Myocardial production of prostaglandins: its role in atrial natriuretic peptide release

Abstract

In recent years, considerable evidence has been accumulated on prostaglandins (PG) in modulating atrial natriuretic peptide (ANP) release. In the current study we investigated whether eicosanoids promote isoproterenol-induced ANP secretion from superfused rabbit sliced atria. Inclusion of the cyclooxygenase inhibitor indomethacin (10 mumol) to the superfusing medium abolished isoproterenol-induced ANP release. Next, PGE2, but not PGF2 alpha or PGI2 (10 mumol), increased ANP release. Furthermore, isoproterenol-induced PGE2 formation was fully attenuated by indomethacin. Dibutyl-cAMP (0.5 mmol) had no effect on PGE2 formation, and the protein kinase A (PKA) inhibitor H89 (20 mumol) did not alter isoproterenol-induced PGE2 formation. On the other hand, indomethacin led to a significant decrease in isoproterenol-induced cAMP production. In addition, PGE2 enhanced basal cAMP concentration in superfusates. Superfusion of sliced atria by forskolin (10 mumol) or by dibutyl-cAMP (0.5 mmol) produced a significant rise in ANP release. Finally, H89 was ineffective on basal ANP release but abolished the increase of ANP release in response to isoproterenol or to PGE2. We conclude that: the effect of isoproterenol on ANP release is sensitive to indomethacin and H89; PGE2, but not PGE2 alpha or PGI2, increases ANP release; isoproterenol promotes myocardial PGE2 formation independently of adenylate cyclase and PKA activation pathways; and PGE2-induced ANP release is mediated by cAMP production and subsequent PKA activation. These results suggest that isoproterenol-induced ANP release appears to be mediated at least partly by PGE2 with underlying cAMP formation and PKA activation.

Protein kinase-dependent and Ca2+-independent cAMP inhibition of ANP release in beating rabbit atria

“…The present data are in agreement with previous reports showing an inhibition in ANP secretion by forskolin (12,20,25,30) or IBMX (12) in cultured atrial myocytes or perfused rat hearts. However, the present data contrast to the previous reports on the stimulation of ANP release by cAMP-elevating agents (1,5,24) in cultured cardiac myocytes, isolated atria, or perfused rat hearts. The reasons for the discrepancy are not clear at present.…”

“…Forskolin, an activator of adenylyl cyclase (AC), has been shown to decrease ANP release from cultured atrial myocytes (12,20,30) and perfused rat heart (25); 3-isobutyl-1-methylxanthine (IBMX), a nonselective inhibitor of cyclic nucleotide phosphodiesterase (PDE) (12), and 8-bromoadenosine 3Ј,5Ј-cyclic monophosphate (8-BrcAMP) (12, 30), have also been shown to inhibit ANP secretion. In contrast, it has also been shown that cAMP-elevating agents (1,5,24) and cell membranepermeant cAMP analogs (1,5,27,28) increase ANP secretion in cultured cardiac myocytes (5), sliced atria (1), isolated atria (27,28), and perfused rat heart (24). Hence, the current understanding of cAMP-dependent regulation of ANP secretion is controversial.…”

Role of cell contractions in cAMP-induced cardiomyocyte atrial natriuretic peptide release

“…Overall, these findings are consistent with previous observations indicating that the cAMP-elevating agents forskolin and PGE 2 promote ANP secretion in spontaneously contracting, cultured neonatal rat ventricular cardiomyocytes (6) and further appear to resolve a number of questions related to the effects of cAMP on myocardial ANP release. Indeed, it has previously been demonstrated that cAMP-elevating agents and mimetics such as norepinephrine, calcitonin gene-related peptide, and dibutyryl cAMP promote significant ANP secretion in the paced adult rat heart, paced atria, atrial slices, and/or dispersed rat atrial cells (2,8,19,22,23,26,33), suggesting that cAMP is a positive stimulus for myocardial ANP secretion. Nevertheless, studies investigating the effect of forskolin, phosphodiesterase inhibitor, or ␤-adrenergic receptor stimulation in cardiomyocyte cultures have clearly shown that increases in cellular cAMP formation promote a decrease in ANP release (1,10,11,28), suggesting that cAMP is actually an inhibitor of ANP secretion in isolated cardiomyocyte systems.…”

Mechanisms of atrial natriuretic peptide secretion from the atrium

“…This suggested that PGF 2 a may act as a direct mediator of the stretchinduced ANP response. Others have reported that prostaglandins are a potent stimulator of ANP secretion in rat ventricular myocytes [87,88] and rabbit atria sections [89]. Calmidazolium, a calmodulin inhibitor, suppresses both basal and stretch-stimulated ANP secretion [86] while other calmodulin inhibitors attenuated ANP stimulation by PGF 2 a [89].…”

“…Others have reported that prostaglandins are a potent stimulator of ANP secretion in rat ventricular myocytes [87,88] and rabbit atria sections [89]. Calmidazolium, a calmodulin inhibitor, suppresses both basal and stretch-stimulated ANP secretion [86] while other calmodulin inhibitors attenuated ANP stimulation by PGF 2 a [89]. The cyclooxygenase inhibitor, indomethacin, inhibits prostaglandin synthesis in vitro and reduces basal ANP secretion [61,90].…”