Reflexes from the larynx induce cessation of breathing in newborn animals. The magnitude of respiratory inhibition is inversely related to the level of central chemical input. Recent studies indicate that selective inhibition of Na(+)/H(+) exchanger type 3 (NHE3) activates CO(2)/H(+)-sensitive neurons, resembling the responses evoked by hypercapnic stimuli. Hence, the use of NHE3 inhibitors may reduce reflexly mediated respiratory depression and duration of apnea in the neonatal period. This possibility was examined in decerebrate, vagotomized, ventilated, and paralyzed piglets by testing the effects of i.v. administration of NHE3 blocker S8218 on the response of phrenic nerve amplitude, frequency, and duration of apnea induced by graded electrical stimulation of the superior laryngeal nerve. Superior laryngeal nerve stimulation caused a significant decrease in phrenic nerve amplitude, frequency, minute phrenic activity, and inspiratory time (all p < 0.01) that was proportional to the level of electrical stimulation. Increased levels of stimulation were more likely to induce apnea both during and after cessation of stimulation. NHE3 blocker S8218 reduced the superior laryngeal nerve stimulation-induced decrease in phrenic nerve amplitude, minute phrenic activity, and phrenic nerve frequency (all p < 0.05) and reduced superior laryngeal nerve stimulation-induced apnea and duration of poststimulation apnea (p < 0.05). In six other pigs the brain concentrations of S8218 were measured at different intervals after i.v. administration of the drug and were found to be higher in the brain tissue than plasma at all intervals. These findings suggest that the use of NHE3 blockers may decrease the duration of apnea and possibly reduce the pathophysiologic consequences of potentially life-threatening apnea in infants.