Chemoreflex Activation of Neuroendocrine Versus Pre‐Sympathetic Corticotropin Releasing Hormone Neurons in the Paraventricular Nucleus of the Hypothalamus: Continuous Acute Hypoxia and Intermittent Sodium Cyanide
Authors: Coldren K. Max , Kline David D. , Hasser Eileen M. , Heesch Cheryl M. 
Published: November 2023

Studies in rats demonstrating that acute activation of the arterial chemoreflex increases ventilation, mean arterial pressure (MAP) and sympathetic nerve activity (SNA) often use i.v. cyanide (CN) to mimic an hypoxic stimulus. Responses to i.v. CN are eliminated by section of the carotid sinus nerve or carotid body denervation, and are attenuated by lesions of the paraventricular nucleus of the hypothalamus (PVN). Thus, responses to i.v. CN are likely mediated by activation of the carotid body and the PVN is needed for the full expression of the chemoreflex. Previously we reported that in conscious rats, acute exposure to continuous hypoxia (AH, 10% O2, 2hrs) activated (Fos‐immunoreactive, ‐IR) neurosecretory magnocellular vasopressin (AVP‐IR) (11±3%) and parvocellular corticotropin releasing hormone (CRH‐IR) (14±2%) cells in the PVN, but pre‐sympathetic cells were not activated. Current experiments in conscious rats compared activation of neuroendocrine and spinally projecting CRH‐IR cells in the PVN 2 hrs after initiation of 10% O2, 8% O2, or repeated injections of NaCN (once every 3 min for 30 min). Spinally projecting neurons were labeled by prior injection of the retrograde tracer, CTB‐Alexa 555, in the intermediolateral cell column (IML); Fos‐IR was used as an index of neuronal activation; and CRH‐IR was evaluated. CRH‐IR cells in the medial parvocellular subregion of the PVN were presumed neuroendocrine (~ 1.6 mm caudal to bregma), and IML projecting cells were located throughout the rostral‐caudal PVN (~1.6 to 2.0 mm caudal to bregma). In all groups (including normoxic and saline controls) a significant portion of IML‐projecting neurons contained CRH‐IR. However, only in the NaCN group were IML projecting cells activated (12±2%) and most of these contained CRH (80±3%). Activation of medial parvocellular CRH‐IR neuroendocrine cells was greater in 8% O2 (64±7%) compared to 10% O2 (28±6%) and NaCN (36±6%) treated rats. Activation of CRH neuroendocrine cells was similar between NaCN and 10% O2 groups, suggesting that differential activation of pre‐sympathetic cells by NaCN was not associated with a greater generalized stress response. In summary, two levels of continuous hypoxia failed to activate IML‐projecting neurons, but repeated injections of NaCN did activate these pre‐sympathetic cells in the PVN. We propose that activation of IML‐projecting cells in the NaCN group may be related to the intermittent nature of the stimulus. In this regard, in a model of acute intermittent hypoxia in anesthetized rats, baseline SNA is elevated, consistent with activation of pre‐sympathetic neurons as shown in the current experiments. Ongoing experiments are evaluating potential differential regulation of neuroendocrine versus pre‐sympathetic CRH neurons in the PVN in response to chemoreflex activation.Support or Funding InformationNIH HL 98602