Role of myocardial neuronal nitric oxide synthase-derived nitric oxide in beta-adrenergic hyporesponsiveness after myocardial infarction-induced heart failure in rat.
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.


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 (E(es)) was significantly reduced in HF rats (P<0.05), and tau, the time constant of left ventricular relaxation, was prolonged (both P<0.05). Acute NOS1 inhibition significantly increased E(es) by 33+/-3% and tau by 17+/-2% (P<0.05) in shams, although these effects were significantly attenuated in HF hearts. beta-Adrenergic stimulation induced a marked increase in systolic performance in sham hearts, with the responses being significantly blunted in HF hearts. E(es) 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 E(es) to beta-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.
Bendall
Jennifer K
JK
INSERM U572, Hôpital Lariboisière, IFR J. Marrey Paris-7, Université D. Diderot, Paris, France.
Damy
Thibaud
T
Ratajczak
Philippe
P
Loyer
Xavier
X
Monceau
Virginie
V
Marty
Isabelle
I
Milliez
Paul
P
Robidel
Estelle
E
Marotte
Françoise
F
Samuel
Jane-Lise
JL
Heymes
Christophe
C
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D019898:Autocrine Communication; D051244:Caveolin 3; D022461:Caveolins / Q000378:metabolism; D004280:Dobutamine / Q000494:pharmacology; D004790:Enzyme Induction; D006333:Heart Failure / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009203:Myocardial Infarction / Q000150:complications*; D009206:Myocardium / Q000201:enzymology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012508:Sarcolemma / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000201:enzymology / Q000209:etiology
D000318:Adrenergic beta-Agonists; C495549:Cav3 protein, rat; D051244:Caveolin 3; D022461:Caveolins; D009419:Nerve Tissue Proteins; D011943:Receptors, Adrenergic, beta; D019837:Ryanodine Receptor Calcium Release Channel; D009569:Nitric Oxide; D004280:Dobutamine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D007545:Isoproterenol