Central histaminergic neurons are distributed in areas of the medulla and pons concerned with respiratory rhythm generation, but their effects on breathing pattern are unknown. We examined breathing pattern during hypercapnic responses in wild type (WT) and H1 receptor knockout (H1RKO) mice at 9-10 weeks of age before and after vagotomy. Minute ventilation increased with PaCO(2) increase equally in both genotypes; respiratory rate response was lower and tidal volume (V(T)) response higher in H1RKO mice than in WT mice. The V(T)-inspiratory time (T(I)) relation during hypercapnia was hyperbolic in both groups, with the curve in H1RKO mice shifted right-upward. After vagotomy, the V(T)-T(I) relation was a vertical line, which shifted right in H1RKO mice. We conclude that alterations of inspiratory off-switch and respiratory rhythm generation change breathing pattern without affecting central chemosensitivity in H1RKO. Histamine might affect breathing pattern centrally via H1 receptors.