Background and aims– 

17b-estradiol (E2) plays an important cardiovascular role by activating the estrogen receptor (ER) a and ERb. Previous studies have demonstrated that the novel estrogen G protein-coupled receptor, namely GPR30/GPER, mediates estrogen action in different tissues.

We have recently shown in the rat heart that E2 elicits negative inotropism through ERa, ERb and GPR30, triggering activation of ERK1/2, phosphatidylinositol 3-kinase (PI3K), protein kinase A (PKA) and endothelial Nitric oxide synthase (eNOS) signaling.

In the present study, using the isolated and Langendorff-perfused rat heart as a model system we analyzed: i) whether and to which extent E2 modifies mammalian ventricular myocardial relaxation (lusitropism); ii) the type of ERs and the signaling pathways involved in this effect.

Results– 

We found that E2 modulates negatively, in an endothelium dependent manner, the rat ventricular lusitropic performance. In particular, this effect involved ERb and occurred via PI3K, eNOS-NO-cGMP-protein kinase G (PKG) transduction cascade. Of note, E2-mediated negative lusitropism associated with a modification of phospholamban (PLN) S-nitrosylation.

Conclusions– 

Taken together, our results provide new evidence regarding the E2-dependent modulation of ventricular relaxation which occurs through the involvement of PI3K, eNOS-NO-cGMP-PKG transduction pathway and PLN. These findings may be not only related to the normal heart function, but also to physio-pathologic conditions affecting ventricular diastolic performance.