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- W156901277 abstract "Background: Alpha-1-adrenergic receptor (AR) agonists classically increase blood pressure (BP). Among the 3 alpha-1-AR subtypes, A, B, and D, the alpha-1A is required for cardiac protection in a knockout (KO) mouse, and is sufficient for protection of cultured cardiac myocytes, via ERK activation. However, it is unknown if activation of the alpha-1A-subtype by a drug can protect the heart in vivo. Hypothesis: At a dose that does not increase BP, an agonist selective for the alpha-1A-AR subtype can prevent cardiomyopathy. Methods: We gave the alpha-1A agonist A61603 (A6) to 11 week-old wild type (WT) male C57Bl6J mice by osmotic minipump. We induced cardiomyopathy with a single dose of doxorubicin (DOX) (25 mg/kg IP), a cardiotoxic cancer drug. We measured BP by tail cuff, activated (phosphorylated, P)-ERK by immunoblot, heart mRNAs by RT-qPCR, fractional shortening (FS) by echocardiog-raphy (ECHO), myocyte necrosis by serum creatine kinase (CK), apoptosis by TUNEL stain, and fibrosis by sirius red stain. Results : In dose-finding experiments (0.01–100 ug/kg/d), A6 at 10 ng/kg/d over 7 days had no effect on daily tail cuff BP (average mmHg Vehicle 115 ± 4; A6 119 ± 4), but increased heart P-ERK (1.7-fold) and the mRNAs for beta-MyHC and ANF (5-fold). A6 at higher doses increased BP. Next, A6 at the non-hypertensive dose (10 ng/kg/d) or vehicle was infused over 7 days after a single DOX injection. The TABLE shows that DOX caused cardiomyopathy, with reduced survival and FS, and increased necrosis, apoptosis, and fibrosis (data are mean ± SE). A6 prevented all of these abnormalities. In alpha-1A-subtype KO mice, DOX caused increased apoptosis and mortality compared with WT mice, and A6 had no beneficial effect (not shown), indicating specificity of A6. Conclusions: A very low dose of an agonist selective for the alpha-1A-AR subtype can activate cardiac survival signaling (P-ERK), induce cardiac fetal genes, and prevent DOX-induced cardiomyopathy, all without increasing BP." @default.
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- W156901277 date "2008-10-28" @default.
- W156901277 modified "2023-10-09" @default.
- W156901277 title "Abstract 5355: An Alpha-1A-Adrenergic Receptor Subtype Agonist Prevents Cardiomyopathy Without Increasing Blood Pressure" @default.
- W156901277 doi "https://doi.org/10.1161/circ.118.suppl_18.s_533-b" @default.
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