Increases in blood flow and CO2 return to the heart and lungs at the onset of exercise have been proposed to initiate reflexive feedback which increases ventilation (VE), via mechanoreceptors in the heart and/or intrapulmonary CO2 flow receptors. Both lower body negative pressure (-40 mm Hg) release (LBNP-release) and acute head-down (-30 degrees) tilt (TILT) provide physiological models to focus upon the effects of increased venous return and CO2 flow on VE, without the confounding influence of limb afferents or the descending efferents associated with central command. We examined the ventilatory responses to LBNP-release and TILT while inhaling one of four gas mixtures: a) room air (R); b) 95% O2 (O); c) 95% O2, 1.25% CO2 (LC); and d) 95% O2, 2.25% CO2 (HC). Breath-by-breath measurements for VE end-tidal CO2 (PETCO2), tidal volume (VT), and breathing frequency (fB) were taken. VE and VT for HC were significantly higher (p < 0.05) than those for R, O, and LC throughout the test session, while fB and PETCO2 were not significantly different among the gas treatments. VE increased (p < 0.05) above resting baseline with LBNP-release and TILT for R, O, LC, and HC primarily through an elevation of fB. Further, the maximal change in VE following LBNP-release or TILT were not different among inhaled gas mixtures. However, area under the VE curve following LBNP-release and TILT was higher for HC compared to the other gas mixtures. We conclude that these results are inconsistent with the theory that carotid bodies are essential in driving VE with these models.(ABSTRACT TRUNCATED AT 250 WORDS)