Altered Cerebral Blood Flow and Potential Neuroprotective Effect of Human Relaxin-2 (Serelaxin) During Hypoxia or Severe Hypovolemia in a Sheep Model.

René Schiffner,Andrey Irintchev,Thomas Lehmann,Marius Nistor,Sabine J Bischoff,Cornelius Lemke,Martin Schmidt

doi:10.3390/ijms21051632

Abstract

Specific neuroprotective strategies to minimize cerebral damage caused by severe hypoxia or hypovolemia are lacking. Based on previous studies showing that relaxin-2/serelaxin increases cortical cerebral blood flow, we postulated that serelaxin might provide a neuroprotective effect. Therefore, we tested serelaxin in two emergency models: hypoxia was induced via inhalation of 5% oxygen and 95% nitrogen for 12 min; thereafter, the animals were reoxygenated. Hypovolemia was induced and maintained for 20 min by removal of 50% of the total blood volume; thereafter, the animals were retransfused. In each damage model, the serelaxin group received an intravenous injection of 30 µg/kg of serelaxin in saline, while control animals received saline only. Blood gases, shock index values, heart frequency, blood pressure, and renal blood flow showed almost no significant differences between control and treatment groups in both settings. However, serelaxin significantly blunted the increase of lactate during hypovolemia. Serelaxin treatment resulted in significantly elevated cortical cerebral blood flow (CBF) in both damage models, compared with the respective control groups. Measurements of the neuroproteins S100B and neuron-specific enolase in cerebrospinal fluid revealed a neuroprotective effect of serelaxin treatment in both hypoxic and hypovolemic animals, whereas in control animals, neuroproteins increased during the experiment. Western blotting showed the expression of relaxin receptors and indicated region-specific differences in relaxin receptor-mediated signaling in cortical and subcortical brain arterioles, respectively. Our findings support the hypothesis that serelaxin is a potential neuroprotectant during hypoxia and hypovolemia. Due to its preferential improvement of cortical CBF, serelaxin might reduce cognitive impairments associated with these emergencies.

Highlights

The human hormone relaxin-2 mediates cardiovascular adaptations during pregnancy and, systemic vasodilatation [1]
Our results imply a neuroprotective effect during hypoxia and hypovolemia in a sheep model
The heart rate (HR) increase was more significant in the serelaxin-treated group, which correlates with both the known properties of the substance and the results of another study in a sheep model [11]

Summary

Introduction

The human hormone relaxin-2 mediates cardiovascular adaptations during pregnancy and, systemic vasodilatation [1]. Recombinant human relaxin-2 (serelaxin®, Novartis Pharma, Basel, Switzerland) mediates systemic hemodynamic changes and increases renal blood flow by reducing systemic intravascular resistance concomitant with an increase in arterial compliance [2,3,4,5,6]. Serelaxin induces nitric-oxide-mediated vasodilatation [7] and can reduce the infarction size in the cerebral cortex [8,9,10]. All of the above-mentioned findings suggest a neuroprotective effect of relaxin-2/serelaxin. While the hypothesis that serelaxin might be beneficial in acute heart failure was proved wrong [12,13], serelaxin exhibits no negative impact on hemodynamic effects under normal conditions or during hypoxia or hypovolemia [14,15,16]. There is a lack of specific neuroprotective strategies for hypovolemia [17]

Methods

Results

Discussion

Conclusion