Lead Acetate Induces Epithelium-Dependent Contraction of Airway Smooth Muscle
Animal studies have demonstrated that low-level lead exposure produces hypertension and that lead can cause contraction of vascular smooth muscle directly. The physiological effects of lead have been associated with both stimulation and inhibition of protein kinase C (PKC). Given that vascular smooth muscle contractility is generally enhanced when protein kinase C is activated, we have tested the hypothesis that lead contracts vascular smooth muscle via stimulation of PKC. Helically-cut strips of rabbit mesenteric artery were mounted in muscle baths for measurement of isometric force development. Cumulative addition of lead acetate (10(-10)-10(-3) M) to the muscle bath produced contractions (concentration necessary to produce half-maximal response -log EC50 = 5.16 +/- 0.07). Maximal contraction to lead acetate in arteries denuded of endothelium did not differ from those in intact vessels, supporting the hypothesis that lead-induced contraction is an endothelium-independent event. Contractions to lead acetate were potentiated by the PKC activators, phorbol 12-myristate 13-acetate (TPA; 3 x 10(-7) M) and mezerein (3 x 10(-7) M), as indicated by leftward shifts in the concentration-response curve and increase in the potency of lead (-log EC50 with TPA: 6.94 +/- 0.07; -log EC50 with mezerein: 6.07 +/- 0.04). H-7 (6 x 10(-6) M), an inhibitor of PKC, decreased maximal contraction to lead approximately 65% and slightly, but insignificantly, decreased the potency of lead (-log EC50 = 4.82 +/- 0.1). The inactive phorbol ester, phorbol 12-myristate 13-acetate 4-0-methyl ether (1 x 10(-6) M), did not alter contractile responses to lead (-log EC50 = 4.92 +/- 0.09). Vascular contraction to lead partially depends on extracellular calcium as the L-type voltage-gated calcium channel antagonist, verapamil (3 x 10(-6) M), decreased lead-induced contractions by 50%. These data indicate that lead interacts with PKC in an endothelium-independent, calcium-dependent manner to cause vascular smooth muscle contraction and suggest that lead-induced increases in vascular contractility may play a role in lead-induced hypertension.