Midazolam produces transient hypotension when administered pre-operatively, or to induce sedation. This hypotension appears to be secondary to decreased vascular resistance and vasodilation. The hypothesis that midazolam-induced vasodilation may be mediated in part by the drug's effects on systemic and cerebrovascular prostanoids was tested in 6 newborn piglets (1-3 days old). The piglets were administered a loading dose of 300 ug/kg IV over 15 minutes, followed by a continuous IV infusion of 100 ug/kg/hr for 6 hours. 1.0 ml blood samples from the sagittal sinus vein and carotid artery were collected serially before (0 hr), and during (0.5, 2, 4 & 6 hours) midazolam administration for drug and prostanoid levels. Midazolam and prostanoid levels were determined by high performance liquid chromatography and enzyme immunoassay kits, respectively. Midazolam infusion induced a 78% reduction in systemic PGE2 levels at 30 minutes (p<0.001 vs baseline) which remained attenuated throughout the study. In contrast, cerebrovascular PGE2 levels increased by 60% at 30 minutes (p<0.01 vs baseline) but returned to baseline values by 2 hours. Systemic 6-ketoPGF1α levels increased markedly (180%, p<0.001 vs baseline) at 30 minutes but returned to baseline values by 2 hours. Systemic TxB2 was significantly reduced at 2 hours (p<0.05 vs baseline) and did not return to baseline values up to 6 hours of infusion(p<0.01 vs baseline). Systemic midazolam levels correlated linearly with systemic 6-ketoPGF1α (r=0.512,p<0.0001) and cerebrovascular Ca2+ (r=0.431,p<0.006) levels. These data suggest that the vasodilatory effect of midazolam may be mediated, at least in part, by vasodilator prostanoids. Increased extracellular cerebrovascular Ca2+ levels with increasing systemic midazolam levels indicate that Ca2+ may also be linked to the midazolam-induced cerebrovascular vasodilatory mechanism(s), in the newborn piglet.