Activation of the Sympathoadrenal System under the Influence of Glucagon-Like Peptide-1 Mimetic in Rats

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Abstract

Glucagon-like peptide-1 (GLP-1) is the main incretin that ensures insulin secretion and normalization of postprandial glycemia. GLP-1 mimetics are used for treatment of type 2 diabetes mellitus and obesity. Besides the insulinotropic effect, GLP-1 and its mimetics have been shown to affect on the functions of the cardiovascular and endocrine systems, the central mechanisms of appetite and metabolism regulation, the ion-regulatory and osmoregulatory renal functions, and a paradoxical hyperglycemic effect of incretin mimetics was also discovered. In current work the mechanisms by which the sympathoadrenal system is involved in the development of hyperglycemic and natriuretic effects of the GLP-1 mimetic exenatide in rats were studied. Experiments with healthy rats revealed that GLP-1 and its mimetic exenatide augmented the renal sodium excretion. Exenatide at doses of 0.15-5 nmol/kg, but not GLP-1 (1.5 nmol/kg), showed a hyperglycemic effect (blood glucose increased to 7.2–9.1 mM during the first hour). It has been shown that the rise of blood glucose level in rats administrated with incretin mimetic was associated with increase in renal excretion of catecholamine metabolites, was delayed by preliminary injection of a ganglionic blocker (pentamine 30 mg/kg) and was considerably leveled by non-selective β- and selective β2-adrenergic blockers (propranolol 5 mg/kg, ICI-118551 1 mg/kg). A significant modulation of natriuresis was revealed in response to the administration of exenatide during blockade of various adrenergic receptors subtypes. α1- and α2-blockers appreciably reduced (by 80%), and β1- and β2-blockers increased (by 150%) exenatide-stimulated renal sodium excretion. Thus, the data obtained indicate on the exenatide-induced activation of the sympathoadrenal system, which modulates the direction and severity of the incretin mimetic effects on blood glucose level and renal sodium excretion in healthy animals. The potential action on the sympathoadrenal system is important to consider when assessing the risk of adverse side effects during incretin mimetic therapy.

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About the authors

E. V. Balbotkina

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: kutina_anna@mail.ru
Russian Federation, Saint Petersburg

A. S. Marina

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: kutina_anna@mail.ru
Russian Federation, Saint Petersburg

A. V. Kutina

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Author for correspondence.
Email: kutina_anna@mail.ru
Russian Federation, Saint Petersburg

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2. Fig. 1. Schematic of the experimental groups. P - randomisation into groups (3, 4 or 6 groups of 10 animals each), O - rest, M 2 and M 4 - urine collection 2 and 4 h, G 30 and G din - determination of capillary blood glucose from the tail tip at 30 min or in dynamics at 0, 30, 60, 90 and 120 min of the experiment. E 0.05, E 0.15, E 0.5, E 1.5 and E 5 - exenatide at doses of 0.05, 0.15, 0.5, 1.5 and 5 nmol/kg, GPP-1 - glucagon-like peptide-1 (1. 5 nmol/kg), B - vildagliptin (1 mg/kg), P - pentamine (30 mg/kg), α - phentolamine (1 mg/kg), α1 - doxazosin (1 mg/kg), α2 - rauwolscine (1 mg/kg), β - propranolol (5 mg/kg), β1 - atenolol (2 mg/kg), β2 - ICI-118551 (1 mg/kg), β3 - L-748337 (1 mg/kg), K - control ($ - 0. 9% NaCl solution intramuscularly 1 ml/kg, # - 5% DMSO intraperitoneally 1 ml/kg + 0.9% NaCl solution intramuscularly 1 ml/kg, & - 0.9% NaCl intraperitoneally 1 ml/kg, § - water for injection intraperitoneally 1 ml/kg + 0.9% NaCl solution intramuscularly 1 ml/kg). In some series, in addition to exenatide, adrenoreceptor antagonists were administered as a control: @ - water for injection intraperitoneally 1 ml/kg, * - 5% aqueous DMSO solution intraperitoneally 1 ml/kg

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3. Fig. 2. Blood glucose concentration and urinary excretion of sodium ions in rats after administration of exenatide at different doses. Here and in Figs. 3-9 data are presented as median and interquartile ranges, here and in Figs. 3-6 and 8-9 dots show individual observations. * - statistically significant differences compared to control (0 nmol/kg), Mann-Whitney test with Bonferroni correction for 5 comparisons

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4. Fig. 3. Blood glucose concentration and excretion of sodium ions with urine in rats after administration of GPP-1, vildagliptin, GPP-1 + vildagliptin. K - control (0.9% NaCl solution intraperitoneally 1 ml/kg), B - vildagliptin (1 mg/kg), GPP-1 - glucagon-like peptide-1 (1.5 nmol/kg). * - statistically significant differences compared to control, Mann-Whitney test with Bonferroni correction for 3 comparisons

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5. Fig. 4. Excretion of adrenaline and noradrenaline metabolites with urine in rats after exenatide administration. * - statistically significant differences compared to control (0 nmol/kg), Mann-Whitney test with Bonferroni correction for 2 comparisons

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6. Fig. 5. Effect of gangliblocker pentamine on the development of hyperglycaemia in rats after exenatide administration. K - control (water for injection intraperitoneally 1 ml/kg + 0.9% NaCl solution intramuscularly 1 ml/kg), P - pentamine (30 mg/kg), E 0.5 and E 5 - exenatide (0.5 and 5 nmol/kg). * - statistically significant differences compared to the corresponding group without pentamine administration, Mann-Whitney test

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7. Fig. 6. Effect of non-selective α- and β-adrenoblockers on blood glucose concentration in rats. K - control (water for injection intraperitoneally 1 ml/kg + 0.9% NaCl solution intramuscularly 1 ml/kg), E 0.5 and E 5 - exenatide (0.5 and 5 nmol/kg), β - non-selective β-adrenoblocker propranolol at a dose of 5 mg/kg, α - non-selective α-adrenoblocker phentolamine at a dose of 1 mg/kg. * - statistically significant differences compared with the corresponding group without adrenoblocker administration, Mann-Whitney test without or with Bonferroni correction for 2 comparisons

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8. Fig. 7. Dynamics of blood glucose concentration within 2 hours after exenatide administration at a dose of 5 nmol/kg. 1 - control (water for injection intraperitoneally 1 ml/kg + 0.9% NaCl solution intramuscularly 1 ml/kg), 2 - exenatide, 3 - pentamin + exenatide, 4 - propranolol + exenatide. Statistically significant differences (p<0.05): * - compared to control, # - compared to exenatide 5 nmol/kg, Mann-Whitney test with correction for 6 comparisons

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9. Fig. 8. Blood glucose concentration in rats in response to exenatide after prior administration of blockers of individual β-adrenoreceptor subtypes. E - exenatide (0.5 nmol/kg), β1 - atenolol (2 mg/kg), β2 - ICI-11855 (1 mg/kg), β3 - L-748337 (1 mg/kg). In the group without antagonists, water for injection intraperitoneally 1 ml/kg (n = 5) or 5% aqueous DMSO solution intraperitoneally 1 ml/kg (n = 5) was administered as a control. * - statistically significant differences compared to the group without adrenoblocker administration, Mann-Whitney test with Bonferroni correction for 3 comparisons

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10. Fig. 9. Sodium ion excretion in rats after exenatide administration against the background of preliminary blockade of adrenoreceptors. E - exenatide (0.5 nmol/kg), α - phentolamine (1 mg/kg), α1 - doxazosin (1 mg/kg), α2 - rauwolscine (1 mg/kg), β - propranolol (5 mg/kg), β1 - atenolol (2 mg/kg), β2 - ICI-11855 (1 mg/kg), β3 - L-748337 (1 mg/kg). In the group without antagonists, water for injection intraperitoneally 1 ml/kg (n = 5) or 5% aqueous DMSO solution intraperitoneally 1 ml/kg (n = 5) was administered as a control. * - statistically significant differences compared to the group without adrenoblocker administration, Mann-Whitney test with Bonferroni correction for 7 comparisons

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