finally, raising the CO2 content and flow in the systemic blood was unable to stimulate significantly ventilation provided the peripheral and central chemoreceptors were unaware of the changes in blood CO2/H+ composition. Our results support the existence of a system capable of controlling blood PaCO2 homeostasis when the metabolism increases independent of peripheral and central respiratory chemoreceptors. Information from the skeletal muscles related to the local vascular response provides the central nervous system with a respiratory stimulus proportional to the rate at which gas are exchanged in the muscles, thereby coupling ventilation to the metabolic rate.