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 cyclic-3',5'-guanosine monophosphate (cGMP) synthesis by soluble guanylate cyclase (sGC). sGC is a heterodimer comprised of a β1 and an α1 or α2 subunit. sGCα1β1 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 (LV) cardiac myocytes (CM) isolated from adult mice deficient in the sGCα1 subunit (sGCα1-/-) and from wild-type (WT) mice. Sarcomere shortening under basal conditions was less in sGCα1-/- CM than in WT CM. To activate endogenous NO synthesis from NO synthase 3 (NOS3), CM were incubated with the β3-adrenergic receptor (β3-AR) agonist, BRL 37344. BRL 37344 decreased cardiac contractility in WT CM, but not in sGCα1-/- 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 (ISO), addition of spermine NONOate reduced sarcomere shortening in WT but not in sGCα1-/- CM. Neither BRL 37344 nor spermine NONOate altered calcium handling in CM of either genotype. These findings suggest that sGCα1 exerts a positive inotropic effect under basal conditions, as well as mediates the negative inotropic effect of β3-AR signaling. Additionally, our work demonstrates that sGCα1β1 is required for NO to depress β1/β2-AR-stimulated cardiac contractility, and that this modulation is independent of changes in calcium handling.
- cardiac myocyte
- β3-adrenergic receptor
- cardiac contractility
- Copyright © 2010, American Journal of Physiology - Heart and Circulatory Physiology