Inactivation of the PVN during hypoglycemia partially simulates hypoglycemia-associated autonomic failure

Abstract

The anatomic connections of the paraventricular nucleus of the hypothalamus (PVN) are such that it is ideally situated to modulate and/or control autonomic responses to a variety of stressors, including hypoglycemia. In our experimental model of hypoglycemia-associated autonomic failure (HAAF), a syndrome in which the counterregulatory response to hypoglycemia is partially compromised via unknown mechanisms, activation of the PVN is blunted (15). We hypothesized that this blunted PVN activation during HAAF may be sufficient to cause the impaired counterregulatory response. To test this hypothesis, we anesthetized the PVN with lidocaine during insulin-induced hypoglycemia in rats and measured counterregulatory hormone levels. PVN inactivation decreased indexes of the sympathoadrenal response (plasma epinephrine and norepinephrine) and the hypothalamic-pituitary axis response (ACTH). Inactivation decreased the peak epinephrine response to hypoglycemia by almost half (-42 +/- 6% from control; P = 0.04) and the peak norepinephrine response by 34 +/- 5% (P = 0.01). The peak plasma ACTH levels attained were suppressed by 35 +/- 6% (P = 0.02). Adrenal corticosterone and pancreatic glucagon responses were not impaired. This pattern of neuroendocrine response is unlike that previously seen with our HAAF model. Control infusions of lidocaine >or=1 mm anterior or posterior to the PVN did not simulate this neuroendocrine pattern. Thus it appears that decreased PVN activation, as occurs with HAAF, may be involved in specific components of HAAF (i.e., blunting the sympathoadrenal and hypothalamic-pituitary-adrenocortical axis response), but not in others (i.e., blunting the glucagon response).

Key Role for AMP-Activated Protein Kinase in the Ventromedial Hypothalamus in Regulating Counterregulatory Hormone Responses to Acute Hypoglycemia

“…In the present study, no effect of VMH AMPK knockdown was seen on the corticosterone response to acute hypoglycemia, a finding that is consistent with previous work from our laboratory in which the role of VMH GABA and urocortin on CRRs to acute hypoglycemia were examined (16,40). In rodent models, hypoglycemia induces neuronal activation in the PVN (as measured by cFOS) (e.g., 41), and inactivation of the PVN during hypoglycemia with a chronic lidocaine infusion has been shown to impair peak epinephrine, ACTH, but not corticosterone responses (42). In contrast, local administration of the CRH-1 receptor antagonist antalarmin to the PVN suppressed corticosterone but not epinephrine or glucagon secretory responses to acute hypoglycemia, whereas local administration of antalarmin to the VMH did the converse (43).…”

Acute THPVP inactivation decreases the glucagon and sympathoadrenal responses to recurrent hypoglycemia

“…However, the role of the THPVP may be more complex than originally hypothesized. First, control PBS infusions in SH rats experiencing a single (naive) bout of hypoglycemia had no effect on the neuroendocrine responses, when compared with other data from our laboratory in this model, in subjects with no CNS cannulas (Evans et al, 2001), or identical experimental protocols where cannulas were aimed at the paraventricular or dorsomedial nuclei of the hypothalamus (Evans et al, 2003(Evans et al, , 2004. Likewise, acute LIDO infusions in SH rats had no effect on the neuroendocrine responses.…”

“…Prior to performing experiments, animals were familiarized with square acrylic test chambers (∼30 cm×30 cm×30 cm) and the microinjection procedure as described by Evans et al (2003Evans et al ( , 2004. Subsequent to this, the animals were placed in the test chambers for at least 2 h before experimental procedures began.…”

“…Animals received insulin (Novolin ® R, regular human insulin, recombinant DNA origin, Novo Nordisk, Princeton, NJ; 0.5 U/100 g body weight/h) IV over 120 min infused at a rate of 1.14 ml/h. In combination with the insulin infusions, THPVP infusions of LIDO (2%; Sigma, St. Louis, MO) or PBS vehicle (0.1 M phosphate-buffered saline, pH 7.4; Oxoid, Bastingstoke, England) were carried out by programmable syringe pumps (SP101i, World Precision Instruments, Sarasota, FL) (Evans et al, 2003). Rats either received LIDO infusion together with a single bout of hypoglycemia (SH); or they received LIDO infusion on Day 2 during a third bout of hypoglycemia (RH).…”

“…We observed decreased activation of the paraventricular nucleus of the hypothalamus (PVN) and dorsomedial hypothalamus (DMH) in rats that experienced multiple, vs. a single bout of hypoglycemia. In subsequent studies, we have demonstrated that reversible inactivation of these regions during a single bout of hypoglycemia (SH) resulted in impairments of the sympathoadrenal and HPA axis responses (Evans et al, 2003(Evans et al, , 2004). Thus, decreased medial hypothalamic activation may contribute to the impaired counterregulatory response of recurrent hypoglycemia (RH).…”