The effects of whole body hypothermia on metabolism, blood and medullary acid-base, and respiratory variables were determined in 29 paralyzed, vagotomized and glomectomized cats. Respiratory output was quantified from integrated phrenic nerve activity. Metabolic rate (VCO2) decreased progressively as temperature decreased. When end-tidal PCO2 was kept constant by decreasing artificial ventilation, cooling of the brain to 30.5 degrees C resulted in a large decrease of respiratory frequency (f) with prolongations of both inspiratory (TI) and expiratory (TE) times but an increase in neural tidal activity (VTN). Neural minute activity (MVN) and rate of rise of phrenic activity (RR) decreased moderately despite an acid shift of arterial and medullary extracellular fluid (ECF) pH and a decrease in the fractional dissociation of imidazole (alpha Im). Anesthesia, decerebration and spinal cord section at C7-T1 did not alter the responses. When ventilation was kept constant during cooling so that PCO2 decreased along with metabolic rate, all respiratory variables (VTN, f, MVN and RR) decreased significantly and reached near apneic levels at 30.5 degrees C. These changes were associated with an alkaline shift in ECF pH. Fractional dissociation of imidazole (alpha Im) remained constant at all temperatures. Our findings do not support the hypothesis of 'alphastat' regulation as a general explanation of central chemical control of breathing in homeotherms. We also present arguments that it may not apply to the control of breathing in ectotherms. We conclude that hypothermia affects both respiratory drive and timing mechanisms through its effect on neural synaptic function.