Role of cAMP and calcium influx in endothelin-1-induced ANP release in rat cardiomyocytes.
The mechanism of endothelin-1 (ET-1)-induced atrial natriuretic peptide (ANP) release was studied in neonatal rat ventricular cardiomyocytes. These cells expressed a single high-affinity class of ETA receptor (dissociation constant = 54 +/- 18 pM, n = 3), but no ETB receptors. Incubation of cardiomyocytes with ET-1 led to concentration-dependent ANP release and prostacyclin production. ET-1-induced ANP release was affected by neither protein kinase C (PKC) inhibition or downregulation nor by cyclooxygenase inhibition, indicating that ET-1-stimulated ANP secretion is not a PKC-mediated, prostaglandin-dependent process. Furthermore, ET-1 significantly stimulated adenosine 3',5'-cyclic monophosphate (cAMP) production and increased cytosolic calcium concentration in these preparations. Both ET-1-induced calcium influx and ANP release were decreased by the cAMP antagonist Rp-cAMPS, the Rp diastereoisomer of cAMP. Moreover, ET-1-induced ANP secretion was strongly inhibited in the presence of nifedipine as well as in the absence of extracellular calcium. Thus our results suggest that ET-1 stimulates ANP release in ventricular cardiomyocytes via an ETA receptor-mediated pathway involving cAMP formation and activation of a nifedipine-sensitive calcium channel.
Rebsamen
M C
MC
Division of Endocrinology and Diabetology, University Hospital, Geneva, Switzerland.
Church
D J
DJ
Morabito
D
D
Vallotton
M B
MB
Lang
U
U
D000470:Alkaloids; D000818:Animals; D000831:Animals, Newborn; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis*; D053119:Benzophenanthridines; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D019332:Endothelin-1 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000096:biosynthesis; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles; D007700:Kinetics; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009281:Naphthalenes / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D010617:Phenanthridines / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000096:biosynthesis / Q000502:physiology; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology
D000470:Alkaloids; D053119:Benzophenanthridines; D016861:Cyclooxygenase Inhibitors; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D010617:Phenanthridines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D013873:Thionucleotides; C016957:adenosine-3',5'-cyclic phosphorothioate; D004533:Egtazic Acid; D009320:Atrial Natriuretic Factor; D011464:Epoprostenol; D000242:Cyclic AMP; C016299:chelerythrine; D011493:Protein Kinase C; D019311:Staurosporine; C058819:calphostin C; D009543:Nifedipine; C059539:midostaurin; D002118:Calcium