BACKGROUND: In the diabetic heart, the positive inotropic response to beta-adrenoceptor stimulation is altered and beta1 and beta2 adrenoceptors are down-regulated, whereas beta3 adrenoceptor is up-regulated. In heart failure, beta3-adrenoceptor stimulation induces a negative inotropic effect that results from endothelial nitric oxide synthase (NOS3)-derived nitric oxide production. The objective of our study was to investigate the role of beta3-adrenoceptor in diabetic cardiomyopathy. METHODS: beta-Adrenergic responses were investigated in vivo (dobutamine echocardiography) and in vitro (left ventricular papillary muscle) in healthy and streptozotocin-induced diabetic rats. The effect of beta3-adrenoceptor inhibition on the inotropic response was studied in vitro. Immunoblots and NOS activities were performed in heart homogenates (electron paramagnetic resonance) and isolated cardiomyocytes. Data are mean percentage of baseline +/- SD. RESULTS: The impaired positive inotropic effect was confirmed in diabetes both in vivo (121 +/- 15% vs. 160 +/- 16%; P < 0.05) and in vitro (112 +/- 5% vs. 179 +/- 15%; P < 0.05). In healthy rat, the positive inotropic effect was not significantly modified in presence of beta3-adrenoceptor antagonist (174 +/- 20%), nonselective NOS inhibitor (N -nitro-l-arginine methylester [l-NAME]; 183 +/- 19%), or selective NOS1 inhibitor (vinyl-l-N-5-(1-imino-3-butenyl)-l-ornithine [l-VNIO]; 172 +/- 13%). In diabetes, in parallel with the increase in beta3-adrenoceptor protein expression, the positive inotropic effect was partially restored by beta3-adrenoceptor antagonist (137 +/- 8%; P < 0.05), l-NAME (133 +/- 11%; P < 0.05), or l-VNIO (130 +/- 13%; P < 0.05). Nitric oxide was exclusively produced by NOS1 within diabetic cardiomyocytes. NOS2 and NOS3 proteins were undetectable. CONCLUSIONS: beta3-Adrenoceptor is involved in altered positive inotropic response to beta-adrenoceptor stimulation in diabetic cardiomyopathy. This effect is mediated by NOS1-derived nitric oxide in diabetic cardiomyocyte.
BACKGROUND: In the diabetic heart, the positive inotropic response to beta-adrenoceptor stimulation is altered and beta1 and beta2 adrenoceptors are down-regulated, whereas beta3 adrenoceptor is up-regulated. In heart failure, beta3-adrenoceptor stimulation induces a negative inotropic effect that results from endothelial nitric oxide synthase (NOS3)-derived nitric oxide production. The objective of our study was to investigate the role of beta3-adrenoceptor in diabetic cardiomyopathy. METHODS: beta-Adrenergic responses were investigated in vivo (dobutamine echocardiography) and in vitro (left ventricular papillary muscle) in healthy and streptozotocin-induced diabeticrats. The effect of beta3-adrenoceptor inhibition on the inotropic response was studied in vitro. Immunoblots and NOS activities were performed in heart homogenates (electron paramagnetic resonance) and isolated cardiomyocytes. Data are mean percentage of baseline +/- SD. RESULTS: The impaired positive inotropic effect was confirmed in diabetes both in vivo (121 +/- 15% vs. 160 +/- 16%; P < 0.05) and in vitro (112 +/- 5% vs. 179 +/- 15%; P < 0.05). In healthy rat, the positive inotropic effect was not significantly modified in presence of beta3-adrenoceptor antagonist (174 +/- 20%), nonselective NOS inhibitor (N -nitro-l-arginine methylester [l-NAME]; 183 +/- 19%), or selective NOS1 inhibitor (vinyl-l-N-5-(1-imino-3-butenyl)-l-ornithine [l-VNIO]; 172 +/- 13%). In diabetes, in parallel with the increase in beta3-adrenoceptor protein expression, the positive inotropic effect was partially restored by beta3-adrenoceptor antagonist (137 +/- 8%; P < 0.05), l-NAME (133 +/- 11%; P < 0.05), or l-VNIO (130 +/- 13%; P < 0.05). Nitric oxide was exclusively produced by NOS1 within diabetic cardiomyocytes. NOS2 and NOS3 proteins were undetectable. CONCLUSIONS:beta3-Adrenoceptor is involved in altered positive inotropic response to beta-adrenoceptor stimulation in diabetic cardiomyopathy. This effect is mediated by NOS1-derived nitric oxide in diabetic cardiomyocyte.
Authors: Xiaolin Niu; Vabren L Watts; Oscar H Cingolani; Vidhya Sivakumaran; Jordan S Leyton-Mange; Carla L Ellis; Karen L Miller; Konrad Vandegaer; Djahida Bedja; Kathleen L Gabrielson; Nazareno Paolocci; David A Kass; Lili A Barouch Journal: J Am Coll Cardiol Date: 2012-05-29 Impact factor: 24.094
Authors: Juan P Aragón; Marah E Condit; Shashi Bhushan; Benjamin L Predmore; Sandeep S Patel; D Bennett Grinsfelder; Susheel Gundewar; Saurabh Jha; John W Calvert; Lili A Barouch; Madhav Lavu; Harold M Wright; David J Lefer Journal: J Am Coll Cardiol Date: 2011-12-13 Impact factor: 24.094
Authors: Nadège Salvi; Aziz Guellich; Pierre Michelet; Alexandre Demoule; Morgan Le Guen; Laure Renou; Gisèle Bonne; Bruno Riou; Olivier Langeron; Catherine Coirault Journal: PLoS One Date: 2010-07-08 Impact factor: 3.240
Authors: An L Moens; Jordan S Leyton-Mange; Xiaolin Niu; Ronghua Yang; Oscar Cingolani; Elisabeth K Arkenbout; Hunter C Champion; Djahida Bedja; Kathleen L Gabrielson; Juan Chen; Yong Xia; Ashley B Hale; Keith M Channon; Marc K Halushka; Norman Barker; Floris L Wuyts; Pawel M Kaminski; Michael S Wolin; David A Kass; Lili A Barouch Journal: J Mol Cell Cardiol Date: 2009-09-18 Impact factor: 5.000