Abstract
ABSTRACTWe examined the role of spinally located β-adrenergic receptors in the regulation of the blood glucose level. The intrathecal (i.t.) injections with dobutamine (β1-adrenergic receptor agonist) or terbutaline (β2-adrenergic receptor agonist) caused an elevation of the blood glucose level, whereas metoprolol (β1-adrenergic receptor antagonist) or butoxamine (β2-adrenergic receptor antagonist) did not. In addition, i.t. pretreatment with pertussis toxin (PTX) attenuated the hyperglycemic effect induced by dobutamine or terbutaline. Moreover, plasma insulin level was increased by dobutamine but not by terbutaline, and PTX reduced dobutamine-induced up-regulation of the plasma insulin level. Terbutaline significantly increased plasma corticosterone level, and PTX further enhanced terbutaline-induced corticosterone level. Furthermore, intraperitoneal (i.p.) pretreatment with hexamethonium- (a preganglionic blocker) attenuated dobutamine- and terbutaline-induced hyperglycemic effects. Our results suggest that activation of spinal β1- and β2-adrenergic receptors produces hyperglycemic effects in a different manner. Spinally located PTX-sensitive G-proteins appear to be involved in hyperglycemic effect induced by terbutaline. Furthermore, dobutamine- or terbutaline-induced hyperglycemia appears to be mediated through the spinal nerves.
Highlights
Norepinephrine or epinephrine exerts a variety of physiological functions and the activation of adrenergic receptors by adrenergic receptor agonists produces a several pharmacological effects (Aston-Jones et al 1999; Ramos and Arnsten 2007; Hysek et al 2012)
Dobutamineand terbutaline-induced blood glucose level reached at maximal level at 30 min and returned almost to the control level at 120 min after drug injection, In contrast to the result with β-adrenergic receptor agonists, i.t. administration with metoprolol or butoxamine alone did not have any effect on the blood glucose level (Figure 1(B,D))
Spinal administration of anti-diabetic agents like biguanide, thizolidinediones or repaglidine modulates the blood glucose level, whereas ghrelin receptors located in the spinal cord plays important roles in the elevation of the blood glucose level (Sim et al 2012b; Sim et al 2013; Sim et al 2014a)
Summary
Norepinephrine or epinephrine exerts a variety of physiological functions and the activation of adrenergic receptors by adrenergic receptor agonists produces a several pharmacological effects (Aston-Jones et al 1999; Ramos and Arnsten 2007; Hysek et al 2012). Epinephrine binds to the β-adrenergic receptor of the pancreatic α-cell (Schuit and Pipeleers 1986), leading to protein kinase A (PKA)-dependent enhancement which causes the increase of cAMP and exocytotic response (Gromada et al 2001). Several lines of evidence suggest that β-adrenergic receptor appears to be important for the regulation of the glucose level and metabolism. The elevation of insulin and the reduction of blood glucose levels are observed in β-adrenergic receptor knockout mouse (Asensio et al 2005). Ritodrine (a β2-adrenergic receptor agonist) decreases glucose concentration and increases blood insulin level under fasting condition (Tsuchiya et al 2012). A recent study has reported that β-adrenergic receptors are up-regulated in the skeletal muscle in the streptozotocin-induced diabetic model (Xavier et al 2012)
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