Abstract 13825: Neuronal Nitric Oxide Synthase Modulates Cardiac Metabolism and Contractile Function in LV Myocytes from Hypertensive Rats
Background: Accumulating evidence has shown that fatty acid (FA)-dependent cardiac metabolism is impaired in hypertension. Whether such a modulation attenuates myocardial contractility remains elusive. Here, we examine the hypothesis that FA enhances left ventricular (LV) myocyte contraction in healthy hearts and such an inotropic response is attenuated in hypertension. Furthermore, neuronal nitric oxide synthase (nNOS) is known to modulate cardiac metabolism and contractility. Therefore, we test the functional regulation by nNOS of FA-dependent LV myocyte contraction in healthy and in hypertensive rats.
Methods and Results: Systemic blood pressure (tail-cuff with heating) was elevated in angiotensin II-treated rats (Ang II 125ng/min/kg, osmotic minipump for 4 weeks) compare to that in shams (systolic & diastolic BP, P<0.001 & P<0.001, n=26). Heart weight, heart weight/body weight ratio and the dimensions of LV myocytes (slack sarcomere length, SL, and width) were not greater in Ang II-rats, excluding cardiac structural remodeling. Functional data showed that basal myocyte contraction (ΔSL, field stimulation, 2Hz, 36oC) was similar between groups (P=0.2, n=35 and n=33). However, supplementation with palmitic acid (PA 100 μ M, one of the major metabolic substrates of myocardium) significantly increased ΔSL and ATP in LV myocytes only in shams, as such, LV myocyte contraction was significantly reduced in Ang II-rats (P<0.001, n=33). PA did not affect the amplitude of Ca2+ transient (Fura 2 AM, 2 μ M) or myofilament Ca2+ sensitivity, suggesting that inability to produce ATP may account for impaired PA-dependent contraction in Ang II-rats. Immunoblotting results revealed that nNOS protein expression was significantly increased in LV myocyte homogenates from Ang II-rats (P=0.03, n=8). Inhibition of nNOS (S-methyl-L-thiocitrulline, SMTC, 100 nM) restored the positive inotropic effect of PA in Ang II-rats (P<0.001, n=29).
Conclusions: These results indicate that PA-dependent ATP production and contraction are impaired in LV myocytes from hypertensive rats, which are mediated by nNOS. Our findings suggest a novel mechanism through which nNOS modulates myocardial metabolism and contractility in Ang II-induced hypertensive rats.
- © 2012 by American Heart Association, Inc.