nepicastat and Heart-Failure

Pre-clinical and clinical studies suggest that chronic sympathetic activation in congestive heart failure (CHF) is a maladaptive response which accelerates the progressive worsening of the disease. Consequently, therapeutic interventions which inhibit sympathetic nerve function are likely to favorably alter the natural course of the disease. Indeed, recent clinical studies have shown that treatment with carvedilol, a beta-blocker, reduces mortality and the risk of death and hospitalization. The therapeutic value of beta-blockers, however, may be limited by their propensity to cause acute hemodynamic deterioration which results from abrupt withdrawal of sympathetic support. Thus, although the introduction of beta-blockers represents an important advance in the treatment of CHF, a better tolerated means of modulating the sympathetic nervous system would be highly desirable. An alternative strategy for directly modulating sympathetic nerve function is to inhibit the biosynthesis of norepinephrine (NE) via inhibition of dopamine-beta-hydroxylase (DBH), the enzyme which catalyzes the conversion of dopamine (DA) to NE in sympathetic nerves. This approach may have the following three merits over beta-blockade. First, this class of drugs would be expected to produce gradual modulation, as opposed to abrupt blockade, of sympathetic nerve function and, consequently, would not be associated with acute hemodynamic worsening thereby obviating the need for dose-titration. Second, from a theoretical standpoint, DBH inhibitors, at low doses, would preferentially inhibit NE release in the heart since the storage pool of NE in this organ is selectively depleted in CHF. Lastly, inhibition of DBH would augment the levels of DA which, via agonism of dopamine receptors, could have beneficial effects on renal function. Nepicastat is a novel, selective and potent (IC50 = 9 nM) inhibitor of DBH. Preclinical studies have shown that nepicastal produces gradual modulation of catecholamine levels (reduction in NE and elevation of DA and DA/NE ratio) in cardiovascular tissues and plasma, attenuates sympathetically-mediated cardiovascular responses and also has salutary effects on renal function. In a canine heart failure model, normalization of transmyocardial norepinephrine balance with nepicastat retards the process of ventricular dilation and prevents progressive worsening of cardiac function. Early short-term clinical studies in CHF patients have shown that nepicastat is well tole

Topics: Animals; Dopamine beta-Hydroxylase; Enzyme Inhibitors; Heart Failure; Humans; Imidazoles; In Vitro Techniques; Sympathetic Nervous System; Thiones

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).. 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. 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.

Topics: Animals; Chronic Disease; Disease Models, Animal; Disease Progression; Dogs; Dopamine beta-Hydroxylase; Dose-Response Relationship, Drug; Enalapril; Enzyme Inhibitors; Heart Failure; Imidazoles; Norepinephrine; Stroke Volume; Thiones; Ventricular Dysfunction, Left; Ventricular Function, Left

1. Inhibitory modulation of sympathetic nerve function may have a favourable impact on the progression of congestive heart failure. Nepicastat is a novel inhibitor of dopamine-beta-hydroxylase, the enzyme which catalyses the conversion of dopamine to noradrenaline in sympathetic nerves. The in vitro pharmacology and in vivo catecholamine modulatory effects of nepicastat were investigated in the present study. 2. Nepicastat produced concentration-dependent inhibition of bovine (IC50 = 8.5 +/- 0.8 nM) and human (IC50 = 9.0 +/- 0.8 nM) dopamine-beta-hydroxylase. The corresponding R-enantiomer (RS-25560-198) was approximately 2-3 fold less potent than nepicastat. Nepicastat had negligible affinity (> 10 microM) for twelve other enzymes and thirteen neurotransmitter receptors. 3. Administration of nepicastat to spontaneously hypertensive rats (SHRs) (three consecutive doses of either 3, 10, 30 or 100 mg kg-1, p.o.; 12 h apart) or beagle dogs (0.05, 0.5, 1.5 or 5 mg kg-1, p.o.; b.i.d., for 5 days) produced dose-dependent decreases in noradrenaline content, increases in dopamine content and increases in dopamine/noradrenaline ratio in the artery (mesenteric or renal), left ventricle and cerebral cortex. At the highest dose studied, the decreases in tissue noadrenaline were 47%, 35% and 42% (in SHRs) and 88%, 91% and 96% (in dogs) in the artery, left ventricle and cerebral cortex, respectively. When tested at 30 mg kg-1, p.o., in SHRs, nepicastat produced significantly greater changes in noradrenaline and dopamine content, as compared to the R-enantiomer (RS-25560-198), in the mesenteric artery and left ventricle. 4. Administration of nepicastat (2 mg kg-1, b.i.d, p.o.) to beagle dogs for 15 days produced significant decreases in plasma concentrations of noradrenaline and increases in plasma concentrations of dopamine and dopamine/noradrenaline ratio. The peak reduction (52%) in plasma concentration of noradrenaline and the peak increase (646%) in plasma concentration of dopamine were observed on day-6 and day-7 of dosing, respectively. 5. The findings of this study suggest that nepicastat is a potent, selective and orally active inhibitor of dopamine-beta-hydroxylase which produces gradual modulation of the sympathetic nervous system by inhibiting the biosynthesis of noradrenaline. This drug may, therefore, be of value in the treatment of cardiovascular disorders associated with over-activation of the sympathetic nervous system, such as congestive heart failure.

Topics: Animals; Catecholamines; Cattle; Dogs; Dopamine beta-Hydroxylase; Dose-Response Relationship, Drug; Enzyme Inhibitors; Heart Failure; Humans; Imidazoles; Male; Rats; Rats, Inbred SHR; Thiones