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 lumen into the interstitium. This is also true for bronchial edema. Previous studies have indicated that an elevation of intracellular adenosine-3',5'-cyclic monophosphate (cAMP) or guanosine-3',5'-cyclic monophosphate (cGMP), respectively, can counteract this vascular leakage by improving the endothelial barrier function in analogy to the relaxation of smooth muscle cells. To investigate the potential antiedemateous effects of ularitide acetate (CAS 115966-23-9), isoproterenol hemisulfate (CAS 6078-56-4), sodium nitroprusside (CAS 13755-38-9, SNP), aminophylline (CAS 317-34-0), and combinations of these compounds, their effects on thrombin-induced macromolecular permeability raise in relation to cGMP- or cAMP-levels, respectively, in a model of human umbilical vein endothelial cells (HUVECs) were examined. Ularitide acetate, isoproterenol hemisulfate, and SNP all increased the amount of cyclic nucleotides and decreased the raise in permeability in the following order of potency: isoproterenol hemisulfate > ularitide acetate > SNP. Aminophylline raised both cGMP- and cAMP-levels in a weaker amount and was not able to decrease the thrombin-induced permeability raise on its own. By way of contrast, preincubation of HUVECs with aminophylline resulted in a more than additive potentiation of the cGMP-levels and the permeability lowering induced by ularitide-acetate. These in vitro-data indicate that ularitide-acetate, especially in combination with phosphodiesterase (PDE) inhibitors, could probably have beneficial effects in bronchial permeability edema.
Korn
C
C
Pharmaceutical-Chemical Institute, University of Heidelberg, Germany.
Neidlein
R
R
Strein
K
K
Wilhelms
O H
OH
D000418:Albumins / Q000378:metabolism; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D001993:Bronchodilator Agents / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D005260:Female; D006801:Humans; D010446:Peptide Fragments / Q000494:pharmacology*; D011247:Pregnancy; D013917:Thrombin / Q000494:pharmacology*; D014343:Trypan Blue
D000418:Albumins; D001993:Bronchodilator Agents; D010446:Peptide Fragments; C056452:Ularitide; D009320:Atrial Natriuretic Factor; D000242:Cyclic AMP; D013917:Thrombin; D006152:Cyclic GMP; D014343:Trypan Blue