Magnesium sulfate (MgSO4) has been proposed to be an efficient treatment in persistent pulmonary hypertension of the newborn. We compared the ability of MgSO4 to inhibit the responses to several vasoconstrictors in isolated intrapulmonary and mesenteric arteries from 10-17-d-old piglets. MgSO4 (3-100 mM) produced a slight vasodilator effect in pulmonary arteries precontracted with the thromboxane A2 mimetic U46619 (10(-6) M), noradrenaline (10(-5) M), and KCl (80 mM) (15.1 +/- 3.7%; 20 +/- 3.33%; 10.4 +/- 0.9% at 100 mM MgSO4 respectively). In contrast, in mesenteric arteries MgSO4, produced a marked vasodilation (80.4 +/- 4.0%, 93.1 +/- 3.46%, and 87.5 +/- 1.93% at 100 mM MgSO4, respectively, p < 0.01 versus pulmonary arteries). The vasodilator effect of MgSO4 was endothelium-independent and reversed by increasing the extracellular Ca2+ concentration. After incubation for 1 h of pulmonary arteries with three different MgSO4 concentrations (0, 1.2, and 4.8 mM) there were no differences in the contractile responses to U46619 nor in the vasodilator effects of acetylcholine or sodium nitroprusside. Rapid removal of Mg2+ from bath medium produced a transient vasodilation which was more marked in pulmonary than in mesenteric arteries and was greatly reduced by the removal of endothelium or by the nitric oxide synthase inhibitor L-NAME (10(-4) M). We conclude that MgSO4 is a poor vasodilator of pulmonary arteries in vitro and at physiologic concentrations appears to inhibit nitric oxide release from the pulmonary endothelium. Thus, the possible beneficial clinical effects of MgSO4 in persistent pulmonary hypertension of the newborn do not seem to be related to a direct effect on pulmonary vascular smooth muscle.