Hypoxia results in decreased arterial Po, arterial chemoreflex activation, and compensatory increases in breathing, sympathetic outflow, and neuroendocrine secretions, including increased secretion of AVP, corticotropin-releasing hormone (CRH), adrenocorticotropin hormone (ACTH), and corticosterone. In addition to a brain stem pathway, including the nucleus tractus solitarius (nTS) and the rostral ventrolateral medulla (RVLM), medullary pathways to the paraventricular nucleus of the hypothalamus (PVN) contribute to chemoreflex responses. Experiments evaluated activation of specific cell phenotypes within the PVN following an acute hypoxic stimulus (AH; 2 h, 10% O) in conscious rats. Retrograde tracers (from spinal cord and RVLM) labeled presympathetic (PreS) neurons, and immunohistochemistry identified AVP- and CRH-immunoreactive (IR) cells. c-Fos-IR was an index of neuronal activation. Hypoxia activated AVP-IR (~6%) and CRH-IR (~15%) cells, but not PreS cells in the PVN, suggesting that sympathoexcitation during moderate AH is mediated mainly by a pathway that does not include PreS neurons in the PVN. Approximately 14 to 17% of all PVN cell phenotypes examined expressed neuronal nitric oxide synthase (nNOS-IR). AH activated only nNOS-negative AVP-IR neurons. In contrast ~23% of activated CRH-IR neurons in the PVN contained nNOS. In the median eminence, CRH-IR terminals were closely opposed to tanycyte processes and end-feet (vimentin-IR) in the external zone, where vascular NO participates in tanycyte retraction to facilitate neuropeptide secretion into the pituitary portal circulation. Results are consistent with an inhibitory role of NO on AVP and PreS neurons in the PVN and an excitatory role of NO on CRH secretion in the PVN and median eminence.

Coldren KM, Brown R, Hasser EM, Heesch CM. Relaxin increases sympathetic nerve activity and activates spinally projecting neurons in the paraventricular nucleus of nonpregnant, but not pregnant, rats. Am J Physiol Regul Integr Comp Physiol 309: R1553-R1568, 2015. First published September 23, 2015; doi:10.1152/ajpregu.00186.2015.-Pregnancy is characterized by increased blood volume and baseline sympathetic nerve activity (SNA), vasodilation, and tachycardia. Relaxin (RLX), an ovarian hormone elevated in pregnancy, activates forebrain sites involved in control of blood volume and SNA through ANG II-dependent mechanisms and contributes to adaptations during pregnancy. In anesthetized, arterial baroreceptordenervated nonpregnant (NP) rats, RLX microinjected into the subfornical organ (SFO; 0.77 pmol in 50 nl) produced sustained increases in lumbar SNA (8 Ϯ 3%) and mean arterial pressure (MAP; 26 Ϯ 4 mmHg). Low-dose intracarotid artery infusion of RLX (155 pmol·ml Ϫ1 ·h Ϫ1 ; 1.5 h) had minor transient effects on AP and activated neurons [increased Fos-immunoreactivity (IR)] in the SFO and in spinally projecting (19 Ϯ 2%) and arginine-vasopressin (AVP)-IR (21 Ϯ 5%) cells in the paraventricular nucleus of the hypothalamus of NP, but not pregnant (P), rats. However, mRNA for RLX and ANG II type 1a receptors in the SFO was preserved in pregnancy. RLX receptor-IR is present in the region of the SFO in NP and P rats and is localized in astrocytes, the major source of angiotensinogen in the SFO. These data provide an anatomical substrate for a role of RLX in the resetting of AVP secretion and increased baseline SNA in pregnancy. Since RLX and ANG II receptor expression was preserved in the SFO of P rats, we speculate that the lack of response to exogenous RLX may be due to maximal activation by elevated endogenous levels of RLX in near-term pregnancy.Fos; paraventricular nucleus; subfornical organ; circumventricular organs; ANG II; arginine-vasopressin WITH ITS HIGHEST CIRCULATING levels achieved during pregnancy, relaxin (RLX) is a 6-kDa peptide hormone secreted primarily by the corpus luteum of the ovary. RLX-2 in humans is functionally equivalent to RLX-1 in all other mammals, and often both are called simply "relaxin" (2, 4, 21). Although best known for its role in growth and remodeling of the female reproductive tract during pregnancy, RLX peptide and RLX binding sites are present in male reproductive tissue and the heart, vasculature, kidney, and brain of both males and females. In regards to the cardiovascular system, in both male and female humans and rats, chronic administration of RLX causes vascular remodeling, angiogenesis, and systemic vasodilation (8). Endogenous RLX is a major contributor to peripheral vasodilation and augmented renal function seen in pregnancy, and recent clinical trials suggest that exogenously administered RLX may have therapeutic value in treating heart-failure patients (2,8,14).In addition to peripheral vascular effects, circulating RLX plays an important role in the central nervous sys...

No abstract

Acute hypoxia activates peripheral chemoreceptors. Previously we reported that PVN‐projecting second order nTS neurons were activated (Fos‐IR) by AH. We hypothesized that, within the PVN, AH increases Fos‐IR in RVLM projecting, nNOS, and vasopressin (AVP) neurons. Microinjection of fluorogold (FG) in the RVLM retrogradely labeled RVLM‐projecting PVN neurons. Rats (n = 6) underwent either 3 h normoxia (N, 21% O2) or 3 h AH (10% O2). Immunohistochemistry was performed on forebrain sections and cell phenotypes were quantified. AH increased the total number of Fos‐IR cells (N= 24±2; AH= 118±14) at Bregma ~ −1.8 in the PVN. Also at this level, AH increased the number and % of nNOS cells that were activated (nNOS‐Fos) (N = 3±.0.4, 2± 0.4%; AH =15± 2, 12±1%). Activation of AVP cells (AVP‐Fos) tended to increase (P = 0.06) with AH (N = 1±.0.3, 2± 0.5%; AH = 5± 1, 7±2%). Although AH increased the number of nNOS cells more caudally (Bregma ~ −2.1), activation of RVLM‐projecting cells at either level of the PVN was unchanged by AH. These preliminary data suggest that activation of nNOS and AVP containing cells in the PVN contribute to cardiorespiratory responses to AH. NIH HL 98602.

Relaxin (RLX), an ovarian hormone which is secreted in pregnancy, activates the subfornical organ (SFO) and hypothalamic regions associated with control of blood volume and sympathetic nerve activity (SNA). The current experiments phenotyped cells in the paraventricular nucleus (PVN) which are activated by RLX. Carotid and femoral artery and vein catheters were implanted in female virgin rats. Spinally projecting cells were retrogradely labeled by microinjection of fluorogold (FG) or cholera toxin‐b (CTb) (90nl) into the intermediolateral cell column. After 5 days human RLX 2 (1μg/hr) or saline (Sal, 1ml/hr) was infused (1.5 hr) into the forebrain circulation (intra‐carotid artery, ica) of conscious rats. RLX (n=3) increased mean arterial pressure (MAP, 9±2 mmHg) while Sal (n=5) had no effect (+1 ± 1mmHg). Rats were euthanized, perfused with 4% paraformaldehyde, brains sectioned (30 μm), and Fos‐, CTb‐, and vasopressin (VP‐) immunoreactivity (IR) were evaluated. Following RLX, cells in the lateral margins of the SFO expressed Fos‐IR, consistent with activation of PVN projecting neurons. Forty ±11% of VP‐IR cells (bregma −1.8mm) and 36±7% of spinally projecting cells (bregma −2.12mm) were activated (Fos‐IR) by ica RLX. In contrast, Fos‐IR was minimal in Sal treated rats. These data provide an anatomical substrate for a role of RLX in the adaptations in regulation of VP and SNA in pregnancy. HL091164(CMH)