Phosphodiesterase 5 restricts NOS3/Soluble guanylate cyclase signaling to L-type Ca2+ current in cardiac myocytes.

摘要: Abstract Endothelial nitric oxide synthase (NOS3) regulates the functional response to β-adrenergic (β-AR) stimulation via modulation of L-type Ca 2+ current ( I ). However, NOS3 signaling pathway modulating is unknown. This study investigated contribution soluble guanylate cyclase (sGC) and phosphodiesterase type 5 (PDE5), a cGMP-specific PDE, in NOS3-mediated regulation . Myocytes were isolated from knockout −/− ) wildtype (WT) mice. We measured (whole-cell voltage-clamp), simultaneously transients (Fluo-4 AM) cell shortening (edge detection). Zaprinast (selective inhibitor PDE5), decreased β-AR stimulated (isoproterenol, ISO)- , transient amplitudes WT myocytes. YC-1 (NO-independent activator sGC) only reduced ISO-stimulated but not cardiac contraction. further NOS3/sGC/PDE5 PDE5 mislocalized these myocytes we observed dissimilar effects inhibition sGC activation compared WT. That is, zaprinast had no effect on or amplitudes. Conversely, significantly both Further confirming that localizes NOS3/cGMP ; YC-1, presence zaprinast, now The contraction blocked by KT5823 (a selective cGMP-dependent protein kinase, PKG). Our data suggests novel physiological role for restricting NOS3/sGC/PKG while limiting