Prostaglandin E1 Increases cGMP Levels in Beating Rabbit Atria: Lack of Effects of PGE1-induced Cyclic Nucleotides on Secretory and Contractile Functions

Members of prostaglandin (PG) E-series elicit cellular effects mainly through adenylyl cyclase-cAMP signaling. The role of PGE2-induced increase in cAMP has been shown to be compartmentalized in the cardiac myocytes: PGE2-induced increase of cAMP is not involved in the control of cardiomyocytic contraction. The purpose of the present study was to define the effect of PGE1 on the cGMP levels and the role of PGE1 in the atrial secretory function. Experiments were performed in perfused beating rabbit atria and atrial contractile responses, cGMP and cAMP efflux, and atrial natriuretic peptide (ANP) secretion were measured. PGE1 increased cGMP as well as cAMP efflux concentration in a concentration-dependent manner, however, no significant changes in atrial secretory responses were observed (with 1.0microM PGE1; for cGMP, 144.76+/-37.5%, n=11 versus -16.81+/-4.76%, n=6, control, p<0.01; for cAMP, 187.60+/-41.52%, n=11 versus 7.38+/-19.44%, n=6, control, p<0.01). PGE1 decreased atrial dynamics slightly but transiently, whereas PGE2 showed similar effects but with lower potency. Isoproterenol increased atrial cAMP efflux (with 2.0 nM; 145.71+/-41.89, n=5 versus 7.38+/-19.44%, n=6, control, p<0.05) and mechanical dynamics and decreased ANP secretion. The PGE1-induced increase in cGMP efflux showed a bell-shaped concentration-response curve. PGE1-induced increase of cGMP efflux was not observed in the presence of L-NAME, an inhibitor of nitric oxide (NO) synthase, or ODQ, an inhibitor of NO-sensitive guanylyl cyclase. L-NAME and ODQ showed no significant effect on the PGE1-induced transient decrease of atrial dynamics. These data indicate that PGE1 increases cGMP levels via NO-soluble GC signaling in the cardiac atrium and also show that PGE1-induced increases in cGMP and cAMP levels are not involved in the regulation of atrial secretory and contractile functions.

Effects of Phosphodiesterase 5 Inhibition with Sildenafil on Atrial Contractile and Secretory Function

Selective inhibition of phosphodiesterase (PDE) 5 opened a new therapeutic approach for cardiovascular disorders. Therefore, the effect of PDE5 inhibition on the cardiac function should thoroughly be defined. The purpose of the present study was to define the effects of sildenafil, a selective inhibitor of PDE5, on the atrial cGMP efflux, atrial dynamics, and the release of atrial natriuretic peptide (ANP). By perfusing rabbit left atria to allow atrial pacing, changes in atrial stroke volume and pulse pressure, transmural extracellular fluid translocation, cGMP efflux, and ANP secretion were measured. SIN-1, an NO donor and soluble (s) guanylyl cyclase (GC) activator, and C-type natriuretic peptide (CNP), an activator of particulate (p) GC activator, were used. Sildenafil increased basal levels of cGMP efflux slightly but not significantly. Sildenafil in a therapeutic dose increased atrial dynamics (for atrial stroke volume, 2.84+/-1.71%, n=12, vs -0.71+/-0.86%, n=21; p<0.05) and decreased ANP release (-9.02+/-3.36%, n=14, vs 1.35+/-3.25%, n=23; p<0.05), however, it had no effect on the SIN-1- or CNP-induced increase of cGMP levels. Furthermore, sildenafil in a therapeutic dose accentuated SIN-1-induced, but not CNP-induced, decrease of atrial pulse pressure and ANP release. These data indicate that PDE5 inhibition with sildenafil has a minor effect on cGMP levels, but has a distinct effect on pGC-cGMP- and sGC-cGMP-induced contractile and secretory function.

Ca2+-induced Ca2+ Release from Sarcoplasmic Reticulum Negatively Regulates Myocytic ANP Release in Beating Rabbit Atria

It is not clear whether Ca2+-induced Ca2+ release from the sarcoplasmic reticulum (SR) is involved in the regulation of atrial natriuretic peptide (ANP) release. Previously, we have shown that nifedipine increased ANP release, indicating that Ca2+ entry via voltage-gated L-type Ca2+ channel activation decreases ANP release. The purpose of the present study was two-fold: to define the role of SR Ca2+ release in the regulation of ANP release and whether Ca2+ entry via L-type Ca2+ channel is prerequisite for the SR-related effect on ANP release. Experiments were performed in perfused beating rabbit atria. Ryanodine, an inhibitor of SR Ca2+ release, increased atrial myocytic ANP release (8.69+/-3.05, 19.55+/-1.09, 27.31+/-3.51, and 18.91+/-4.76% for 1, 2, 3, and 6microM ryanodine, respectively; all P< 1) with concomitant decrease in atrial stroke volume and pulse pressure in a dose-dependent manner. In the presence of thapsigargin, an inhibitor of SR Ca2+ pump, ryanodine-induced increase in ANP release was not observed. Thapsigargin attenuated ryanodine-induced decrease in atrial dynamic changes. Blockade of L-type Ca2+ channel with nifedipine abolished ryanodine-induced increase in ANP release (0.69+/-5.58% vs. 27.31+/-3.51%; P< 0.001). In the presence of thapsigargin and ryanodine, nifedipine increased ANP release and decreased atrial dynamics. These data suggest that Ca2+-induced Ca2+ release from the SR is inversely involved in the regulation of atrial myocytic ANP release.