sGC 1 mediates the negative inotropic effects of NO in cardiac myocytes independent of changes in calcium handling

Cawley SM, Kolodziej S, Ichinose F, Brouckaert P, Buys ES, Bloch KD. sGC 1 mediates the negative inotropic effects of NO in cardiac myocytes independent of changes in calcium handling. Am J Physiol Heart Circ Physiol 301: H157–H163, 2011. First published May 2, 2011; doi:10.1152/ajpheart.01273.2010.—In the heart, nitric oxide (NO) modulates contractile function; however, the mechanisms responsible for this effect are incompletely understood. NO can elicit effects via a variety of mechanisms including S-nitrosylation and stimulation of cGMP synthesis by soluble guanylate cyclase (sGC). sGC is a heterodimer comprised of a 1and an 1or 2-subunit. sGC 1 1 is the predominant isoform in the heart. To characterize the role of sGC in the regulation of cardiac contractile function by NO, we compared left ventricular cardiac myocytes (CM) isolated from adult mice deficient in the sGC 1-subunit (sGC 1 / ) and from wild-type (WT) mice. Sarcomere shortening under basal conditions was less in sGC 1 / CM than in WT CM. To activate endogenous NO synthesis from NO synthase 3, CM were incubated with the 3-adrenergic receptor ( 3-AR) agonist BRL 37344. BRL 37344 decreased cardiac contractility in WT CM but not in sGC 1 / myocytes. Administration of spermine NONOate, an NO donor compound, did not affect sarcomeric shortening in CM of either genotype; however, in the presence of isoproterenol, addition of spermine NONOate reduced sarcomere shortening in WT but not in sGC 1 / CM. Neither BRL 37344 nor spermine NONOate altered calcium handling in CM of either genotype. These findings suggest that sGC 1 exerts a positive inotropic effect under basal conditions, as well as mediates the negative inotropic effect of 3-AR signaling. Additionally, our work demonstrates that sGC 1 1 is required for NO to depress 1/ 2-ARstimulated cardiac contractility and that this modulation is independent of changes in calcium handling.