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Abstract P224: Zamicastat Prevents the Deterioration of Cardiometabolic and Inflammatory Biomarkers in a Genetic Model of Salt-sensitive Hypertension

The Dahl salt-sensitive (Dahl/SS) rat, a genetic model of salt-sensitive hypertension and heart failure, develops left ventricle (LV) hypertrophy after five to six weeks and cardiac failure with LV dilation and contractile dysfunction after 10 to 12 weeks of high-salt (HS) intake. The aim of the present study was to evaluate the effect of zamicastat, a selective peripheral dopamine β-hydroxylase inhibitor, on cardiometabolic and inflammatory biomarkers in Dahl/SS during chronic HS intake.
 Eight week-old Dahl/SS rats were randomized into three groups; two groups received for 10 weeks a HS (8% NaCl) diet, one of which received 30 mg/kg/day zamicastat (HS+ZAMI); a third cohort received normal-salt diet (NS-0.3% NaCl) and served as controls. In the last week of treatment, 3 out of 10 animals from the HS group and 1 out of 10 from HS+ZAMI group were found dead. All animals from the NS group survived (n=8). Rats in the HS and HS+ZAMI groups showed heart and kidney hypertrophy as indicated by higher heart/body weight ratios (3.86±0.05 and 3.63±0.09 vs 2.96±0.05 mg/g) and kidney/body weight ratios (5.23±0.29 and 4.80±0.24 vs 3.41±0.06 mg/g), as compared to the NS group. A multiplex inflammatory cytokine assay was used to profile expression of 23 inflammatory mediators. Plasma levels of IL-1β, IL-4, IL-5, IL-7 and GM-CSF were significantly increased in the HS, but not in the HS-ZAMI group. Plasma levels of monocyte chemoattractant protein (MCP)-1 were higher in the HS and HS+ZAMI than in NS group (105.0±10.4 and 85.2±5.9 vs 67.6±2.8 pg/ml). The HS group, but not HS+ZAMI, showed hypercholesterolemia (4.45±0.23 and 3.72±0.37 vs 3.07±0.22 mmol/l). Both HS and HS+ZAMI cohorts had reduced levels of free fatty acids (0.23±0.02 and 0.23±0.02 vs 0.35±0.02 mmol/l) and normal levels of triglycerides in plasma (1.87±0.29 and 1.69±0.18 vs 1.28±0.15 mmol/l). Insulin plasma levels in HS and HS+ZAMI groups were lower than in NS group (1.45±0.26 and 1.90±0.22 vs 4.03±0.40 ng/ml), but the glucose levels were similar in all three groups (162±5 and 168±7 vs 150±7 mg/dl).
 In conclusion, chronic HS intake deteriorates several cardiometabolic and inflammatory biomarkers in Dahl/SS rats, which can be prevented by dopamine β-hydroxylase inhibition with zamicastat.