The impaired ability of the autonomic nervous system to respond to hypoglycemia is termed “hypoglycemia-associated autonomic failure” (HAAF). This life-threatening phenomenon results from at least two recent episodes of hypoglycemia, but the pathology underpinning HAAF remains largely unknown. Although naloxone appears to improve hypoglycemia counterregulation under controlled conditions, hypoglycemia prevention remains the current mainstay therapy for HAAF. Epinephrine-synthesizing neurons in the rostroventrolateral (C1) and dorsomedial (C3) medulla project to the subset of sympathetic preganglionic neurons that regulate peripheral epinephrine release. Here we determined whether or not C1 and C3 neuronal activation is impaired in HAAF and whether or not 1 wk of hypoglycemia prevention or treatment with naloxone could restore C1 and C3 neuronal activation and improve HAAF. Twenty male Sprague-Dawley rats (250–300 g) were used. Plasma epinephrine levels were significantly increased after a single episode of hypoglycemia ( n = 4; 5,438 ± 783 pg/ml vs. control 193 ± 27 pg/ml, P < 0.05). Repeated hypoglycemia significantly reduced the plasma epinephrine response to subsequent hypoglycemia ( n = 4; 2,179 ± 220 pg/ml vs. 5,438 ± 783 pg/ml, P < 0.05). Activation of medullary C1 ( n = 4; 50 ± 5% vs. control 3 ± 1%, P < 0.05) and C3 ( n = 4; 45 ± 5% vs. control 4 ± 1%, P < 0.05) neurons was significantly increased after a single episode of hypoglycemia. Activation of C1 ( n = 4; 12 ± 3%, P < 0.05) and C3 ( n = 4; 19 ± 5%, P < 0.05) neurons was significantly reduced in the HAAF groups. Hypoglycemia prevention or treatment with naloxone did not restore the plasma epinephrine response or C1 and C3 neuronal activation. Thus repeated hypoglycemia reduced the activation of C1 and C3 neurons mediating adrenal medullary responses to subsequent bouts of hypoglycemia.
Intermittent hypoxia causes a persistent increase in sympathetic activity that progresses to hypertension in chronic conditions such as obstructive sleep apnea. Pituitary adenylate cyclase-activating polypeptide (PACAP) is an excitatory neurotransmitter that causes long-lasting sympathetic excitation. We aimed to determine if intermittent activation of the rostral ventrolateral medulla (RVLM) causes PACAP-mediated elevation of sympathetic nerve activity, termed sympathetic long-term facilitation (sLTF). The role of PACAP in mediating sLTF in response to intermittent activation of the RVLM was investigated in urethane-anaesthetized and artificially ventilated rats ( n = 65, Sprague-Dawley). Bilateral RVLM microinjections of the PACAP type 1 receptor/vasoactive intestinal polypeptide receptor type 2 receptor antagonist PACAP-(6-38) [ n = 6, change (Δ): -16.4 ± 6.5%) or an ionotropic glutamate antagonist, kynurenate ( n = 6, Δ:-7.2 ± 2.3%), blocked the development of acute intermittent hypoxia-induced sLTF ( n = 6, Δ: 49.2 ± 14.2%). Intermittent RVLM microinjections of glutamate caused sLTF ( n = 5, Δ: 56.9 ± 14.7%) that was abolished by PACAP-(6-38) pretreatment ( n = 5, Δ:-1.2 ± 4.7%). Conversely, intermittent microinjections of PACAP in the RVLM did not elicit sLTF. Intermittent bilateral disinhibition of the RVLM by microinjection of γ-aminobutyric acid in the caudal ventrolateral medulla did not elicit sLTF. Direct activation of RVLM neurons is crucial for the development of sLTF. PACAP and glutamate act synergistically in the RVLM, with both being necessary for the sLTF response. We found that activation of glutamate but not PACAP receptors is necessary and sufficient to generate sLTF, even in the absence of intermittent hypoxia. Our results demonstrate that PACAP within the RVLM may contribute to the development of obstructive sleep apnea -induced hypertension. NEW & NOTEWORTHY Pharmacological blockade of either pituitary adenylate cyclase-activating polypeptide (PACAP) or ionotropic glutamate receptors in the rostral ventrolateral medulla prevents development of sympathetic long-term facilitation. PACAP receptor inhibition prevents the occurrence of hypoxia-induced peripheral chemoreflex sensitization. Thus, PACAP receptors may be a potential therapeutic target serving to reduce heightened sympathetic tone and hypersensitized cardiovascular reflexes.
Intensive insulin therapy is the gold standard for managing serum glucose levels in patients with insulin‐deficient diabetes mellitus. Hypoglycaemia‐associated autonomic failure (HAAF) is a clinical syndrome characterised by the absence of a glucose counter‐regulatory response to hypoglycaemia or glucoprivation. The precise physiologic mechanisms underlying HAAF remain unknown. Recent data from human studies suggests activation of the endogenous opioid system during antecedent hypoglycaemia may contribute to unawareness of hypoglycaemia. Here, we aimed to determine whether or not activation of rostral ventrolateral medullary (RVLM) μ‐opioid receptors results in downstream sympathoinhibition, resulting in attenuated glucose production, and an impaired counter‐regulatory response following glucoprivation. Experiments were performed in sodium pentobarbital anaesthetised (65 mg/kg) male Sprague‐Dawley rats (250–350g). Bilateral activation of RVLM μ‐opioid receptors with DAMGO (8 mM, 50 nl) caused depression of adrenal sympathetic nerve activity (ASNA), that lasted at least 60 minutes (Δ−56.9 ± 9.8% vs saline: Δ1.7 ± 4.4%, P<0.05). In parallel, blood glucose levels were also reduced (Δ−0.8 ± 0.2 mM vs saline: Δ0.2 ± 0.3 mM, P<0.05). The counter‐regulatory response to glucoprivation (measured by ASNA efferent activity) induced by 2‐deoxyglucose was completely attenuated 60 minutes following DAMGO microinjections (Δ−4.4 ± 0.7% vs saline+2‐DG: Δ59.6 ± 8.0%, P<0.05). Bilateral μ‐opioid receptor activation also caused a significant decrease in mean arterial pressure (Δ−28.7 ± 6.1 mmHg vs saline: Δ−9.9 ± 7.3 mmHg, P<0.05) and heart rate (Δ−40.4 ± 14.9 bpm vs saline: Δ−11.1 ± 9.7 bpm, P<0.05). In conclusion, activation of RVLM μ‐opioid receptors reproduces features of HAAF (attenuated neural efferent response to glucoprivation). The mechanism underlying HAAF may include activation of RVLM μ‐opioid receptors to facilitate sympathoinhibition. Coupled with this sympathoinhibition, the reduced blood glucose levels may contribute to HAAF by increasing the threshold to elicit counter‐regulatory response. Support or Funding Information National Health and Medical Research Council of Australia, The University of Sydney, The Heart Research Institute This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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