title: Blood pressure decrease in spontaneously hypertensive rats folowing renal denervation or dopamine β-hydroxylase inhibition with etamicastat.
abstract: Overactivity of the sympathetic nervous system has an important role in the development and progression of arterial hypertension. Catheter-based renal nerve ablation for the treatment of drug-resistant hypertension has recently been developed. An alternative strategy for the modulation of sympathetic nerve function is to reduce the biosynthesis of noradrenaline (NA) by inhibiting dopamine β-hydroxylase (DβH), the enzyme that catalyzes the conversion of dopamine (DA) to NA in the sympathetic nerves. Renal denervation (RDN) surgery was performed in spontaneously hypertensive rats (SHR) to evaluate the effect of RDN on the DA and NA levels and on blood pressure over a 28-day period. The selective peripheral DβH inhibitor etamicastat (30 mg kg (-1)day(-1)) was administered to another cohort of SHR. RDN and etamicastat treatment had no effect on the renal function, as assessed by measuring the water balance response, renal function and urinary electrolyte levels. RDN significantly decreased the systolic blood pressure (SBP) and the diastolic blood pressure (DBP). A gradual return of the SBP and the DBP to the high baseline levels was observed over time. Conversely, treatment with etamicastat resulted in a significant decrease in the SBP and the DBP at all time points. On the last day of the assessment, NA levels in renal tissue were significantly decreased in both RDN and etamicastat-treated groups. In contrast, the NA levels in the left ventricle were decreased only in the etamicastat-treated group. Thus, RDN produces transitory decreases in blood pressure, whereas prolonged downregulation of sympathetic drive with the DβH inhibitor etamicastat results in a sustained decrease in the SBP and the DBP.
authors: Department of Research & Development, BIAL-Portela & Ca, S.A., S. Mamede do Coronado, Portugal.
authors: Nuno Miguel
authors: NM
authors: Pires
authors: Department of Research & Development, BIAL-Portela & Ca, S.A., S. Mamede do Coronado, Portugal.
authors: Bruno
authors: B
authors: Igreja
authors: Department of Research & Development, BIAL-Portela & Ca, S.A., S. Mamede do Coronado, Portugal.
authors: Eduardo
authors: E
authors: Moura
authors: Department of Research & Development, BIAL-Portela & Ca, S.A., S. Mamede do Coronado, Portugal.
authors: Lyndon Christopher
authors: LC
authors: Wright
authors: Department of Pharmacology & Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal.|MedInUP - Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal.
authors: Maria Paula
authors: MP
authors: Serrão
authors: Department of Research & Development, BIAL-Portela & Ca, S.A., S. Mamede do Coronado, Portugal.|Department of Pharmacology & Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal.|MedInUP - Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal.
authors: Patrício
authors: P
authors: Soares-da-Silva
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D003714:Denervation; D004298:Dopamine / Q000378:metabolism; D004299:Dopamine beta-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D007093:Imidazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D007668:Kidney / Q000294:innervation*; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D014882:Water-Electrolyte Balance / Q000187:drug effects
chemical_list: D001578:Benzopyrans; D004791:Enzyme Inhibitors; D007093:Imidazoles; C509002:etamicastat; D004299:Dopamine beta-Hydroxylase; D004298:Dopamine; D009638:Norepinephrine