Effects of dopamine β-hydroxylase inhibition in pressure overload-induced right ventricular failure.

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 β H) 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 β H 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 β H activity.
Competing Interests: B. I. and N. P were employees of BIAL‐Portela & Cª, S.A. (the sponsor of the study) at the time of the study. The remaining authors declare no conflict of interest.
(© 2024 BIAL. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)