Medullary Noradrenergic Neurons Mediate Hemodynamic Responses to Osmotic and Volume Challenges.

Stefanne Madalena Marques,Carlos Henrique De Castro,James Oluwagbamigbe Fajemiroye,Andre Henrique Freiria-Oliveira,Eduardo Colombari,Marcos Luiz Ferreira-Neto,Carlos Henrique Xavier,Lara Marques Naves,Gustavo Rodrigues Pedrino,Rodrigo Mello Gomes,Talita De Melo E Silva,Juliana Milan Alves,Keilah Valéria Naves Cavalcante

doi:10.3389/fphys.2021.649535

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.

Highlights

Hemorrhagic trauma is a leading cause of mortality and morbidity in people below 44 years old (Curry and Davis, 2012)
tyrosine hydroxylase (TH)-positive neurons were found within the VLM and nucleus of the solitary tract (NTS) at ∼1,900 μm caudal and 1,900 μm rostral from the obex (Figures 1A,B)
The nanoinjection of anti-DβH-saporin conjugated into caudal ventrolateral medulla (CVLM) region (A1 lesioned group; n = 8) reduced the average number of TH-positive neurons caudal to the obex to ∼11 cells per section

Summary

Introduction

Hemorrhagic trauma is a leading cause of mortality and morbidity in people below 44 years old (Curry and Davis, 2012). Studies have shown that hemorrhagic shock is responsible for about 40% of trauma-related deaths (Kauvar et al, 2006). The hemorrhage control and blood volume replacement are an important therapeutic intervention, a better understanding on the pathophysiological mechanisms composing hypovolemic shock could engender efficient treatment. Hyperosmolarity induced by intravenous hypertonic saline infusion (HSI) solution (0.3 M of NaCl) is an efficient strategy to suppress hemorrhagic shock (Krausz, 2006). Studies have shown improvements in cardiovascular and immunological parameters after HSI during hypovolemic state, sepsis, or traumatic injury (Velasco et al, 1980; Lopes et al, 1981; Kramer, 2003). The HSI-induced improvement in cardiovascular function during hemorrhage partially depends on the central nervous system (CNS) activation (de Almeida Costa et al, 2009). It was demonstrated that the blood pressure restoration after HSI-induced hypotensive hemorrhage (HH) was blocked by denervation of the carotid body chemoreceptors (Pedrino et al, 2011)

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Conclusion