Effects of dopamine beta-hydroxylase inhibition with nepicastat on the progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure.
BACKGROUND
Inhibition of dopamine beta-hydroxylase (DBH) results in a decrease in norepinephrine synthesis. The present study was a randomized, blinded, placebo-controlled investigation of the long-term effects of therapy with the DBH inhibitor nepicastat (NCT) on the progression of left ventricular (LV) dysfunction and remodeling in dogs with chronic heart failure (HF).


RESULTS
Moderate HF (LV ejection fraction [LVEF] 30% to 40%) was produced in 30 dogs by intracoronary microembolization. Dogs were randomized to low-dose NCT (0.5 mg/kg twice daily, n=7) (L-NCT), high-dose NCT (2 mg/kg twice daily, n=7) (H-NCT), L-NCT plus enalapril (10 mg twice daily, n=8) (L-NCT+ENA), or placebo (PL, n=8). Transmyocardial (coronary sinus-arterial) plasma norepinephrine (tNEPI), LVEF, end-systolic volume, and end-diastolic volume were measured before and 3 months after initiating therapy. tNEPI levels were higher in PL compared with NL (86+/-20 versus 13+/-14 pg/mL, P:<0.01). L-NCT alone and L-NCT+ENA reduced tNEPI toward normal (28+/-4 and 39+/-17 pg/mL respectively), whereas HD-NCT reduced tNEPI to below normal levels (3+/-10 pg/mL). In PL dogs, LVEF decreased but was unchanged with L-NCT and increased with L-NCT+ENA. L-NCT and L-NCT+ENA prevented progressive LV remodeling, as evidenced by lack of ongoing increase in end-diastolic volume and end-systolic volume, whereas H-NCT did not


CONCLUSIONS
In dogs with HF, therapy with L-NCT prevented progressive LV dysfunction and remodeling. The addition of ENA to L-NCT afforded a greater increase in LV systolic function. NCT at doses that normalize tNEPI may be useful in the treatment of chronic HF.
Sabbah
H N
HN
Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Heart and Vascular Institute, Detroit, MI, USA. hsabbah1@hfhs.org
Stanley
W C
WC
Sharov
V G
VG
Mishima
T
T
Tanimura
M
M
Benedict
C R
CR
Hegde
S
S
Goldstein
S
S
D000818:Animals; D002908:Chronic Disease; D004195:Disease Models, Animal; D018450:Disease Progression; D004285:Dogs; D004299:Dopamine beta-Hydroxylase / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004656:Enalapril / Q000008:administration & dosage / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006333:Heart Failure / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D009638:Norepinephrine / Q000097:blood; D013318:Stroke Volume / Q000187:drug effects; D013871:Thiones / Q000008:administration & dosage / Q000494:pharmacology*; D018487:Ventricular Dysfunction, Left / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D016277:Ventricular Function, Left / Q000187:drug effects
D004791:Enzyme Inhibitors; D007093:Imidazoles; D013871:Thiones; D004656:Enalapril; D004299:Dopamine beta-Hydroxylase; C109487:nepicastat; D009638:Norepinephrine