Evidence against the involvement of a cytochrome P-450 mechanism in pulmonary hemodynamics in the newborn pig

Abstract

Control mechanisms operating through a cytochrome P-450 system have emerged lately as a possible important determinant of pulmonary hemodynamics. Their action may be expressed in the adjustment of vascular tone under both physiologic and pathophysiologic conditions. One such condition is the pulmonary constrictor response to hypoxia. The identity of the effector agent, or agents, is not known, though there are data implicating monooxygenase products of arachidonic acid. From this premise, we wanted to evaluate the effect of cytochrome P-450 inhibitors on basal pulmonary vascular tone during normoxia, and their effect upon hypoxic pulmonary vasoconstriction response. Experiments were performed in an isolated, perfused lung preparation from 1- and 7-day-old piglets, and the effects of two cytochrome P-450 inhibitors (metyrapone and ketoconazole) were tested on the perfusion pressure. At 10−5 and 10−4 M, metyrapone caused a modest, but significant, increase in pulmonary pressure (p < 0.05) in 7-day-old preparations, while it was without effect in the 1-day-old preparation. Similarly, ketoconazole at concentrations from 10−6 M upwards increased the perfusion pressure in the older animal (p < 0.01). Responses to the inhibitors were not seen in preparations that had been pretreated with a cyclooxygenase inhibitor (indomethacin, 2.8 × 10−6 M) or a dual cyclooxygenase–lipoxygenase inhibitor (BW755C, 10−5 M). Hypoxic vasoconstriction was marginally enhanced by 10−4 M metyrapone, while it was affected inconsistently by 10−5 M ketoconazole. We conclude that vasoactive agents formed through cytochrome P-450 reactions have a minor role, or no role at all, in the control of pulmonary hemodynamics in the newborn pig.Key words: neonatal pulmonary circulation, hypoxia, metyrapone, ketoconazole.