Introduction
Despite advances in treatment options for pulmonary arterial hypertension (PAH), the disease is still associated with worsening symptoms and increased mortality, so research for novel treatments persists.
The development of more effective therapeutic treatments has been recently focused on the hyperactivation of neurohumoral systems – essentially the sympathetic nervous system (SNS) – involved in the development and progression of hypertension and chronic heart failure. In fact, hyperactivation of SNS has been implicated in the progression of right heart failure and arrhythmia as premature ventricular contractions, ventricular arrhythmia, and sudden cardiac death. This involvement has been confirmed by both indirect (elevated plasma concentrations of catecholamines) and direct evidence, such as muscle sympathetic nerve activity, via microneurography of the peroneal nerve, and heart rate (HR) and baroreceptor reflex variability.
In this context, the inhibition of the sympathetic nerve function with adrenoceptor antagonists appeared to be a promising approach to manage the hyperactivation of the SNS. However, most patients, particularly those with heart failure, do not tolerate the immediate hemodynamic deterioration that follows β-blocker treatment. An alternative strategy is to reduce the biosynthesis of norepinephrine (NE) through the inhibition of the enzyme dopamine-β-hydroxylase (DβH). This approach has several putative merits, such as gradual modulation, as opposed to abrupt inhibition of the sympathetic system, and increased availability of dopamine (DA), which can improve renal function. Therefore, it could be anticipated that inhibitors of DβH may provide significant clinical advantages in PAH patients over conventional adrenoceptor antagonists.
In this setting, zamicastat (also known as BIA 5-1058), a reversible DβH inhibitor developed by Bial-Portela & Cª S.A., emerged as an orally administered small molecule for the treatment of cardiovascular disorders, including PAH. It is a potent peripheric selective inhibitor of DβH, with limited access to the brain, that converts DA to NE in sympathetically innervated tissues, reducing the drive of the SNS. At this point, the confirmation of the mechanism of action of zamicastat in the SNS overdrive, through DβH inhibition, would validate and strengthen the efficacy and safety data collected so far.
Different methods for the evaluation of the autonomic nervous system (ANS) have been described, including the cold pressor test (CPT) and measurements of the levels of neurotransmitters. CPT is a simple, non-invasive validated test of sympathetic activation. It consists of a sympatho-excitatory stressor (cold) that activates afferent pain and temperature neurons, resulting in a centrally mediated stimulation of sympathetic efferent neurons. This induces vascular sympathetic activation, causing arteriolar constriction, increased HR, and increased cardiac contractility, with consequent increase in diastolic (DBP) and systolic blood pressure (SBP).
Measurements of plasma and urine catecholamines are a classic and reliable method for assessing ANS function. The concentration of plasma catecholamines has been shown to increase following various stressor stimuli, being an excellent tool to evaluate the impact of drugs on the SNS.
This study aimed to validate the proposed mechanism of action of zamicastat by studying its effects on the SNS, through the evaluation of the impact on blood pressure (BP) and HR response and assessment of plasma and urinary concentration of catecholamines and their metabolites, before and after CPT.