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.