The effects of forebrain stimulation on the pulmonary vascular bed were investigated in the intact-chest cat under conditions of controlled blood flow and constant left atrial pressure. When pulmonary vascular tone was raised to a high steady level, direct electrical stimulation of the forebrain elicited a biphasic change in lobar arterial pressure. The response was characterized by an initial transient increase in lobar arterial pressure that was followed by a prolonged secondary decrease in pressure. When a delay coil was added to the extracorporeal perfusion circuit, the secondary vasodilator response was separated into initial brief and delayed prolonged components, suggesting that it was mediated in part by the release of a humoral factor. The entire response to forebrain stimulation was abolished by cervical cord section or freezing. The initial constrictor response and early brief dilator response were not blocked by classic pharmacological blocking agents. The delayed humorally mediated vasodilator response was blocked by propranolol or ICI 118551, indicating that it was mediated by a circulating factor with beta 2-stimulating properties. The delayed vasodilator response was associated with a large increase in arterial epinephrine levels, and this rise in plasma epinephrine was not altered by propranolol. The present data suggest that electrical stimulation of the forebrain causes a prolonged pulmonary vasodilator response that is mediated by way of a descending pathway, which results in a large rise in arterial epinephrine levels.