title: 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.
authors.affiliation: Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Pharmacy, The Second Affiliated Hospital of Hunan University of Traditional Chinese Medicine, Changsha, Hunan 410013, P.R. China.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Liu
authors.affiliation: Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China.
authors.forename: Jia
authors.initials: J
authors.lastname: Wen
authors.affiliation: Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China.
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Huang
authors.affiliation: Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China.
authors.forename: Ru-Jia
authors.initials: RJ
authors.lastname: Miao
authors.affiliation: Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China.
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China.
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Xing
authors.affiliation: Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yuan
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects*; D002460:Cell Line; D000229:Dependovirus / Q000235:genetics; D015536:Down-Regulation; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D008790:Metoprolol / Q000494:pharmacology* / Q000627:therapeutic use; D009206:Myocardium / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D018342:Receptors, Adrenergic, beta-1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000959:Antihypertensive Agents; D034741:RNA, Small Interfering; D018342:Receptors, Adrenergic, beta-1; D008790:Metoprolol