Published online before print October 4, 2004, doi: 10.1161/01.CIR.0000145160.04084.AC
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(Circulation. 2004;110:2368-2375.)
© 2004 American Heart Association, Inc.
Coronary Heart Disease |
Role of Myocardial Neuronal Nitric Oxide Synthase–Derived Nitric Oxide in ß-Adrenergic Hyporesponsiveness After Myocardial Infarction–Induced Heart Failure in Rat
From INSERM U572 Hôpital Lariboisière (J.K.B., T.D., P.R., X.L., V.M., P.M., E.R., F.M., J.-L.S., C.H.), IFR J. Marrey Paris-7, Université D. Diderot, Paris, France, and INSERM E9931 DBMS/CEA (I.M.), Grenoble, France.
Correspondence to Christophe Heymes, INSERM U572, Hôpital Lariboisière, 41 Boulevard de la Chapelle, 75475 Paris Cedex 10, France. E-mail Christophe.Heymes{at}larib.inserm.fr
Received February 13, 2004; revision received May 24, 2004; accepted May 25, 2004.
Background— An emerging concept is that a neuronal isoform of nitric oxide synthase (NOS1) may regulate myocardial contractility. However, a role for NOS1-derived nitric oxide (NO) in heart failure (HF) has not been defined.
Methods and Results— Using a model of myocardial infarction-induced HF, we demonstrated that cardiac NOS1 expression and activity increased in HF rats (P<0.05 and P<0.001 versus shams, respectively). This was associated with translocation of NOS1 from the ryanodine receptor to the sarcolemma through interactions with caveolin-3 in HF hearts. With ex vivo and in vivo pressure-volume analysis, cardiac NOS1-derived NO was found to be negatively inotropic in shams but not HF hearts. Ventricular elastance (Ees) was significantly reduced in HF rats (P<0.05), and 
, the time constant of left ventricular relaxation, was prolonged (both P<0.05). Acute NOS1 inhibition significantly increased Ees by 33±3% and by 17±2% (P<0.05) in shams, although these effects were significantly attenuated in HF hearts. ß-Adrenergic stimulation induced a marked increase in systolic performance in sham hearts, with the responses being significantly blunted in HF hearts. Ees increased by 163±42% (P<0.01) in sham hearts and 56±9% in HF hearts, and LV +dP/dt increased by 97±9% (P<0.01) in shams and 37±7% (P<0.05) in the HF group. Interestingly, preferential NOS1 inhibition enhanced the blunted responses of LV +dP/dt and Ees to ß-adrenergic stimulation in HF rats but had no effect in shams.
Conclusions— These results provide the first evidence that increased NOS1-derived NO production may play a role in the autocrine regulation of myocardial contractility in HF.
Key Words: nitric oxide synthase • contractility • receptors, adrenergic, ß • heart failure
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