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(Circulation. 2000;102:1990.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Effects of Dopamine ß-Hydroxylase Inhibition With Nepicastat on the Progression of Left Ventricular Dysfunction and Remodeling in Dogs With Chronic Heart Failure

Hani N. Sabbah, PhD; William C. Stanley, PhD; Victor G. Sharov, MD, PhD; Takayuki Mishima, MD; Mitsuhiro Tanimura, MD; Claude R. Benedict, MD; Sharath Hegde, PhD; Sidney Goldstein, MD

From the Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Heart and Vascular Institute, Detroit, Mich (H.N.S., V.G.S., T.M., M.T., S.G.); Case Western Reserve University, Cleveland, Ohio (W.C.S.); the University of Texas, Houston (C.R.B.); and Roche Bioscience, Palo Alto, Calif (S.H.).

Correspondence to Hani N. Sabbah, PhD, Cardiovascular Research, Henry Ford Health System, 2799 W Grand Blvd, Detroit, MI 48202. E-mail hsabbah1{at}hfhs.org

Background—Inhibition of dopamine ß-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).

Methods and 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.

Key Words: heart failure • drugs • myocytes • norepinephrine

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