Antithrombin increases pulmonary endothelins: inhibition by heparin and Ca2+ channel antagonism

We investigated the mechanism of antithrombin III-induced vascular release of endothelins in rat isolated lung. The antithrombin III-stimulated release of big endothelin-1 and endothelin-1 (1.7-fold and 1.3-fold over baseline) was abolished by nicardipine (L-type Ca2+ channel blocker), heparin, and N-acetyl heparin (a derivative devoid of antithrombin affinity), whereas staurosporine and genistein (inhibitors of protein kinase C and tyrosine kinase, respectively) were ineffective. Thus, (i) the antithrombin III-induced release of endothelins requires extracellular Ca2+, but not protein kinase C or tyrosine kinase activation, and (ii) heparin binding to antithrombin III is not necessary for its inhibitory effect.