Mc. Rebsamen et al., ROLE OF CAMP AND CALCIUM INFLUX IN ENDOTHELIN-1-INDUCED ANP RELEASE IN RAT CARDIOMYOCYTES, American journal of physiology: endocrinology and metabolism, 36(5), 1997, pp. 922-931
The mechanism of endothelin-1 (ET-1)-induced atrial natriuretic peptid
e (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. In
cubation of cardiomyocytes with ET-1 led to concentration-dependent AN
P release and prostacyclin production. ET-1-induced ANP release was af
fected 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. Furt
hermore, ET-1 significantly stimulated adenosine 3',5'-cyclic monophos
phate (cAMP) production and increased cytosolic calcium concentration
in these preparations. Both ET-1-induced calcium influx and ANP releas
e were decreased by the cAMP antagonist Rp-cAMPS, the Rp diastereoisom
er of cAMP. Moreover, ET-1-induced ANP secretion was strongly inhibite
d in the presence of nifedipine as well as in the absence of extracell
ular calcium. Thus our results suggest that ET-1 stimulates ANP releas
e in ventricular cardiomyocytes via an ETA receptor-mediated pathway i
nvolving cAMP formation and activation of a nifedipine-sensitive calci
um channel.