In this study we examined differences in pulmonary vasoreactivity between cattle that were bred to be either susceptible or resistant to the development of severe pulmonary hypertension during hypoxia. We considered that there might be a greater production of endogenous dilator prostaglandin, and therefore less hypoxic pulmonary vasoconstriction, in the resistant cattle. However, the administration of an inhibitor of prostaglandin synthesis, meclofenamate, did not increase the pulmonary pressor response to hypoxia in resistant cattle to the levels recorded in susceptible cattle, thus making the vasodilator prostaglandin hypothesis unlikely. We did observe that the magnitude of the pulmonary vascular response to prostaglandin F(2α), prostaglandin E1, and 5-hydroxytryptamine correlated with the response to hypoxia, suggesting that the degree of responsiveness was not selective for hypoxia. We then considered that varying degrees of lung arteriolar medial hypertrophy might account for the differences in vasoreactivity, both to hypoxia and to the vasoactive substances. Lung biopsies taken from five susceptible and five resistant calves showed greater medial arterial hypertrophy in the susceptible calves. Thus it seemed likely that susceptible calves had more reactive pulmonary vessels than resistant calves because they had more vascular smooth muscle.