Upregulation 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) in cultured human endothelial cells.


METHODS
Cultured endothelial cells from human umbilical veins (HUVEC) were treated with ANP (0.3-30 nM), 8-Br-cGMP (1-100 microM), Rp-8-Br-PET-cGMPS (1 microM), or the phosphodiesterase inhibitors, zaprinast (10-100 microM), dipyridamole (1-10 microM), or isobutyl methyl xanthine (IBMX, 0.1-0.5 mM). ACE amounts were measured by inhibitor binding assay and cellular cGMP levels by radioimmunoassay.


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 cyclic GMP analog, 8-Br-cGMP and the cyclic GMP specific phosphodiesterase inhibitor, zaprinast, both increased ACE. Increase of ACE was also caused by nonspecific phosphodiesterase inhibitors, dipyridamole and IBMX. Intracellular cGMP levels were shown to increase by ANP, and phosphodiesterase inhibitors.


CONCLUSIONS
These data suggest that cGMP is an intracellular mediator regulating ACE and that ANP induced increase of ACE is mediated via a cGMP dependent mechanism.
Saijonmaa
O
O
Minerva Institute for Medical Research, Helsinki University Central Hospital, Finland. outi.saijonmaa@kruuna.helsinki.fi
Fyhrquist
F
F
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology; D004176:Dipyridamole / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D011688:Purinones / Q000494:pharmacology; D013268:Stimulation, Chemical; D013873:Thionucleotides / Q000494:pharmacology; D014471:Umbilical Veins; D014665:Vasodilator Agents / Q000494:pharmacology
D004791:Enzyme Inhibitors; D010726:Phosphodiesterase Inhibitors; D047428:Protein Kinase Inhibitors; D011688:Purinones; D013873:Thionucleotides; D014665:Vasodilator Agents; C098740:8-bromo-beta-phenyl-1,N(2)-ethenoguanosine 3',5'-cyclic monophosphorothioate; C016276:8-bromocyclic GMP; D004176:Dipyridamole; D009320:Atrial Natriuretic Factor; D007703:Peptidyl-Dipeptidase A; C011145:zaprinast; D006152:Cyclic GMP; D015056:1-Methyl-3-isobutylxanthine