Effects of dopamine beta-hydroxylase inhibition with nepicastat on the progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure.

Abstract

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).

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.

• Authors: H N Sabbah, W C Stanley, V G Sharov, T Mishima, M Tanimura, C R Benedict, S Hegde, S Goldstein
• Journal: Circulation (Circulation) Vol. 102 Issue 16 Pg. 1990-5 (Oct 17 2000) ISSN: 1524-4539 [Electronic] United States
• PMID: 11034950 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Enzyme Inhibitors
• Imidazoles
• Thiones
• Enalapril
• Dopamine beta-Hydroxylase
• nepicastat
• Norepinephrine

Topics

• Animals
• Chronic Disease
• Disease Models, Animal
• Disease Progression
• Dogs
• Dopamine beta-Hydroxylase (antagonists & inhibitors)
• Dose-Response Relationship, Drug
• Enalapril (administration & dosage, pharmacology)
• Enzyme Inhibitors (administration & dosage, pharmacology)
• Heart Failure (complications, drug therapy, enzymology)
• Imidazoles (administration & dosage, pharmacology)
• Norepinephrine (blood)
• Stroke Volume (drug effects)
• Thiones (administration & dosage, pharmacology)
• Ventricular Dysfunction, Left (blood, complications, drug therapy)
• Ventricular Function, Left (drug effects)