ß2 -Adrenoceptors indirectly support impaired ß1 -adrenoceptor responsiveness in the isolated type 2 diabetic rat heart.
Exp Physiol
; 104(6): 808-818, 2019 06.
Article
em En
| MEDLINE
| ID: mdl-30889297
ABSTRACT
NEW FINDINGS:
What is the central question of this study? Are there specific contributions of ß1 - and ß2 -adrenoceptor subtypes to the impaired ß-adrenoceptor responsiveness of the type 2 diabetic heart? What is the main finding and its importance? In hearts isolated from the Zucker diabetic fatty rat model of type 2 diabetes, we showed that the ß1 -adrenoceptors are the main subtype to regulate heart rate, contraction and relaxation. Notably, the ß2 -adrenoceptor subtype actions seem to support function in the diabetic heart indirectly. ABSTRACT Impaired ß-adrenoceptor (ß-AR) responsiveness causes cardiac vulnerability in patients with type 2 diabetes, but the independent contributions of ß1 - and ß2 -AR subtypes to ß-AR-associated cardiac dysfunction in diabetes are unknown. Our aim was to determine the specific ß1 - and ß2 -AR responsiveness of heart rate (HR), contraction and relaxation in the diabetic heart. Isolated Langendorff-perfused hearts of Zucker type 2 diabetic fatty (ZDF) rats were stimulated with the ß-AR agonist isoprenaline (1 × 10-11 to 3 × 10-8 mol l-1 ) with or without the selective ß1 -AR antagonist CGP20712A (3 × 10-8 mol l-1 ) or the ß2 -AR antagonist ICI-118,551 (5 × 10-8 mol l-1 ), and HR, contraction and relaxation were measured. Diabetic hearts showed lower basal HR (non-diabetic 216 ± 17 beats min-1 versus diabetic 151 ± 23 beats min-1 , P < 0.05). However, the ß-AR-induced increase in HR was similar and was completely blocked by the ß1 -AR antagonist, but not by the ß2 -AR antagonist. The ß-AR-induced increase in contraction and acceleration of relaxation was impaired in diabetic hearts, completely blocked by the ß1 -AR antagonist and partly impaired by the ß2 -AR antagonist. Western blots revealed 41% higher phosphorylation levels of AMP kinase (AMPK), a key regulator of cardiac energy metabolism, in diabetic hearts (non-diabetic 1.62 ± 0.19 a.u. versus diabetic 2.30 ± 0.25 a.u., P < 0.05). In conclusion, the ß1 -AR is the main subtype regulating chronotropic, inotropic and lusitropic ß-AR responses in the healthy heart and the type 2 diabetic heart. The ß2 -AR subtype indirectly supports the ß1 -AR functional response in the diabetic heart. This suggests that ß2 -ARs could be an indirect target to improve the function of the heart in type 2 diabetes.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Receptores Adrenérgicos beta 2
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Receptores Adrenérgicos beta 1
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Diabetes Mellitus Tipo 2
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Coração
/
Miocárdio
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Exp Physiol
Assunto da revista:
FISIOLOGIA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Nova Zelândia