Epidermal growth factor augments reactivity to angiotensin II in the rat pulmonary circulation

To determine if epidermal growth factor (EGF), a vascular smooth muscle mitogen exhibiting systemic vasoactivity, causes constriction or dilation of the pulmonary vascular bed, this study evaluated the actions of EGF in isolated, buffer-perfused rat lungs and in isolated rat pulmonary arteries. In perfused rat lungs with baseline vasomotor tone, EGF administered at bolus doses of 10^-9 to 3 x 10^-7 M failed to exert either constrictor or dilator actions or to promote edema formation as evidenced by a constant lung wet-to-dry-weight ratio. Elevation of baseline tone with either prostaglandin (PG)F(2alpha) or angiotensin II also failed to unmask an effect of EGF on pulmonary vascular resistance. In contrast to these negative observations, pretreatment with 5 x 10^-8 M EGF consistently augmented pressor responses evoked by angiotensin II. Constrictor responses to potassium chloride and to PGF(2alpha) were unaffected by EGF pretreatment. In isolated rat extrapulmonary arteries, EGF provoked contraction in 40% of the preparations studied. Responsive vessels exhibited maximal EGF-induced contractions that were approximately 25% of that associated with angiotensin II and were characterized by an ED₅₀ of 7 x 10^-8 M. Relaxant activity of EGF could not be demonstrated in isolated arterial preparations with normal resting tone or with tone elevated by addition of norepinephrine to the tissue bath. Endothelial denudation also failed to unmask contractile or relaxant efects of EGF. Similar to its actions in isolated, perfused rat lungs, EGF potentiated contractions of isolated pulmonary arteries induced by angiotensin II. The potentiating effect on angiotensin II responses occured in all vessels studied and did not depend on whether the preparations contracted in response to EGF. Results of this study extend a new biologic property of EGF to the pulmonary circulation: in addition to the possibility that EGF may influence pulmonary vascular structure through promotion of smooth muscle proliferation, the present findings indicate that the mitogen has the potential to influence pulmonary vascular responsiveness to angiotensin II. If such effects occur in the intact organism, it is reasonable to postulate that EGF released in pathologic settings could augment vasoconstrictor influences in the pulmonary circulation and thereby contribute to development of acute pulmonary hypertension.