Nitric Oxide-Mediated Endothelial Function and Limits the Alteration in Left Ventricular Function During Pacing-Induced Heart Failure in Conscious Dogs

Conclusions. These data suggest that anemia is associated with reduced QoL in patients with HF. Additional studies will be required to establish if this is a cause and effect relationship. donor. Methods: Pressure-volume relations were assessed in conscious dogs under basal con- ditions and after induction of heart failure (HF) by tachypacing. Results: IPA/NO (5µg/kg/min) increased contractility (end-systolic elastance, Ees,) by 58.0±8.1% (p<0.001) in control and 46.8±10.2% (p<0.01) in HF, and lowered preload and afterload similarly in healthy and CHF dogs. This contrasted to negative inotropic effects from equidilative doses of diethylamine/NO (DEA/NO, pure NO donor, 2µg/kg/min), S- Nitrosoglutathione (GSNO, pure NO doror, 0.625µg/kg/min) or nitroglycerin (NTG, 10µg/ kg/min). Isovolumic relaxation was 6.1±3.8% faster with IPA/NO in control hearts, and this effect was more pronounced in HF (28.3±6.4%; p<0.05 vs. control hearts). Co-infu- sion of dobutamine with IPA/NO further augmented contractility by 46.0±16% (p<0.05) in control and 31.4+/-6.5% (p<0.05) in HF above dobutamine alone, whereas DEA/NO, GSNO or NTG blunted β-stimulation. IPA/NO inotropic/lusitropic action was unaffected by β-blockade (timolol, 2mg/kg). IPA/NO increased arterial plasma CGRP (30.3±6.0 to 65.1±2.8 pg/ml; p<0.005) and neurotensin (78.6±7.3 to 170.0±25.3pg/ml; p<0.01), reflecting NANC stimulation. Responses to IPA/NO were very similar to those previously reported from AS. Conclusion: The novel HNO/NO- donor, IPA/NO, has potent inotropic and lusitropic effects in failing hearts that are synergistic with β-agonist stimulation. Unlike inorganic AS, this new organic compound has potential for clinical development as an NO-related species with both vasoactive and cardiotropic effects, for use in the treatment of heart failure.