Medullary Noradrenergic Neurons Mediate Hemodynamic Responses to Osmotic and Volume Challenges

Abstract

Despite being involved in homeostatic control and hydro-electrolyte balance, the contribution of medullary (A1 and A2) noradrenergic neurons to the hypertonic saline infusion (HSI)-induced cardiovascular response after hypotensive hemorrhage (HH) remains to be clarified. Hence, the present study sought to determine the role of noradrenergic neurons in HSI-induced hemodynamic recovery in male Wistar rats (290–320 g) with HH. Medullary catecholaminergic neurons were lesioned by nanoinjection of antidopamine-β-hydroxylase–saporin (0.105 ng·nl−1) into A1, A2, or both (LES A1; LES A2; or LES A1+A2, respectively). Sham rats received nanoinjections of free saporin in the same regions (SHAM A1; SHAM A2; or SHAM A1+A2, respectively). After 15 days, rats were anesthetized and instrumented for cardiovascular recordings. Following 10 min of stabilization, HH was performed by withdrawing arterial blood until mean arterial pressure (MAP) reaches 60 mmHg. Subsequently, HSI was performed (NaCl 3 M; 1.8 ml·kg−1, i.v.). The HH procedure caused hypotension and bradycardia and reduced renal, aortic, and hind limb blood flows (RBF, ABF, and HBF). The HSI restored MAP, heart rate (HR), and RBF to baseline values in the SHAM, LES A1, and LES A2 groups. However, concomitant A1 and A2 lesions impaired this recovery, as demonstrated by the abolishment of MAP, RBF, and ABF responses. Although lesioning of only a group of neurons (A1 or A2) was unable to prevent HSI-induced recovery of cardiovascular parameters after hemorrhage, lesions of both A1 and A2 made this response unfeasible. These findings show that together the A1 and A2 neurons are essential to HSI-induced cardiovascular recovery in hypovolemia. By implication, simultaneous A1 and A2 dysfunctions could impair the efficacy of HSI-induced recovery during hemorrhage.

Locus Coeruleus Noradrenergic Modulation of Diurnal Corticosterone, Stress Reactivity, and Cardiovascular Homeostasis in Male Rats

“…As indicated, after hemorrhage, medullary A2-NA neurons relay hemodynamic signals to the PVN in the activation of HPA axis [2, 28, 33, 62, 63]. In the present study, after hemorrhage the DSP rats responded with increases in plasma ACTH and CORT, suggesting that DSP4 treatment spared the A2-NA neurons.…”

“…However, little is known about the effect of corticolimbic circuitry in the modulation of HPA axis response after hemorrhage. Stress signals after hemorrhage are primarily conveyed to the PVN via medullary A2 NA neurons [28, 33]. However, an interaction, if any, between the medullary circuitry and the corticolimbic circuitry remains to be investigated.…”

A Toolbox to Investigate the Impact of Impaired Oxygen Delivery in Experimental Disease Models

“…Hemorrhage leads to tissue hypoperfusion and to a shift to anaerobic cell metabolism ( 14 , 15 ). During the last years, the pathophysiological understanding of hemorrhagic shock states developed from a hemodynamic and mechanistic point of view to a more complex process including a differentiated neuronal ( 16 ), humoral, ( 17 ), microcirculatory and immunological response ( 18 ). To gain deeper insights into the mechanisms associated with hemorrhagic shock, multiple small animal models were developed which can be roughly subdivided into (i) controlled hemorrhage, (ii) uncontrolled hemorrhage or (iii) hemorrhagic shock combined with traumatic injury (see below and Table 1 for an overview).…”

“…Generally, fixed-pressure models or uncontrolled hemorrhage are combined with additional tissue damage ( 16 ). Those models pay attention to neurohumoral, endocrinological and immunological changes during hemorrhage.…”

“…For example, long bone fractures can be performed as open or close fracture models. Bone fragment implantation and bone marrow injection are called pseudo-fractures and are expected to imitate the immunological effect of long bone fractures without a soft tissue damage through open fracture types ( 16 ).…”