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

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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 (D βH) 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 D βH 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 D βH activity.

OriginalsprogEngelsk
Artikelnummere70008
TidsskriftPulmonary Circulation
Vol/bind14
Nummer4
Sider (fra-til)e70008
ISSN2045-8932
DOI
StatusUdgivet - okt. 2024

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