A nitric oxide-releasing derivative of enalapril, NCX 899, prevents progressive cardiac dysfunction and remodeling in hamsters with heart failure.
Nitric oxide (NO) production is known to be impaired in heart failure. A new compound (NCX 899), a NO-releasing derivative of enalapril was characterized, and its actions were evaluated in Bio 14.6 cardiomyopathic (CM) hamsters with heart failure. The hamsters were randomized to oral treatment for 4 weeks with vehicle (n=11), NCX 899 (NCX, 25 mg/kg, n=10), or enalapril (25 mg/kg, n=10). In the vehicle group, fractional shortening by echocardiography decreased (-23.6+/-2.0%) and LV end-diastolic dimension) increased (+10.9+/-1.0%), whereas fractional shortening increased (+17.5+/-4.4%) in NCX and was unchanged in the enalapril group (both P<0.01 vs. vehicle). End-diastolic dimension decreased only in NCX. LV contractility (LVdP/dt max and Emax) was significantly greater in NCX than in enalapril or vehicle, while relaxation (Tau) was shortened in both NCX and enalapril vs. vehicle. ACE activity was inhibited equally by NCX and enalapril in the CM hamster, and plasma nitrate levels were increased only in NCX (P<0.05 vs. enalapril and vehicle). In aortic strips endothelium-independent relaxation occurred only with NCX. The superior effects of NO-releasing enalapril (NCX) vs. enalapril alone to enhance vascular effects, increase LV contractility and prevent unfavorable remodeling and are consistent with vascular delivery of exogenous NO. NCX 899 may hold promise for the future treatment of heart failure.
Iwanaga
Yoshitaka
Y
Institute of Molecular Medicine, University of California, San Diego, La Jolla, California 92093, USA.
Gu
Yusu
Y
Dieterle
Thomas
T
Presotto
Cristina
C
Del Soldato
Piero
P
Peterson
Kirk L
KL
Ongini
Ennio
E
Condorelli
Gianluigi
G
Ross
John
J
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001011:Aorta; D002311:Cardiomyopathy, Dilated / Q000150:complications* / Q000000981:diagnostic imaging / Q000235:genetics; D006224:Cricetinae; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D004656:Enalapril / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D004730:Endothelium, Vascular / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000209:etiology; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics; D008647:Mesocricetus; D009200:Myocardial Contraction / Q000187:drug effects; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology / Q000627:therapeutic use*; D009573:Nitrites / Q000097:blood; D010069:Oxadiazoles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D011817:Rabbits; D049031:Sarcoglycans; D014463:Ultrasonography; D014661:Vasoconstriction / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000806:Angiotensin-Converting Enzyme Inhibitors; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; C485988:NCX 899; D009566:Nitrates; D020030:Nitric Oxide Donors; D009573:Nitrites; D010069:Oxadiazoles; D011810:Quinoxalines; D049031:Sarcoglycans; D009569:Nitric Oxide; D004656:Enalapril