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.
D000704:Analysis of Variance; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D000990:Antithrombin III / Q000037:antagonists & inhibitors* / Q000494:pharmacology* / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004347:Drug Interactions; D019332:Endothelin-1 / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D006493:Heparin / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009529:Nicardipine / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology* / Q000502:physiology; D019311:Staurosporine / Q000494:pharmacology; D015854:Up-Regulation