Cheng Jiang1, Aude Carillion, Na Na, Audrey De Jong, Sarah Feldman, Jean-Marc Lacorte, Dominique Bonnefont-Rousselot, Bruno Riou, Julien Amour. 1. 1Sorbonne Universités UPMC Univ Paris 06, UMR INSERM-UPMC 1166, IHU ICAN, Paris, France. 2Emergency Department, Zonghnan Hospital, Wuhan University, Wuhan, The People's Republic of China. 3Department of Anesthesiology and Critical Care Medicine, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France. 4Department of Emergency Medicine and Surgery, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France. 5Department of Anesthesia and Critical Care B, Hôpital Saint-Eloi, CHU de Montpellier, Montpellier, France. 6Department of Endocrinologic and Oncologic Biochemistry, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France. 7Department of Metabolic Biochemistry, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France. 8Department of Biochemistry, Faculty of Pharmacy, Université Paris Descartes, Paris, France.
Abstract
OBJECTIVES: Although metabolic syndrome is associated with increased sympathetic activity that chronically stimulates β-adrenoceptors, the β-adrenoceptor signaling pathway has been poorly studied in this situation. We studied the β-adrenoceptor signaling pathway in Zucker lean, obese, and obese diabetic rats. DESIGN: Experimental, prospective study. SETTING: University medical research laboratory. SUBJECTS: Adult male Zucker lean (control), obese, and obese diabetic rats. INTERVENTIONS: The effects of β-adrenoceptor stimulation were investigated in vitro in isolated left ventricular papillary muscles in control, obese, and obese diabetic rats. β1-, β2-, and β3-adrenoceptors and multidrug resistance-associated protein 4 were quantified by Western Blotting. Triglyceride, cholesterol, leptin, adiponectin, and C-peptide plasma concentrations were measured. Data are mean ± SD. MEASUREMENTS AND MAIN RESULTS: Hyperlipidemia, high leptin, and C-peptide concentrations were observed in obese and obese diabetic strains, whereas hyperglycemia occurred only in the diabetic strain. The positive inotropic effect of isoproterenol was slightly reduced in obese rats (183% ± 11% of baseline; p = 0.003; n = 7) and markedly reduced in obese diabetic rats (137% ± 18% of baseline; p < 0.001; n = 10) when compared with control rats (210% ± 17% of baseline; n = 9). β1-adrenoceptors were down-regulated in obese (-41%; p = 0.02) and diabetic (-54%; p = 0.003) when compared with control rats, whereas β3-adrenoceptors and multidrug resistance-associated protein expression remained unchanged. Direct stimulation of adenylate cyclase with forskolin or administration of 3',5'-cyclic adenosine monophosphate suggests that subtle impairments also occurred beside the down-regulation of β1-adrenoceptor. CONCLUSIONS: The positive inotropic effect of β-adrenoceptor stimulation is slightly decreased in Zucker obese rats and was more markedly decreased in Zucker diabetic rats. These decreases are mainly related to β1-adrenoceptor down-regulation.
OBJECTIVES: Although metabolic syndrome is associated with increased sympathetic activity that chronically stimulates β-adrenoceptors, the β-adrenoceptor signaling pathway has been poorly studied in this situation. We studied the β-adrenoceptor signaling pathway in Zucker lean, obese, and obese diabeticrats. DESIGN: Experimental, prospective study. SETTING: University medical research laboratory. SUBJECTS: Adult male Zucker lean (control), obese, and obese diabeticrats. INTERVENTIONS: The effects of β-adrenoceptor stimulation were investigated in vitro in isolated left ventricular papillary muscles in control, obese, and obese diabeticrats. β1-, β2-, and β3-adrenoceptors and multidrug resistance-associated protein 4 were quantified by Western Blotting. Triglyceride, cholesterol, leptin, adiponectin, and C-peptide plasma concentrations were measured. Data are mean ± SD. MEASUREMENTS AND MAIN RESULTS:Hyperlipidemia, high leptin, and C-peptide concentrations were observed in obese and obese diabetic strains, whereas hyperglycemia occurred only in the diabetic strain. The positive inotropic effect of isoproterenol was slightly reduced in obeserats (183% ± 11% of baseline; p = 0.003; n = 7) and markedly reduced in obese diabeticrats (137% ± 18% of baseline; p < 0.001; n = 10) when compared with control rats (210% ± 17% of baseline; n = 9). β1-adrenoceptors were down-regulated in obese (-41%; p = 0.02) and diabetic (-54%; p = 0.003) when compared with control rats, whereas β3-adrenoceptors and multidrug resistance-associated protein expression remained unchanged. Direct stimulation of adenylate cyclase with forskolin or administration of 3',5'-cyclic adenosine monophosphate suggests that subtle impairments also occurred beside the down-regulation of β1-adrenoceptor. CONCLUSIONS: The positive inotropic effect of β-adrenoceptor stimulation is slightly decreased in Zucker obeserats and was more markedly decreased in Zucker diabeticrats. These decreases are mainly related to β1-adrenoceptor down-regulation.
Authors: Gizele Cabral Costa; Tadeu Lima Montagnoli; Jaqueline Soares Da Silva; Allan Kardec Nogueira de Alencar; Luis Eduardo Reina Gamba; Bryelle Eccard Oliveira Alves; Marina Moraes Carvalho da Silva; Margarete Manhães Trachez; José Hamilton M do Nascimento; Pedro Moreno Pimentel-Coelho; Rosália Mendez-Otero; Lidia Moreira Lima; Eliezer J Barreiro; Roberto Takashi Sudo; Gisele Zapata-Sudo Journal: Drug Des Devel Ther Date: 2020-08-17 Impact factor: 4.162