Angiotensin II AT2 Receptors Contribute to Regulate the Sympathoadrenal and Hormonal Reaction to Stress Stimuli.

Angiotensin II, through AT1 receptor stimulation, mediates multiple cardiovascular, metabolic, and behavioral functions including the response to stressors. Conversely, the function of Angiotensin II AT2 receptors has not been totally clarified. In adult rodents, AT2 receptor distribution is very limited but it is particularly high in the adrenal medulla. Recent results strongly indicate that AT2 receptors contribute to the regulation of the response to stress stimuli. This occurs in association with AT1 receptors, both receptor types reciprocally influencing their expression and therefore their function. AT2 receptors appear to influence the response to many types of stressors and in all components of the hypothalamic-pituitary-adrenal axis. The molecular mechanisms involved in AT2 receptor activation, the complex interactions with AT1 receptors, and additional factors participating in the control of AT2 receptor regulation and activity in response to stressors are only partially understood. Further research is necessary to close this knowledge gap and to clarify whether AT2 receptor activation may carry the potential of a major translational advance.

Glucose intolerance induced by blockade of central FGF receptors is linked to an acute stress response.

OBJECTIVE: Central administration of ligands for fibroblast growth factor receptors (FGFRs) such as fibroblast growth factor-19 (FGF19) and FGF21 exert glucose-lowering effects in rodent models of obesity and type 2 diabetes (T2D). Conversely, intracerebroventricular (icv) administration of the non-selective FGFR inhibitor (FGFRi) PD173074 causes glucose intolerance, implying a physiological role for neuronal FGFR signaling in glucose homeostasis. The current studies were undertaken to identify neuroendocrine mechanisms underlying the glucose intolerance induced by pharmacological blockade of central FGFRs. METHODS: Overnight fasted, lean, male, Long-Evans rats received icv injections of either PD173074 or vehicle (Veh) followed 30 min later by performance of a frequently sampled intravenous glucose tolerance test (FSIGT). Minimal model analysis of glucose and insulin data from the FSIGT was performed to estimate insulin-dependent and insulin-independent components of glucose disposal. Plasma levels of lactate, glucagon, corticosterone, non-esterified free fatty acids (NEFA) and catecholamines were measured before and after intravenous (iv) glucose injection. RESULTS: Within 20 min of icv PD173074 injection (prior to the FSIGT), plasma levels of lactate, norepinephrine and epinephrine increased markedly, and each returned to baseline rapidly (within 8 min) following the iv glucose bolus. In contrast, plasma glucagon levels were not altered by icv FGFRi at either time point. Consistent with a previous report, glucose tolerance was impaired following icv PD173074 compared to Veh injection and, based on minimal model analysis of FSIGT data, this effect was attributable to reductions of both insulin secretion and the basal insulin effect (BIE), consistent with the inhibitory effect of catecholamines on pancreatic ß-cell secretion. By comparison, there were no changes in glucose effectiveness at zero insulin (GEZI) or the insulin sensitivity index (SI). To determine if iv glucose (given during the FSIGT) contributed to the rapid resolution of the sympathoadrenal response induced by icv FGFRi, we performed an additional study comparing groups that received iv saline or iv glucose 30 min after icv FGFRi. Our finding that elevated plasma catecholamine levels returned rapidly to baseline irrespective of whether rats subsequently received an iv bolus of saline or glucose indicates that the rapid reversal of sympathoadrenal activation following icv FGFRi was unrelated to the subsequent glucose bolus. CONCLUSIONS: The effect of acute inhibition of central FGFR signaling to impair glucose tolerance likely involves a stress response associated with pronounced, but transient, sympathoadrenal activation and an associated reduction of insulin secretion. Whether this effect is a true consequence of FGFR blockade or involves an off-target effect of the FGFR inhibitor requires additional study.

Dexmedetomidine attenuates sympathoadrenal response to tracheal intubation and reduces perioperative anaesthetic requirement.

BACKGROUND: Dexmedetomidine, an α-2 adrenoreceptor agonist, is gaining popularity for its sympatholytic, sedative, anaesthetic sparing and haemodynamic stabilising properties without significant respiratory depression. METHODS: We assessed the efficacy of dexmedetomidine in attenuating sympathoadrenal response to tracheal intubation and analysed reduction in intraoperative anaesthetic requirement. Sixty patients scheduled for elective surgery of more than 3 hours were randomly selected. Control group received isoflurane-opioid and study group received isoflurane-opioid-dexmedetomidine anaesthesia. Dexmedetomidine infusion in a dose of 1 µg/kg was given over 10 min before the induction of anaesthesia and was continued in a dose of 0.2-0.7 µg/kg/Hr until skin closure. All patients were induced with thiopentone, fentanyl and vecuronium. Haemodynamic variables were continuously recorded. RESULTS: The need for thiopentone and isoflurane was decreased by 30% and 32%, respectively, in the dexmedetomidine group as compared to the control group. After tracheal intubation, maximal average increase was 8% in systolic and 11% in diastolic blood pressure in dexmedetomidine group, as compared to 40% and 25%, respectively, in the control group. Similarly, average increase in heart rate was 7% and 21% in the dexmedetomidine and control groups, respectively. Fentanyl requirement during the operation was 100±10 µg in the control group and 60±10 µg in the dexmedetomidine group. CONCLUSION: Perioperative infusion of dexmedetomidine is effective in attenuating sympathoadrenal response to tracheal intubation. It has significant anaesthetic and opioid sparing effect.