Effects of dopamine β-hydroxylase inhibition in pressure overload-induced right ventricular failure
Stine Andersen, Julie Sørensen Axelsen, Anders H. Nielsen-Kudsk, Janne Schwab, Caroline D. Jensen, Steffen Ringgaard, Asger Andersen, Rowan Smal, Aida Llucià-Valldeperas, Frances Handoko de Man, Bruno Igreja, Nuno Pires
https://doi.org/10.1002/pul2.70008
Abstract
Activation of the sympathetic nervous system is observed in pulmonary arterial hypertension patients. This study investigates whether inhibiting the conversion of dopamine into noradrenaline by dopamine β-hydroxylase (DβH) inhibition with BIA 21-5337 improved right ventricular (RV) function or remodeling in pressure overload-induced RV failure. RV failure was induced in male Wistar rats by pulmonary trunk banding (PTB). Two weeks after the procedure, PTB rats were randomized to vehicle (n = 8) or BIA 21-5337 (n = 11) treatment. An additional PTB group treated with ivabradine (n = 11) was included to control for the potential heart rate-reducing effects of BIA 21-5337. A sham group (n = 6) received vehicle treatment. After 5 weeks of treatment, RV function was assessed by echocardiography, magnetic resonance imaging, and invasive pressure–volume measurements before rats were euthanized. RV myocardium was analyzed to evaluate RV remodeling. PTB caused a fourfold increase in RV afterload which led to RV dysfunction, remodeling, and failure. Treatment with BIA 21-5337 reduced adrenal gland DβH activity and 24-h urinary noradrenaline levels confirming relevant physiological response to the treatment. At end-of-study, there were no differences in RV function or RV remodeling between BIA 21-5337 and vehicle-treated rats. In conclusion, treatment with BIA 21-5337 did not have any beneficial—nor adverse—effects on the development of RV failure after PTB despite reduced adrenal gland DβH activity.