XXXX regulation of myocardial contractility and calcium cycling: independent impact of neuronal and endothelial @entity842 synthases.

@entity19 @entity7097 @entity5834 @entity17693 @entity72507 @entity842 @entity141 @entity13471
The mechanisms by which @entity842 (NO) influences myocardial @entity141 cycling remain controversial. Because NO synthases (NOS) have specific spatial localization in cardiac myocytes, we hypothesized that neuronal NOS ( @entity17693 ) found in cardiac sarcoplasmic reticulum (SR) preferentially regulates SR @entity141 release and reuptake resulting in potentiation of the cardiac force-frequency response (FFR). Transesophageal pacing (660 to 840 bpm) in intact C57Bl/6 @entity19 ( @entity7097 ) stimulated both contractility (dP/dtmax normalized to end-diastolic volume; dP/dt- @entity72507 ) by 51+/-5% (P<0.001) and lusitropy (tau; tau) by 20.3+/-2.0% (P<0.05). These responses were markedly attenuated in @entity19 lacking @entity17693 ( @entity17693 -/-) (15+/-2% increase in dP/dt- @entity72507 ; P<0.001 versus @entity7097 ; and no change in tau; P<0.01 versus @entity7097 ). Isolated myocytes from @entity17693 -/- (approximately 2 months of age) also exhibited suppressed frequency-dependent sarcomere shortening and @entity141 transients ([ @entity141 ]i) compared with @entity7097 . SR @entity141 stores, a primary determinant of the FFR, increased at higher frequencies in @entity7097 ( @entity5834 -induced [ @entity141 ]i at 4 Hz increased 107+/-23% above 1 Hz response) but not in @entity17693 -/- (13+/-26%; P<0.01 versus @entity7097 ). In contrast, @entity19 lacking @entity13471 ( @entity13471 -/-) had preserved FFR in vivo, as well as in isolated myocytes with parallel increases in sarcomere shortening, [ @entity141 ]i, and SR @entity141 stores. @entity17693 -/- had increased SR @entity141 ATPase and decreased phospholamban protein abundance, suggesting compensatory increases in SR reuptake mechanisms. Together these data demonstrate that @entity17693 selectively regulates the cardiac FFR via influences over SR @entity141 cycling. Thus, there is NOS isoform-specific regulation of different facets of rate-dependent excitation-contraction coupling; inactivation of @entity17693 has the potential to contribute to the pathophysiology of states characterized by diminished frequency-dependent inotropic responses.
