Hegde S S, Friday K F
Roche Bioscience, Neurobiology Unit, Palo Alto, CA 94304, USA.
Curr Pharm Des. 1998 Dec;4(6):469-79.
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 tolerated and produces significant and dose-dependent increases in plasma DA/NE concentrations.
临床前和临床研究表明，充血性心力衰竭（CHF）中的慢性交感神经激活是一种适应性不良反应，会加速疾病的进行性恶化。因此，抑制交感神经功能的治疗干预措施可能会有利地改变疾病的自然进程。事实上，最近的临床研究表明，使用β受体阻滞剂卡维地洛进行治疗可降低死亡率以及死亡和住院风险。然而，β受体阻滞剂的治疗价值可能会受到其导致急性血流动力学恶化倾向的限制，这种恶化是由于交感神经支持突然撤除所致。因此，尽管引入β受体阻滞剂是CHF治疗的一项重要进展，但一种耐受性更好的调节交感神经系统的方法将非常可取。直接调节交感神经功能的另一种策略是通过抑制多巴胺-β-羟化酶（DBH）来抑制去甲肾上腺素（NE）的生物合成，DBH是一种在交感神经中催化多巴胺（DA）转化为NE的酶。与β受体阻滞剂相比，这种方法可能具有以下三个优点。首先，预计这类药物会对交感神经功能产生逐渐调节，而不是突然阻断，因此不会与急性血流动力学恶化相关，从而无需进行剂量滴定。其次，从理论角度来看，低剂量的DBH抑制剂会优先抑制心脏中的NE释放，因为在CHF中该器官中NE的储存池会被选择性耗尽。最后，抑制DBH会增加DA的水平，通过多巴胺受体激动作用，DA可能对肾功能产生有益影响。奈匹卡司他是一种新型、选择性且强效（IC50 = 9 nM）的DBH抑制剂。临床前研究表明，奈匹卡司他可使心血管组织和血浆中的儿茶酚胺水平逐渐调节（NE降低，DA和DA/NE比值升高），减弱交感神经介导的心血管反应，并且对肾功能也有有益作用。在犬类心力衰竭模型中，使用奈匹卡司他使跨心肌去甲肾上腺素平衡正常化可延缓心室扩张过程，并防止心脏功能的进行性恶化。CHF患者的早期短期临床研究表明，奈匹卡司他耐受性良好，可使血浆DA/NE浓度显著且呈剂量依赖性增加。
