TASK-1 potassium channel is not critically involved in mediating hypoxic pulmonary vasoconstriction of murine intra-pulmonary arteries

Abstract

The two-pore domain potassium channel KCNK3 (TASK-1) is expressed in rat and human pulmonary artery smooth muscle cells. There, it is associated with hypoxia-induced signalling, and its dysfunction is linked to pathogenesis of human pulmonary hypertension. We here aimed to determine its role in hypoxic pulmonary vasoconstriction (HPV) in the mouse, and hence the suitability of this model for further mechanistic investigations, using appropriate inhibitors and TASK-1 knockout (KO) mice. RT-PCR revealed expression of TASK-1 mRNA in murine lungs and pre-acinar pulmonary arteries. Protein localization by immunohistochemistry and western blot was unreliable since all antibodies produced labelling also in TASK-1 KO organs/tissues. HPV was investigated by videomorphometric analysis of intra- (inner diameter: 25–40 μm) and pre-acinar pulmonary arteries (inner diameter: 41–60 μm). HPV persisted in TASK-1 KO intra-acinar arteries. Pre-acinar arteries developed initial HPV, but the response faded earlier (after 30 min) in KO vessels. This HPV pattern was grossly mimicked by the TASK-1 inhibitor anandamide in wild-type vessels. Hypoxia-provoked rise in pulmonary arterial pressure (PAP) in isolated ventilated lungs was affected neither by TASK-1 gene deficiency nor by the TASK-1 inhibitor A293. TASK-1 is dispensable for initiating HPV of murine intra-pulmonary arteries, but participates in sustained HPV specifically in pre-acinar arteries. This does not translate into abnormal rise in PAP. While there is compelling evidence that TASK-1 is involved in the pathogenesis of pulmonary arterial hypertension in humans, the mouse does not appear to serve as a suitable model to study the underlying molecular mechanisms.

TASK‐1 channel blockade by AVE1231 increases vasocontractile responses and BP in 1‐ to 2‐week‐old but not adult rats

“…However, a functional role of TASK-1 channels in pulmonary arteries of mice was not observed (Manoury, Lamalle, Oliveira, Reid, & Gurney, 2011;Murtaza et al, 2017). We also did not observe consid- (Mulvany, Nilsson, & Flatman, 1982;Neild & Kotecha, 1987).…”

Cannabidiol Ameliorates Monocrotaline-Induced Pulmonary Hypertension in Rats

“…AEA and NAGly have been demonstrated to possess potential vasodilatory properties, as has AEA in hPAs and rPAs [ 10 ] and NAGly in the systemic arterial bed [ 43 ]. So far, only AEA has been shown to reduce hypoxia-induced vasoconstriction (an important feature of PH), although it failed to modify the vascular caliber under normoxia in murine intra-acinar and pre-acinar arteries [ 44 ]. Metabolites of AEA have been demonstrated to mediate hypoxia-induced PH in mice [ 37 ].…”

Potassium channels in vascular smooth muscle: a pathophysiological and pharmacological perspective

“… showed that the guanylate cyclase activator, riociguat, a novel treatment for pulmonary hypertension, enhances current through TASK‐1 channels but does not recover current through mutant TASK‐1 channels, seen in pulmonary hypertension patients. While there is compelling evidence that KCNK3 is involved in the pathogenesis of pulmonary hypertension in humans , KCNK3 does not play a key role in initiating HPV of mice pulmonary hypertension , but it may participate in its maintenance . However, KCNK3 /TASK‐1 channel did not form a functional channel in mice which is not a suitable model to study KCNK3 in PA hypertension .…”