EFFECTS OF INHIBITORS OF EDRF AND EDHF ON VASOREACTIVITY OF PERFUSED RAT LUNGS

Recent studies indicate that the endothelium of isolated rat pulmonary arteries releases two different factors, endothelium-derived relaxing factor (EDRF) and hyperpolarizing factor (EDHF), which participate in histamine-and acetylcholine-induced relaxation. There is evidence for EDRF vasoreactivity in perfused lungs, but a role for EDHF, which hyperpolarizes vascular smooth muscle by activating membrane K+ channels, has not been reported. We used the inhibitors of EDRF, 20-mu-M hemoglobin, 200-mu-M N(G)-monomethyl-L-arginine, and 2 mM L-canavanine, the nonselective blocker of K+ channels, 10 mM tetraethylammonium (TEA), and the inhibitor of ATP-sensitive K+ channels, 20-mu-M glibenclamide, to compare the roles of EDRF and EDHF in the vasoregulation of meclofenamate-treated, salt solution-perfused rat lungs. The three EDRF inhibitors had little or no effect on baseline perfusion pressure, but each potentiated the peak pressor response to airway hypoxia. Neither of them inhibited the pulmonary vasodilation to 5-mu-M histamine. TEA, but not glibenclamide, increased baseline pressure and potentiated the peak hypoxic response. Both K+ channel blockers, but not the EDRF inhibitors, also prolonged the hypoxic response by reducing the rate of spontaneous vasodilation. TEA, but not glibenclamide, inhibited histamine vasodilation. These results suggest roles for both EDRF and EDHF in the control of rat pulmonary vascular reactivity. EDRF is apparently not responsible for the low vascular tone of the normoxic lung and does not mediate the vasodilation to histamine, but it does modulate the hypoxic pressor response. The exact role of EDHF is uncertain, but it may also modulate hypoxic vasoconstriction and mediate at least part of the histamine vasodilation.