doi: 10.1161/01.RES.0000080783.34092.AF
© 2003 American Heart Association, Inc.
Editorials |
The Real Estate of NOS Signaling
Location, Location, Location
From the Department of Physiology, Loyola University Chicago, Maywood, Ill.
Correspondence to Donald M. Bers, Department of Physiology, Loyola University Chicago, 2160 S First Ave, Maywood, IL 60153. E-mail dbers@lumc.edu
Key Words: nitric oxide synthase • cardiac myocyte • ryanodine receptor • L-type Ca2+ current • compartmentalization
An extract of the first 250 words of the full text is provided, because this article has no abstract. |
While sympathetic stimulation of the heart produces chronotropic, inotropic, and lusitropic effects, increased frequency alone causes a positive force-frequency 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) Ca2+ load, due to increased Ca2+ influx and decreased Ca2+ efflux.1,2 Ca2+ influx increases due to more L-type Ca2+ current (ICa) per unit time, while Ca2+ efflux via Na+-Ca2+ exchange (NCX) decreases because the diastolic time is reduced and [Na+]i increases. Enhanced SR Ca2+-pump function causes FDAR and also augments SR Ca2+ 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 Ca2+ 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
Nitric Oxide and Cardiac Function
NO synthase (NOS) produces NO from L-arginine, and cardiac myocytes express all three NOS isoforms.6,7 NOS1 (nNOS) and NOS3 (eNOS) are constitutively expressed and produce low amounts of NO (regulated by [Ca2+-calmodulin]i levels). NOS2 (iNOS) is expressed during inflammatory responses (eg, cytokines, sepsis, heart failure) and continuously produces large amounts of NO (compared with NOS1 and NOS3),7 independent of Ca2+
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