Carvedilol induces biased ß1 adrenergic receptor-nitric oxide synthase 3-cyclic guanylyl monophosphate signalling to promote cardiac contractility.
Cardiovasc Res
; 117(10): 2237-2251, 2021 08 29.
Article
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| MEDLINE
| ID: mdl-32956449
ABSTRACT
AIMS:
ß-blockers are widely used in therapy for heart failure and hypertension. ß-blockers are also known to evoke additional diversified pharmacological and physiological effects in patients. We aim to characterize the underlying molecular signalling and effects on cardiac inotropy induced by ß-blockers in animal hearts. METHODS ANDRESULTS:
Wild-type mice fed high-fat diet (HFD) were treated with carvedilol, metoprolol, or vehicle and echocardiogram analysis was performed. Heart tissues were used for biochemical and histological analyses. Cardiomyocytes were isolated from normal and HFD mice and rats for analysis of adrenergic signalling, calcium handling, contraction, and western blot. Biosensors were used to measure ß-blocker-induced cyclic guanosine monophosphate (cGMP) signal and protein kinase A activity in myocytes. Acute stimulation of myocytes with carvedilol promotes ß1 adrenergic receptor (ß1AR)- and protein kinase G (PKG)-dependent inotropic cardiac contractility with minimal increases in calcium amplitude. Carvedilol acts as a biased ligand to promote ß1AR coupling to a Gi-PI3K-Akt-nitric oxide synthase 3 (NOS3) cascade and induces robust ß1AR-cGMP-PKG signal. Deletion of NOS3 selectively blocks carvedilol, but not isoproterenol-induced ß1AR-dependent cGMP signal and inotropic contractility. Moreover, therapy with carvedilol restores inotropic contractility and sensitizes cardiac adrenergic reserves in diabetic mice with minimal impact in calcium signal, as well as reduced cell apoptosis and hypertrophy in diabetic hearts.CONCLUSION:
These observations present a novel ß1AR-NOS3 signalling pathway to promote cardiac inotropy in the heart, indicating that this signalling paradigm may be targeted in therapy of heart diseases with reduced ejection fraction.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Cardiotónicos
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Receptores Adrenérgicos beta 1
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GMP Cíclico
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Miocitos Cardíacos
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Óxido Nítrico Sintasa de Tipo III
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Antagonistas de Receptores Adrenérgicos alfa 1
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Carvedilol
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Cardiopatías
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Contracción Miocárdica
Límite:
Animals
Idioma:
En
Revista:
Cardiovasc Res
Año:
2021
Tipo del documento:
Article
País de afiliación:
China