Cellular mechanism of natriuretic peptides-induced inhibition of endothelin-1 biosynthesis in rat endothelial cells.
We studied the cellular mechanism by which natriuretic peptides inhibit the synthesis and release of endothelin-1 (ET-1) in cultured rat aortic endothelial cells (EC). Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) showed dose-dependent and equipotent effects on displacement of [125I]ANP binding and generation of cGMP production in rat EC, whereas C-type natriuretic peptide and biologically inactive ANP analog had lesser effects. ANP and BNP as well as 8-bromo-cGMP had potent inhibitory effects on immunoreactive ET-1 release, the transient increase in the intracellular Ca2+ concentration, and the formation of inositol 1,4,5-trisphosphate stimulated by thrombin in rat EC. A cGMP-dependent protein kinase inhibitor (KT5823), but not a cAMP-dependent protein kinase inhibitor (KT5720), completely abolished the inhibitory effect of ANP on thrombin-induced immunoreactive Et-1 release. Northern blot analysis using cDNA for rat prepro-ET-1 as a probe showed that ANP and 8-bromo-cGMP, but not C-type natriuretic peptide, inhibited thrombin-induced prepro-ET-1 mRNA expression, whose effect was abolished by KT5823. These data suggest that ANP and BNP inhibit the thrombin-induced synthesis and release of ET-1 in cultured rat aortic EC by blocking phosphoinositide breakdown, possibly via natriuretic peptides type A receptor-mediated cGMP-dependent mechanism.
Emori
T
T
Second Department of Internal Medicine, Tokyo Medical and Dental University, Japan.
Hirata
Y
Y
Imai
T
T
Eguchi
S
S
Kanno
K
K
Marumo
F
F
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D019332:Endothelin-1; D016232:Endothelins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D007295:Inositol Phosphates / Q000096:biosynthesis; D007425:Intracellular Membranes / Q000378:metabolism; D020097:Natriuretic Peptide, Brain; D020098:Natriuretic Peptide, C-Type; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors; D011498:Protein Precursors / Q000378:metabolism; D051381:Rats; D013917:Thrombin / Q000494:pharmacology
D019332:Endothelin-1; D016232:Endothelins; D007295:Inositol Phosphates; D009419:Nerve Tissue Proteins; D047428:Protein Kinase Inhibitors; D011498:Protein Precursors; D020097:Natriuretic Peptide, Brain; D020098:Natriuretic Peptide, C-Type; C016276:8-bromocyclic GMP; D009320:Atrial Natriuretic Factor; D013917:Thrombin; D006152:Cyclic GMP; D002118:Calcium