Cardiometabolic and Inflammatory Benefits of Sympathetic Down-Regulation with Zamicastat in Aged Spontaneously Hypertensive Rats

Abstract

The hyperactivity of the sympathetic nervous system (SNS) plays a major role in the development and progression of several cardiovascular diseases. One strategy to mitigate the SNS overdrive is by restricting the biosynthesis of norepinephrine via the inhibition of dopamine β-hydroxylase (DBH). Zamicastat is a new DBH inhibitor that decreases norepinephrine and increases dopamine levels in peripherally sympatheticinnervated tissues. The cardiometabolic and inflammatory effects of sympathetic down-regulation were evaluated in 50 week old male spontaneously hypertensive rats (SHRs) receiving zamicastat (30 mg/kg/ day) for 9 weeks. After 8 weeks of treatment, the blood pressure (BP) and heart rate (HR) were assessed by tail cuff plethysmography. At the end of the study, 24 h urine, plasma, heart, and kidney were collected for biochemical and morphometric analyses. Zamicastat-induced sympathetic down-regulation decreased the high BP in SHRs, with no observed effect on HR. The heart-tobody weight ratio was lower in SHRs treated with zamicastat, whereas the body weight and kidney-to-body weight ratio were similar between both SHR cohorts. Zamicastat-treated SHRs showed reduced 24 h urine output, but the urinary amount of protein excreted and creatinine clearance rate remained unchanged. Zamicastat treatment significantly decreased plasma triglycerides, free fatty acids, and aspartate aminotransferase levels. Aged SHRs showed higher plasma levels of inflammatory markers as compared with age-matched normotensive Wistar-Kyoto rats. The inflammatory benefits attained with DBH inhibition were expressed by a decrease in CRP, MCP-1, IL-5, IL-17α, GRO/KC, MIP-1α, and RANTES plasma levels as compared with untreated SHRs. In conclusion, DBH inhibition decreased norepinephrine levels, reduced end-organ damage, and improved cardiometabolic and inflammatory biomarkers in aged male SHRs.

In vitro Species Different Metabolism and CYP Phenotyping of Zamicastast

“… Background Zamicastat (1) is an inhibitor of dopamine‐β‐hydroxylase, enzyme that catalyzes the hydroxylation of dopamine to norepinephrine in sympathetic nerves and adrenal medulla, and it was shown to increase the survival rate in the monocrotaline rat model of pulmonary arterial hypertension. Objectives The purpose of this study was to evaluate zamicastat clearance and metabolic profile in hepatocytes from different species (human, rat, dog, mouse and monkey) and to identify the CYP450 enzymes isoforms that are involved in zamicastat metabolism. Methods.…”

“…Zamicastat (1) is an inhibitor of dopamine‐β‐hydroxylase, enzyme that catalyzes the hydroxylation of dopamine to norepinephrine in sympathetic nerves and adrenal medulla, and it was shown to increase the survival rate in the monocrotaline rat model of pulmonary arterial hypertension.…”

Absorption, Distribution and Excretion of [14C] Zamicastat after Single Oral and Intravenous Administration in Rats and Dogs

“… Background Zamicastat is a dopamine‐β‐hydroxylase inhibitor (1), previously showed to increase the survival rate in the monocrotaline rat model of pulmonary arterial hypertension. Objectives The purpose of this study was to characterize the absorption, distribution and elimination of 14 C‐zamicastat in rat and dog, after single oral (p.o.) or intravenous (i.v.)…”

“…Zamicastat is a dopamine‐β‐hydroxylase inhibitor (1), previously showed to increase the survival rate in the monocrotaline rat model of pulmonary arterial hypertension.…”

Innovation and Discovery in Cardiovascular Biology

“…The study by Igreja and colleagues 5 uses the preclinical, aged spontaneously hypertensive rat (SHR) model to explore the therapeutic potential of a relatively new dopamine βhydroxylase inhibitor, zamicastat, as a possible therapeutic strategy to reduce overactivity of the sympathetic nervous systema clinical condition that is commonly associated with essential hypertension and congestive heart failure. Consistent with early stage clinical trials, the authors found that a daily dosage of zamicastat for 9 weeks significantly decreased norepinephrine levels and improved overall cardiometabolic health in the aged SHR rats compared to nonhypertensive controls.…”