STIMULATION OF ATRIAL-NATRIURETIC-PEPTIDE RELEASE BY NEUROKININS IN NEONATAL RAT VENTRICULAR CARDIOMYOCYTES

The effect of substance P (SP) on atrial natriuretic peptide (ANP) rel ease was studied in neonatal rat ventricular cardiomyocytes. Incubatio n of cells with SP led to a marked increase in ANP secretion, a respon se accompanied by increases in alpha-type protein kinase C (PKC) in th e membranous cell fraction and 6-keto-prostaglandin F-1 alpha (6-keto- PGF(1 alpha)) formation and a small increase in adenosine 3',5'-cyclic monophosphate (cAMP) production. A role for PKC in SP-induced 6-keto- PGF(1 alpha) formation and ANP release was apparent insofar as the res ponses were supressed by PKC inhibitors and in PKC-downregulated cells . Furthermore, SP-induced 6-keto-PGF(1 alpha) production was strongly correlated with SP-induced ANP secretion (r = 0.91, P < 0.0001, n = 27 ), suggesting a role for prostaglandins in SP-mediated ANP release. Su pporting this, indomethacin abolished SP-induced ANP release, whereas PGE(2), PGF(2 alpha), and prostacyclin (PGI(2)) promoted ANP secretion in this system. Both the profile of SP-induced cAMP production and re sults obtained with prostaglandin antagonists suggest that a prostanoi d FP receptor is at the basis of this response. Finally, both neurokin ins A and B induced similar ANP responses, whereas cultured cells were found to contain mRNA transcripts coding for both neurokinin NK1 and NK3 receptor subtypes. Overall, these results suggest that SP induces ANP secretion in neonatal ventricular cardiomyocytes through a PKC- an d prostaglandin-dependent signaling pathway.