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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online January 20, 2004 as doi:10.1096/fj.03-0872fje. |
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* Institute of Molecular Medicine, University of California, San Diego, California, USA;
Nicox Research Institute, Bresso, Milan, Italy;
Laboratory of Molecular Cardiology, San Raffaele Biomedical Science Park, University "La Sapienza," Rome 00128, Italy; and
National Cardiovascular Center, Osaka, Japan
2Correspondence: Department of Medicine, 9500 Gilman Dr. 0641, University of California, San Diego, La Jolla, CA 92093, USA. E-mail: jross{at}ucsd.edu
SPECIFIC AIMS
1. Determine whether an NO-releasing derivative of enalapril, NCX-899 (N), improves cardiac function in a heart failure model of cardiomyopathic (CM) hamster
2. Compare the echocardiographic and hemodynamic effects of NCX-899 to those of the parent compound enalapril (E) and vehicle (V) in this model of heart failure
PRINCIPAL FINDINGS
1. NCX-899 significantly improved fractional shortening (FS) and decreased LV end-diastolic dimension (EDD) during 4 wk treatment compared with enalapril and vehicle.
2. LV contractility, represented by LVdP/dtmax and Emax, was significantly greater in N than in E or V whereas relaxation (Tau) was shortened in both N and E vs V.
3. NCX-899 and enalapril equally inhibited ACE-activity in the CM hamster, while plasma nitrate levels were increased only in N group.
4. N induced endothelium-independent relaxation in aortic strips.
CONCLUSIONS AND SIGNIFICANCE
Angiotensin converting enzyme (ACE) inhibitors are widely used to treat cardiovascular and renal disease and several large, randomized, placebo-controlled trials have had a major effect on the management of congestive heart failure by demonstrating that treatment with ACE inhibitors reduces mortality. ACE inhibitors act to decrease the formation of angiotensin II and reduce the degradation of bradykinin. Beneficial effects appear to be mediated partly by increased bradykinin-mediated NO production. However, NO production is blunted in the microvasculature of the failing myocardium and the peripheral circulation, contributing to the development of endothelial dysfunction in heart failure. Therefore, in heart failure the effects of ACE inhibitors on the vascular bed and myocardium may be limited by preexisting endothelial dysfunction and reduced NO availability.
We postulated that the beneficial effects of ACE inhibition on left ventricular (LV) function and remodeling would be enhanced by the presence of an exogenous NO donor; accordingly, we have synthesized a new compound, an NO-releasing derivative of enalapril (NCX899). NCX 899 releases NO slowly through the action of esterases.
We administered NCX 899 for 4 wk in Bio14.6 cardiomyopathic hamsters with heart failure, a model characterized by severe microvasculature dysfunction, with microvascular spasm possibly generating microinfarctions. Serial echocardiography showed that NCX 899 prevented the progression of LV dysfunction and remodeling to a greater extent than enalapril alone. In fact, fractional shortening (FS) and left ventricular end diastolic dimension (LV EDD) improved in the NCX-treated group compared with enalapril and vehicle (Figs. 1
and 3
). Hemodynamic studies at 4 wk after treatment demonstrated that NCX 899 improved indices of LV contractility (maximum dP/dt, Emax, minimum dP/dt, and Tau), whereas chronic administration of enalapril alone resulted in limited improvement only in Tau and Emax (Figs. 2
and 3
), which were significantly different from values with NCX 899. These results suggest that the superior effects of NO-releasing enalapril compared with enalapril alone relate primarily to effects of exogenous NO on the vascular bed and on the heart, thereby enhancing the efficacy of enalapril in this model of heart failure.
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We further demonstrate that the chemical modifications necessary for NCX 899 synthesis did not alter ACE inhibition efficacy, which was similar to that of the parent compound, enalapril. In rabbit aortic ring preparations, we demonstrated that NCX 899 induces potent vasorelaxation, which was cGMP dependent and endothelium independent. In our study, NCX 899 elicited similar vasodilating activity in both intact and endothelium denuded arterial preparations, effects almost completely abolished by ODQ, a guanylyl cyclase inhibitor. The effects of NCX 899 exceeded the vasodilating effects of enalapril alone, confirming the substantial contribution of exogenous NO to the functional response.
In addition to the vascular effects of NCX 899, direct effects on the heart can be expected from increased availability of exogenous NO through at least two mechanisms: cyclic GMP (cGMP) production and protein thiol nitrosylation. Both can lead to an up-regulation of activities of proteins involved in calcium metabolism within the cardiomyocyte. NO may modulate mitochondrial respiration directly and thereby decrease myocardial oxygen consumption.
In summary, the present study shows that NCX 899 improves cardiac function and remodeling in the CM hamster heart failure model considerably more than enalapril alone. Although a number of mechanisms may be involved, the net actions of these effects lead us to postulate that NCX 899 proved more beneficial than enalapril alone because of exogenous NO actions on the myocardium to enhance contractility, combined with exogenous NO action to further enhance ACE inhibitor-mediated vasodilation and to reduce aortic impedance and afterload on the left ventricle to further improve cardiac function. Vascular effects of exogenous NO might yield further benefit in the setting of myocardial ischemia. NCX 899, by providing continuous exogenous NO delivery in addition to effects of ACE inhibition, may hold future promise for therapy of patients with heart failure.
FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.03-0872fje; 
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