Substance P is a vasoactive peptide. Nerve fibers containing substance P are present in the media of pulmonary arteries but the physiologic function of substance P in the pulmonary vasculature is unknown. Several doses of substance P were infused intravenously in the anesthetized dog to ascertain its effects on the pulmonary vasculature, both during normoxia and following preconstriction with hypoxia (F1O2 0.1) or prostaglandin F2 alpha (PGF2 alpha 5 mug/kg/min). Substance P resulted in systemic vasodilation during normoxia but had minimal effect on the pulmonary vasculature. During hypoxia and PGF2 alpha-induced pulmonary vasoconstriction, substance P significantly lowered pulmonary artery pressure, pulmonary vascular resistance, mean aortic pressure, and total systemic resistance. It had no effect on cardiac output, wedge pressure, and arterial blood gases. To investigate possible mechanisms for substance P-induced vasodilation, substance P was studied following pretreatment with N-acetylcysteine (a radical scavenging agent), methylene blue (an inhibitor of guanylate cyclase), meclofenamate (a cyclooxygenase inhibitor), and atropine (a muscarinic receptor antagonist). None of these agents impaired substance P-induced vasodilation. Substance P given intravenously is a nonselective vasodilator in the dog but the mechanism of its action remains uncertain.