Role Of Pgc-cgmp-pde3 Signaling In Hyperthyroid Beating Rabbit Atria

Objective The role of C-type natriuretic peptide (CNP) in the pathophysiology of atrial function in hyperthyroidism has not been defined. The present investigation was designed to define the role of C-type natriuretic peptide (CNP)-activated particulate (p) guanylyl cyclase (GC)-cGMP-phosphodiesterase (PDE)3 signaling in the regulation of cAMP levels, contractile and secretory functions in the atria from hyperthyroid rabbits. This study will demonstrate the characteristic of cGMP-PDE3-cAMP signaling in pathophysiology, and provide an important theory to treat heart disease.Methods New Zealand White rabbits were used. The experimental model was an isolated beating atria. The beating atria were perfused for 60 min to stabilize atrial dynamics and hormone secretion. [3H]Inulin was introduced to the pericardial fluid 20 minutes before the start of the sample collection. The perfusate was collected at 2-min intervals and 42 tubes in all. The samples were preserved at 4℃for analyses. Experiment were carried out using four groups of atria. Sham-and thyroine (T4)-treated rabbits were divided into CNP and milrinone (Mil) plus CNP groups. Control period (four 12-min period) were followed by an infusion of CNP, an activator of pGC, (100 nM; group 1, n=7, Sham-treated; group 3, n=6, T4-treated). To analyze the effects of pGC,36 min of milrinone, an inhibitor of PDE3, was followed by an infusion of CNP [milrinone (1μM) plus CNP(100 nM); group 2, n=4, Sham-treated; group 4, n=6, T4-treated]. The concentrations of cGMP, cAMP and atrial natriuretic peptide. (ANP) in perfusate were measured by radioimmunoassay. The effects were evaluated after 36 min of administration of the agent.Results①In euthyroid atria from Sham-treated rabbits, CNP (100 nM) increased cGMP and cAMP efflux by 176.7±17.7 and 55.3±10.0%, respectively. CNP decreased stroke volume, pulse pressure and ANP release by 51±7,41±2 and 60.4±3.2%, respectively. Pretreatment with milrinone blocked the CNP-induced increase of cAMP but without significant changes in decrease of atrial dynamics and ANP release. ②In hyperthyroid atria, CNP-induced increase of cGMP levels was accentuated, while CNP-induced increase of cAMP was attenuated. CNP rather increased atrial dynamics in hyperthyroid atria instead of decrease. CNP-induced decrease in atrial ANP release was attenuated. Pretreatment with milrinone blocked the CNP-induced increase of cAMP levels concomitantly with a decrease of atrial dynamics.Conclusions The present study demonstrates that altered role of CNP-activated pGC-cGMP-PDE3-cAMP signaling is involved in the pathophysiology of hyperthyroid heart.