Argon reduces the pulmonary vascular tone in rats and humans by GABA-receptor activation

Said Suleiman,Svetlana Kintsler,Till Braunschweig,Ira Katz,Julia Krabbe,Thomas Schröder,Manfred Moeller,Annette D Rieg,Saskia Von Stillfried,Aaron Babendreyer,Sergej Klassen,Mark Coburn,Stefan Uhlig,Christian Martin,Galina Balakirski,Sebastian Kalverkamp,Jan Spillner

doi:10.1038/s41598-018-38267-y

Said Suleiman, Svetlana Kintsler + Show 15 more

Open Access

https://doi.org/10.1038/s41598-018-38267-y

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Abstract

Argon exerts neuroprotection. Thus, it might improve patients’ neurological outcome after cerebral disorders or cardiopulmonary resuscitation. However, limited data are available concerning its effect on pulmonary vessel and airways. We used rat isolated perfused lungs (IPL) and precision-cut lung slices (PCLS) of rats and humans to assess this topic. IPL: Airway and perfusion parameters, oedema formation and the pulmonary capillary pressure (Pcap) were measured and the precapillary and postcapillary resistance (Rpost) was calculated. In IPLs and PCLS, the pulmonary vessel tone was enhanced with ET-1 or remained unchanged. IPLs were ventilated and PCLS were gassed with argon-mixture or room-air. IPL: Argon reduced the ET-1-induced increase of Pcap, Rpost and oedema formation (p < 0.05). PCLS (rat): Argon relaxed naïve pulmonary arteries (PAs) (p < 0.05). PCLS (rat/human): Argon attenuated the ET-1-induced contraction in PAs (p < 0.05). Inhibition of GABAB-receptors abolished argon-induced relaxation (p < 0.05) in naïve or ET-1-pre-contracted PAs; whereas inhibition of GABAA-receptors only affected ET-1-pre-contracted PAs (p < 0.01). GABAA/B-receptor agonists attenuated ET-1-induced contraction in PAs and baclofen (GABAB-agonist) even in pulmonary veins (p < 0.001). PLCS (rat): Argon did not affect the airways. Finally, argon decreases the pulmonary vessel tone by activation of GABA-receptors. Hence, argon might be applicable in patients with pulmonary hypertension and right ventricular failure.

Highlights

Noble gases were considered to be inert due to their filled outer electron shell: it is recognised that they exert physiological effects by van der Waals forces[1,2]
We studied the effects of argon on Rpre and Rpost in isolated perfused lungs (IPL)[35] which allows for the measurement of the capillary pressure (Pcap) and the calculation of Rpre and Rpost
We evaluated the effects of argon on pulmonary haemodynamic and airway parameters using rat isolated perfused lungs (IPL) and precision-cut lung slices (PCLS) of rats and humans

Summary

Introduction

Noble gases were considered to be inert due to their filled outer electron shell: it is recognised that they exert physiological effects by van der Waals forces[1,2]. A common mechanism of argon and xenon has been identified Both noble gases desensitise acid-sensing ion channels which was shown to be neuroprotective in mouse models of ischaemic stroke[23]. Neuroprotection is warranted in patients suffering primary neurological disorder (traumatic brain injury, cerebral ischaemia and bleeding) or secondary cerebral ischaemia due to cardiac arrest and cardiac surgery These patients are often affected by cardiovascular and pulmonary disorders; e.g. left heart disease (LHD), right ventricular (RV) failure, pulmonary hypertension (PH), chronical asthma or chronic obstructive lung disease. Segmental PVR, expressed as precapillary (Rpre) and postcapillary resistance (Rpost) gives much more evidence about the pulmonary arterial and venous bed This topic is even more relevant, as pulmonary arteries (PAs) and veins (PVs) react quite differently[30,31,32] and PH due to LHD primarily affects PVs33,34. PCLS are viable for 72 hours and enable the real time evaluation of the tone of PAs, PVs and airways[31,36,37]

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