Role of hypotonic swelling-induced nitric oxide release on cardiac EC-coupling.

MARTIN G. VILA PETROFF

Conferencia; 1st PanAmerican Congress of Physiological Sciences; 2014

INTERNATIONAL SOCIETY FOR HEART RESEARCH

Tissue osmolarity is tightly regulated under physiological conditions. However, under diverse pathological situations cells undergo hypotonic swelling that dilutes intracellular components and deforms cellular membranes and the underlying cytoskeleton. This results in changes in the activity of signaling molecules and ion channels leading to alterations in cellular function. In the heart, cell swelling occurs in diabetic or septic shock, elective cardioplegia and is particularly important in the context of ischemia and reperfusion (I/R) where it results in structural, ionic and electrical remodeling that have been shown to contribute to contractile dysfunction, cell death and enhanced propensity for arrhythmias. Nitric oxide (NO), synthesized by the nitric oxide synthase (NOS), has been defined as a second messenger and a regulator of cardiac excitation and contraction coupling (ECC). Recent evidence has emerged showing that hypotonic swelling can promote NO release in endothelial cell and in outer hair cells of the cochlea. However, until present whether hypotonic swelling can promote NO release in cardiac ventricular myocytes and if so, whether it has functional implications on swelling-induced contractile dysfunction has not been established. Using rat cardiac myocytes loaded with an NO sensitive fluorescent dye we show for the first time that hypotonic swelling-induced cytoskeleton deformation leads to NOS1-dependent NO release in cardiac myocytes. This NO, through a cGMP/PKG-dependent regulation of ryanodine receptor Ca2+ release provides inotropic support that could reduce the impact of hypotonic swelling-induced contractile dysfunction. Our findings suggest a novel mechanosensory mechanism for NO release in cardiac myocytes with putative pathophysiological relevance in the context of ischemia and reperfusion where it may be cardioprotective by reducing the extent of contractile dysfunction associated with hypotonic swelling.