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 sympathetic-innervated 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-to-body 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.

Figure 1

Levels of zamicastat and its metabolites BIA 5-453 and BIA 5-961 in (A) plasma and (B) urine at the end of the study. Data are shown as the mean ± SEM (n = 6 per group).

Figure 2

Effect of zamicastat (Zami) on norepinephrine (NE) and dopamine (DA) levels in the (A,C) heart left ventricle and the (B,D) brain frontal cortex. Data are shown as the mean ± SEM (n = 4 to 5 per group). Comparisons against the vehicle-SHR (SHR_Veh) group were performed using one-way analysis of variance (ANOVA), followed by Fisher’s least significant difference (LSD) test. P values <0.05 (*) were considered statistically significant.

Figure 3

Effect of zamicastat (Zami) on the (A) systolic and (B) diastolic blood pressure and on the (C) heart rate of SHRs after 8 weeks of treatment. Data are shown as the mean ± SEM (n = 6 per group). Comparisons against the vehicle-SHR (SHR_Veh) group were performed using one-way analysis of variance (ANOVA), followed by Fisher’s least significant difference (LSD) test. P values <0.05 (*) were considered statistically significant.

Figure 4

(A) Cardiac and (B) renal hypertrophy observed at the end of the study. Data are shown as the mean ± SEM (n = 6 per group). Comparisons against the vehicle-SHR (SHR_Veh) group were performed using one-way analysis of variance (ANOVA), followed by the Fisher’s least significant difference (LSD) test. P values <0.05 (*) were considered statistically significant.