Nitric oxide (NO) has been implicated in a number of diverse physiologic processes, including regulation of vascular tone. Carbon monoxide (CO) is another endogenously generated diatomic gas that may play an important physiologic role in vascular smooth muscle homeostasis. The purpose of this study was to compare the responses to exogenous NO and CO in isolated vessels (pulmonary arteries, pulmonary veins, and mesenteric arteries) from 12- to 24-h-old and 2-wk-old piglets. Vessels precontracted with the thromboxane A(2) mimetic U46619 (10(-7) M) relaxed in response to CO (2 x 10(-6) to 2 x 10(-4) M) and NO (2 x 10(-9) to 2 x 10(-7) M); these effects were not affected by endothelium removal but were completely abolished by the soluble guanylate cyclase inhibitor ODQ (10(-5) M). In pulmonary arteries, the maximal relaxation to NO increased with postnatal age from 33 +/- 4% of the precontraction value to 56 +/- 5%, in 12- to 24-h-old and 2-week-old piglets, respectively (p < 0.01), but the response to CO decreased from 25 +/- 3% to 12 +/- 1%, respectively (p < 0.01). The maximal response to CO was greater in pulmonary veins than in pulmonary or mesenteric arteries for both age groups (p < 0.01). Vasorelaxation induced by endogenous NO (stimulated by acetylcholine) was also greater in pulmonary veins when compared with pulmonary arteries and increased with postnatal age in both vessels. In contrast, no age-related differences were observed in the vasorelaxation induced by the cGMP analog 8-bromo cGMP in pulmonary arteries. When the response to NO was analyzed under three different extracellular O(2) concentrations (PO(2) 4.51 +/- 0.03, 19. 32 +/- 0.17, and 86 +/- 0.62, kPa), no significant differences were found. However, in the presence of superoxide dismutase (100 U/mL). the response to CO remained unchanged, and the response to NO improved in pulmonary arteries from 2-week-old but not from newborn piglets. In conclusion, both NO and CO relaxed neonatal vessels through soluble guanylate cyclase activation. However, when compared with NO, CO exhibited a poor vasorelaxant activity. Pulmonary vasorelaxation induced by NO increased with postnatal age, whereas that induced by CO decreased. Changes in extracellular oxygen concentration did not alter the pulmonary vascular response to NO. However, the presence of superoxide dismutase improved the response to NO, indicating that oxidant activity limits the vasorelaxant response to NO but not to CO.