The real estate of NOS signaling: location, location, location.

While sympathetic stimulation of the heart produces chronotropic, inotropic, and lusitropic effects, increased frequency alone causes a positive forcefrequency relationship (FFR) and frequency-dependent acceleration of relaxation (FDAR).1 That is, contraction amplitude and relaxation rate are increased with increasing frequency in most species (including humans). The key mechanism involved in the positive FFR is increased sarcoplasmic reticulum (SR) Ca load, due to increased Ca influx and decreased Ca efflux.1,2 Ca influx increases due to more L-type Ca current (ICa) per unit time, while Ca efflux via Na -Ca exchange (NCX) decreases because the diastolic time is reduced and [Na ]i increases. Enhanced SR Ca pump function causes FDAR and also augments SR Ca loading. Various signaling pathways are involved (eg, CaMKII).3 In human heart failure, the FFR reverses (ie, from positive to negative) due to an inability of the SR to increase Ca content.4 This negative FFR is a main contributor to the loss of contractile reserve in the failing heart. Of many pathways that can modify FFR, nitric oxide (NO) signaling is the topic addressed by Khan et al in this issue of Circulation Research.5