COMPARISON OF THE EFFECTS OF ULARITIDE ACETATE AND OTHER BRONCHORELAXING SUBSTANCES ON THE THROMBIN-INDUCED PERMEABILITY RAISE OF HUMAN ENDOTHELIAL-CELL MONOLAYERS

Endothelial cell contraction plays a pivotal role in vascular leakage. It increases the extravasation of fluid and macromolecules from the l umen into the interstitium. This is also true for bronchial edema. Pre vious studies have indicated that an elevation of intracellular adenos ine-3',5'-cyclic monophosphate (cAMP) or guanosine-3',5'-cyclic monoph osphate (cGMP), respectively, can counteract this vascular leakage by improving the endothelial barrier function in analogy to the relaxatio n of smooth muscle cells. To investigate the potential antiedemateous effects of ularitide acetate (CAS 115966-23-9), isoproterenol hemisulf ate (CAS 6078-56-4), sodium nitroprusside (CAS 13755-38-9, SNP), amino phylline (CAS 317-34-0), and combinations of these compounds, their ef fects on thrombin-induced macromolecular permeability raise in relatio n to cGMP- or cAMP-levels, respectively, in a model of human umbilical vein endothelial cells (HUVECs) were examined. Ularitide acetate, iso proterenol hemisulfate, and SNP all increased the amount of cyclic nuc leotides and decreased the raise in permeability in the following orde r of potency: isoproterenol hemisulfate > ularitide acetate > SNP. Ami nophylline raised both cGMP- and cAMP-levels in a weaker amount and wa s not able to decrease the thrombin-induced permeability raise on its own. By way of contrast, preincubation of HUVECs with aminophylline re sulted in a more than additive potentiation of the cGMP-levels and the permeability lowering induced by ularitide-acetate. These in vitro-da ta indicate that ularitide-acetate, especially in combination with pho sphodiesterase (PDE) inhibitors, could probably have beneficial effect s in bronchial permeability edema.