β3-Adrenoceptor-mediated responses in diabetic rat heart

Abstract

β3-adrenoceptors mediate negative inotropic effect in contrast to classical β1- and β2-adrenoceptors. Cardiac β3-adrenoceptors are upregulated in experimental diabetes. Thus, cardiodepressant effect mediated by β3-adrenoceptors has been proposed to contribute to the impaired cardiac function in this pathology. In our study, we investigated the influence of streptozotocin-diabetes on cardiac contractility to β3-adrenoceptors stimulation by using Langendorff-perfused rat hearts. BRL 37344, a selective β3-adrenoceptor agonist, induced dose-dependent decreases in left ventricular developed pressure (LVDP) in hearts from control rats. BRL 37344 also dose-dependently decreased +dP/dt and -dP/dt values. Effects of BRL 37344 were abolished by SR 59230, but not altered by nadolol pre-treatment. On the other hand, these effects of BRL 37344 were all significantly increased in hearts from diabetic rats. We also observed that diabetes significantly increased the mRNA levels encoding cardiac β3-adrenoceptors. In addition, Giα2 mRNA expressions were found to be increased in the cardiac tissue of diabetic rats as well. The effect of BRL 37344 on cardiac contractility was normalized upon treatment of diabetic rats with insulin. These data demonstrate an increased effect of β3-adrenoceptor stimulation on hemodynamic function of the heart in accordance with an increased mRNA levels encoding cardiac β3-adrenoceptors in 8-week diabetic rats.

Effects of sitagliptin on ß-adrenoceptor mediated relaxation in streptozotocin-diabetic rat aorta

“…Our findings are in line with the previous studies on ß3-AR-mediated-vasorelaxation and the localization of the receptor [9,10,23]. We proposed that the response may be different in diabetic aorta since ß3-AR-mediated cardiac responses have been found to be changed in diabetes [24,25]. Furthermore, the expression of this subtype is upregulated in cardiac pathologies such as diabetes or heart failure [24][25][26][27][28][29].…”

Agonist‐induced desensitisation of β3‐adrenoceptors: Where, when, and how?

“…These data have led to the hypothesis that β 3 ‐adrenoceptor agonists could be useful in patients with heart failure (Rasmussen, Figtree, Krum, & Bundgaard, ). An up‐regulation of cardiac β 3 ‐adrenoceptor expression at the mRNA level has also repeatedly (Amour et al, , ; Dinçer et al, ; Kayki‐Mutlu, Arioglu Inan, Ozakca, Ozcelikay, & Altan, ) but not unequivocally (Haley, Thackeray, Kolajova, Thorn, & DaSilva, ; Jiang et al, ) been observed in animal models of diabetes or of hypothyroidism (Arioglu, Guner, Ozakca, Altan, & Ozcelikay, ). Nevertheless, β 3 ‐adrenoceptors were also reported to be down‐regulated in an animal model of colitis, where treatment with an agonist improved symptoms and reversed the down‐regulation (Vasina et al, ).…”

Cardiac β3‐adrenoceptors—A role in human pathophysiology?

“…* P < 0.05, *** P < 0.001, control versus diabetic; # P < 0.05, ## P < 0.01, diabetic versus insulin‐treated diabetic; ɸ P < 0.05, comparison of the different concentration–response curves by two‐way ANOVA. Adapted with permission from (Kayki‐Mutlu et al, )…”

“…Studies in several, but not all animal models of diabetes, have found increased cardiac β 3 ‐adrenoceptor expression at the mRNA and/or protein level (Table ). Thus, an up‐regulation was found in rats treated with streptozotocin, a type 1 diabetes model, at the mRNA (Dinçer et al, ; Kayki‐Mutlu et al, ) and protein level (Amour et al, ; Amour et al, ; Dinçer et al, ). One of these studies also demonstrated that treatment with insulin restored β 3 ‐adrenoceptor expression to normal levels (Dinçer et al, ).…”

“…Barbier, Mouas, Rannou-Bekono, & Carré, 2007;Kayki-Mutlu, Arioglu Inan, Ozakca, Ozcelikay, & Altan, 2014;Ozakca et al, 2013; …”