UP-REGULATION OF ANGIOTENSIN-CONVERTING ENZYME BY ATRIAL-NATRIURETIC-PEPTIDE AND CYCLIC-GMP IN HUMAN ENDOTHELIAL-CELLS

Objective: To examine the role of atrial natriuretic peptide (ANP) and cyclic GMP in the regulation of angiotensin converting enzyme (ACE) i n cultured human endothelial cells. Methods: Cultured endothelial cell s from human umbilical veins (HUVEC) were treated with ANP (0.3-30 nM) , 8-Br-cGMP (1-100 mu M), Rp-8-Br-PET-cGMPS (1 mu M), or the phosphodi esterase inhibitors, zaprinast (10-100 mu M), dipyridamole (1-10 mu M) , or isobutyl methyl xanthine (IBMX, 0.1-0.5 mM). ACE amounts were mea sured by inhibitor binding assay and cellular cGMP levels by radioimmu noassay. Results: ANP caused a dose dependent increase in ACE measured in intact endothelial cell culture. The stimulatory effect of ANP was blocked by Rp-8-Br-PET-cGMPS, a protein kinase G inhibitor. The cycli c GMP analog, 8-Br-cGMP and the cyclic GMP specific phosphodiesterase inhibitor, zaprinast, both increased ACE. Increase of ACE was also cau sed by nonspecific phosphodiesterase inhibitors, dipyridamole and IBMX . Intracellular cGMP levels were shown to increase by ANP, and phospho diesterase inhibitors. Conclusions: These data suggest that cGMP is an intracellular mediator regulating ACE and that ANP induced increase o f ACE is mediated via a cGMP dependent mechanism. (C) 1998 Elsevier Sc ience B.V. All rights reserved.