Matches in SemOpenAlex for { <https://semopenalex.org/work/W898934942> ?p ?o ?g. }
Showing items 1 to 98 of
98
with 100 items per page.
- W898934942 abstract "INTRODUCTION: The neurohormonal hypothesis that sympathetic activation in heart failure (HF) is toxic to the heart led to class I recommended drugs. However, contrary data suggest that sympathetic blockade in HF has limits, such as the negative effects of alpha-1-adrenergic receptor (a1-AR) blockade in humans in ALLHAT and V-HeFT. Conversely, a1-agonists protect myocytes and hearts of multiple species in multiple models through pleiotropic mechanisms, but this is untested in HF in vivo. HYPOTHESIS: We hypothesized that a1-AR agonism can treat HF in vivo. METHODS: We screened drugs in neonatal rat and adult mouse ventricular myocytes (NRVM, AMVM), measured telemetry blood pressure (BP), and did subcutaneous infusion in mice with HF from cardiotoxin (doxorubicin, DOX) and pressure overload (TAC). RESULTS: In NRVMs, the a1A agonist A61603 (A6) was the most efficacious and potent of 10 a1 agonists in ERK activation (EC50 6±1 nM, Emax 22±7) and protein synthesis (EC50 10±1 nM, Emax 1.7±0.1), and EC50s matched a1A binding affinity. In AMVMs, A6 activated ERK (EC50 39±5 nM) and protected against DOX (EC50 15±8 nM, Emax 35±6), an effect lost in the a1A KO. In isolated hearts, A6 activated ERK target genes. A6 10 ng/kg/d infused sc for 7 days had no effect on BP, but increased cardiac pERK (EC50 0.1±0.1 μg/kg/d). With DOX, A6 10 ng/kg/d started at the same time enhanced survival (A6+DOX 84%, n=21; Veh+DOX 34%, n=49). A6 also preserved function (A6 FS 61±2% vs. Veh 49±3%), and reduced serum CK (571±67 vs. 1204±98), TUNEL staining (0.5±0.1 vs. 1.3±0.2), and Sirius Red staining (25±1 vs. 32±1) (n=3-5). A6 effects on survival and FS after DOX were lost in the a1A KO. With TAC (gradient 109 mmHg), FS fell over 2 weeks to 40±1%. A6 from weeks 2 to 4 increased FS (to 51±2%, n=30), while FS remained low with Veh (39±2%, n=24). A6 after TAC did not change heart or myocytes size, but did increase pERK and bMyHC, and reduced cardiac troponin I (A6 5±2 vs. 11±2), cleaved caspase 3 (77±7% of Veh), collagens I and III (46±5% and 56±8% of Veh), and Sirius Red staining (5±4% vs. 9±8%) (n=3-22). CONCLUSIONS: The high affinity a1A-AR agonist A61603, at a low dose that does not change BP, prevents cell death and fibrosis and improves function and mortality in two mouse models of HF. a1A-AR agonists might be potential HF therapies." @default.
- W898934942 created "2016-06-24" @default.
- W898934942 creator A5015050303 @default.
- W898934942 creator A5023419507 @default.
- W898934942 creator A5035041716 @default.
- W898934942 creator A5039756370 @default.
- W898934942 creator A5044655869 @default.
- W898934942 creator A5073624652 @default.
- W898934942 creator A5080699244 @default.
- W898934942 date "2014-11-25" @default.
- W898934942 modified "2023-09-27" @default.
- W898934942 title "Abstract 20575: An Alpha-1A Adrenergic Receptor Agonist Prevents and Treats Heart Failure" @default.
- W898934942 hasPublicationYear "2014" @default.
- W898934942 type Work @default.
- W898934942 sameAs 898934942 @default.
- W898934942 citedByCount "0" @default.
- W898934942 crossrefType "journal-article" @default.
- W898934942 hasAuthorship W898934942A5015050303 @default.
- W898934942 hasAuthorship W898934942A5023419507 @default.
- W898934942 hasAuthorship W898934942A5035041716 @default.
- W898934942 hasAuthorship W898934942A5039756370 @default.
- W898934942 hasAuthorship W898934942A5044655869 @default.
- W898934942 hasAuthorship W898934942A5073624652 @default.
- W898934942 hasAuthorship W898934942A5080699244 @default.
- W898934942 hasConcept C104317684 @default.
- W898934942 hasConcept C126322002 @default.
- W898934942 hasConcept C127561419 @default.
- W898934942 hasConcept C134018914 @default.
- W898934942 hasConcept C141071460 @default.
- W898934942 hasConcept C150903083 @default.
- W898934942 hasConcept C170493617 @default.
- W898934942 hasConcept C185592680 @default.
- W898934942 hasConcept C202751555 @default.
- W898934942 hasConcept C207001950 @default.
- W898934942 hasConcept C2775944032 @default.
- W898934942 hasConcept C2778198053 @default.
- W898934942 hasConcept C2778468042 @default.
- W898934942 hasConcept C2778938600 @default.
- W898934942 hasConcept C49453240 @default.
- W898934942 hasConcept C55493867 @default.
- W898934942 hasConcept C57074206 @default.
- W898934942 hasConcept C62478195 @default.
- W898934942 hasConcept C64943373 @default.
- W898934942 hasConcept C71924100 @default.
- W898934942 hasConcept C86803240 @default.
- W898934942 hasConcept C96529984 @default.
- W898934942 hasConcept C98274493 @default.
- W898934942 hasConceptScore W898934942C104317684 @default.
- W898934942 hasConceptScore W898934942C126322002 @default.
- W898934942 hasConceptScore W898934942C127561419 @default.
- W898934942 hasConceptScore W898934942C134018914 @default.
- W898934942 hasConceptScore W898934942C141071460 @default.
- W898934942 hasConceptScore W898934942C150903083 @default.
- W898934942 hasConceptScore W898934942C170493617 @default.
- W898934942 hasConceptScore W898934942C185592680 @default.
- W898934942 hasConceptScore W898934942C202751555 @default.
- W898934942 hasConceptScore W898934942C207001950 @default.
- W898934942 hasConceptScore W898934942C2775944032 @default.
- W898934942 hasConceptScore W898934942C2778198053 @default.
- W898934942 hasConceptScore W898934942C2778468042 @default.
- W898934942 hasConceptScore W898934942C2778938600 @default.
- W898934942 hasConceptScore W898934942C49453240 @default.
- W898934942 hasConceptScore W898934942C55493867 @default.
- W898934942 hasConceptScore W898934942C57074206 @default.
- W898934942 hasConceptScore W898934942C62478195 @default.
- W898934942 hasConceptScore W898934942C64943373 @default.
- W898934942 hasConceptScore W898934942C71924100 @default.
- W898934942 hasConceptScore W898934942C86803240 @default.
- W898934942 hasConceptScore W898934942C96529984 @default.
- W898934942 hasConceptScore W898934942C98274493 @default.
- W898934942 hasLocation W8989349421 @default.
- W898934942 hasOpenAccess W898934942 @default.
- W898934942 hasPrimaryLocation W8989349421 @default.
- W898934942 hasRelatedWork W136657042 @default.
- W898934942 hasRelatedWork W1881185621 @default.
- W898934942 hasRelatedWork W2005214015 @default.
- W898934942 hasRelatedWork W2029757582 @default.
- W898934942 hasRelatedWork W2061896812 @default.
- W898934942 hasRelatedWork W2079307894 @default.
- W898934942 hasRelatedWork W2108741646 @default.
- W898934942 hasRelatedWork W2152172464 @default.
- W898934942 hasRelatedWork W2166335848 @default.
- W898934942 hasRelatedWork W2257088277 @default.
- W898934942 hasRelatedWork W2265130141 @default.
- W898934942 hasRelatedWork W2368033733 @default.
- W898934942 hasRelatedWork W2396918018 @default.
- W898934942 hasRelatedWork W2414437564 @default.
- W898934942 hasRelatedWork W2437267076 @default.
- W898934942 hasRelatedWork W2554711070 @default.
- W898934942 hasRelatedWork W2619521044 @default.
- W898934942 hasRelatedWork W2767615987 @default.
- W898934942 hasRelatedWork W3141862099 @default.
- W898934942 hasRelatedWork W91301705 @default.
- W898934942 hasVolume "130" @default.
- W898934942 isParatext "false" @default.
- W898934942 isRetracted "false" @default.
- W898934942 magId "898934942" @default.
- W898934942 workType "article" @default.