Downregulation of the β1 adrenergic receptor in the myocardium results in insensitivity to metoprolol and reduces blood pressure in spontaneously hypertensive rats

Abstract

The β1-adrenergic receptor (AR) is the primary β-AR subtype in the heart and is the target of metoprolol (Met), which is commonly used to treat angina and hypertension. Previous studies have revealed a positive correlation between the methylation levels of the adrenoreceptor β1 gene (Adrb1) promoter in the myocardium with the antihypertensive activity of Met in spontaneously hypertensive rats (SHR), which affects β1-AR expression in H9C2 cells. The aim of the present study was to investigate the effects of myocardial β1-AR downregulation using short-hairpin RNA (shRNA) against Adrb1 on the antihypertensive activity of Met in SHR. Recombinant adeno-associated virus type 9 (rAAV9) vectors carrying Adrb1 shRNA (rAAV9-Adrb1) or a negative control sequence (rAAV9-NC) were generated and used to infect rat hearts via the pericardial cavity. The results of reverse transcription-quantitative polymerase chain reaction, immunohistochemistry and western blotting analyses demonstrated that cardiac β1-AR expression in the rAAV9-Adrb1 group was significantly downregulated when compared with the rAAV9-NC group (P<0.001, P<0.001 and P=0.032, respectively). In addition, a greater reduction in systolic blood pressure (SBP) was observed in the rAAV9-NC group compared with the rAAV9-Adrb1 group following Met treatment (P=0.035). Furthermore, downregulation of myocardial β1-AR was associated with a significant decrease in SBP (P<0.001). In conclusion, these data suggest that suppression of β1-AR expression in the myocardium reduces SBP and sensitivity to Met in SHR.