الملخص
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.
الموضوعات
Alprostadil , Atrial Function , Atrial Natriuretic Factor , Dinoprostone , Guanylate Cyclase , Isoproterenol , Myocytes, Cardiac , NG-Nitroarginine Methyl Ester , Nitric Oxide , Nucleotides, Cyclicالملخص
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.