Phospholamban S-nitrosylation modulates Starling response in fish heart

The Frank–Starling mechanism is a fundamental property of the vertebrate heart, which allows themyocardium to respond to increased filling pressure with a more vigorous contraction of its lengthenedfibres. In mammals, myocardial stretch increases cardiac nitric oxide (NO) release from both vascularendothelium and cardiomyocytes. This facilitates myocardial relaxation and ventricular diastolicdistensibility, thus influencing the Frank–Starling mechanism.In the in vitro working heart of the eel Anguilla anguilla, we previously showed that an endogenous NOrelease affects the Frank–Starling response making the heart more sensitive to preload. Using the samebioassay, we now demonstrate that this effect is confirmed in the presence of the exogenous NO donorS-nitroso-N-acetyl penicillamine, is independent from endocardial endothelium and guanylate cyclase/cGMP/protein kinase G and cAMP/protein kinase A pathways, involves a PI(3)kinase-mediatedactivation of endothelial NO synthase and a modulation of the SR-CA2þATPase (SERCA2a) pumps.Furthermore, we show that NO influences cardiac response to preload through S-nitrosylation of phospholambanand consequent activation of SERCA2a. This suggests that in the fish heart NO modulatesthe Frank–Starling response through a beat-to-beat regulation of calcium reuptake and thus of myocardialrelaxation.We propose that this mechanismrepresents an important evolutionary step for the stretch-induced intrinsicregulation of the vertebrate heart, providing, at the same time, a stimulus for mammalian-orientedstudies