Effects Of Prostaglandin D2on Atrial Natriuretic Peptide Secretion In Perfused Beating Rat Atria

Natriuretic peptides (NPs) as a family of cardiac hormone play important roles in homeostasis including natriuretic diuresis, electrolyte balance, and regulation of blood pressure, cell proliferation as well as cellular differentiations. It has been found that there are three kinds of NPs in mammalian including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). Dendroaspis natriuretic peptide (DNP), another member of NPs, has been found from the green mamba dendroaspis (angusticeps) and has been shown to immunoreactions in human plasma.ANP is mainly synthesized and secreted by myocardial cells and to distribute various tissues including the heart, blood vessels, the central nervous system, lymphatic, and kidney tissues. ANP plays various biological roles via combining NPs receptors A or C (NPRA or NPRC). ANP binds to NPRA receptor and activates G protein coupled guanylate cyclase, by which results in an increasing of intracellular guanosin3’,5’-cyclic monophosphate (cGMP) sequently leads to regulation of cellular functions. NPR-C is a receptor without guanylate cyclase and mainly to clearencs for the NPs. While, it has also been reported that NPR-C may participates to signal transduction by activation of the pertussis toxin sensitive G protein.The secretion of ANP is affected by several factors such as physical, body fluids, and nervous. Atrial mechanical stretch is the most important factor for the governing of ANP secretion. Except for cardiac ischemia (hypoxia), it has been reported that several paracrine factors such as endothelin-1(ET-1), nitric oxide (NO), angiotensin II, and vasopressin are involved in regulation of the ANP secretion. ET-1is one of the most important stimuli for the ANP secretion. However, prostaglandins (PGs) metabolized by arachidonic acid is a eventually modulator for the ANP secretion with atrial tension, ischemia, and ET-1.PGs, a kind of fatty acids derived hormone, distributed to various body tissues and play important roles in the regulation of cellular biological activities easpecially in cardiovascular system. It has been demonstrated that PGs including PGF2a, PGE2, PGI2, and PGD2were synthesized in the cardiac myocyte and to participated myocardial hypertrophy, myocardial infarction and myocardial fibrosis. Early researches showed that atrial ANP secretion was mediated by PGs. However, the mechanism by which PGD2to regulates atrial ANP secretion is not clear.The purpose of the present study, therefore, is to ingestigate the mechanism of PGD2on the regulation of atrial ANP secretion in isolated beating rat atria.The results of the present study showed that:1. PGD2(1.0umol/L) significantly increased atrial secretion of ANP (P<0.001vs control) and showed time-dependant manner. The atrial pulse pressure was also increased by PGD2(P<0.01vs control).2. L-type Ca2+channel blocker nifedipine (1.0μmol/L) atenuated PGD2-increased atrial ANP secretion (P<0.01vs PGD2cycle) without changed of PGD2-promoted atrial pulse pressure (P<0.01vs control).3. PKA blocker H-89(1.0μmol/L) was also attenuated the effect of PGD2-induced atrial ANP secretion (P<0.01vs PGD2cycle), but failed to modulation of PGD2-promoted atrial pulse pressure (P<0.01vs control).4. Staurosporine (0.3μmol/L), a non selective inhibitor of protein kinases, inhibited PGD2-increased atrial ANP secretion (P<0.05vs PGD2cycle, P<0.001vs staurosporine cycle) and PGD2-increased atrial pulse pressure (P<0.01vs staurosporine cycle).5. MAPK/ERK blocker PD98059(30.0μmol/L) was also attenuated PGD2-increased atrial ANP secretion (P<0.015vs PGD2cycle, P<0.01vs PD98059cycle) with inhibition of the PGD2-inceased atrial pulsation pressure (P>0.05vs PD98059cycle).6. PGD2-promoted atrial ANP secretion (P<0.01vs PD98059+PGD2cycle, P>0.05vs PD98059+H89cycle) and pulse pressure (P>0.05vs PD98059+H89cycle) were completely blocked by PD98059combined with H-89.7. Western blotting results showd that PGD2significantly increased atrial ERK1/2phosphorylation in atrial myocytes (P<0.05vs. control). PD98059and/or PD98059plus H-89completely blocked the effect of PGD2-promoted atrial ERK1/2phosphorylation (P<0.05vs PGD2, P>0.05vs control).8. PD98059combined with nifedipine was also completely inhibited the effect of PGD2-increased atrial ANP secretion (P<0.01vs PD98059+PGD2cycle, P>0.05vs PD98059+nifedipine cycle) and pulse pressure (P>0.05vs PD98059+nifedipine cycle). 9. PTK inhibitor genistein (30.0μmol/L) completely blocked the effect of PGD2-increased atrial MAPK/ERK phosphorylation (P<0.05vs PGD2group) concomitantly with inhibition of PGD2-dinced atrial ANP secretion (P<0.001vs PGD2cycle, P<0.05genistein cycle) as well as atrial pulse pressure (P>0.05genistein cycle).10. PD98059combined with genistein completely inhibited the effect of PGD2-promoted atrial ANP secretion (P<0.01vs PGD2cycle, P>0.05vs genistein+PD98059cycle) and pulse pressure (P>0.05vs genistein+PD98059cycle).These results indicate that:1. PGD2significantly increased atrial ANP secretion and pulse pressure in rats.2. PGD2increased atrial ANP secretion was mediated by PTK and PKA-ERK signaling pathway.