The novel KV7 channel activator URO-K10 exerts enhanced pulmonary vascular effects independent of the KCNE4 regulatory subunit.

KV7 channels exert a pivotal role regulating vascular tone in several vascular beds. In this context, KV7 channel agonists represent an attractive strategy for the treatment of pulmonary arterial hypertension (PAH). Therefore, in this study, we have explored the pulmonary vascular effects of the novel KV7 channel agonist URO-K10. Consequently, the vasodilator and electrophysiological effects of URO-K10 were tested in rat and human pulmonary arteries (PA) and PA smooth muscle cells (PASMC) using myography and patch-clamp techniques. Protein expression was also determined by Western blot. Morpholino-induced knockdown of KCNE4 was assessed in isolated PA. PASMC proliferation was measured by BrdU incorporation assay. In summary, our data show that URO-K10 is a more effective relaxant of PA than the classical KV7 activators retigabine and flupirtine. URO-K10 enhanced KV currents in PASMC and its electrophysiological and relaxant effects were inhibited by the KV7 channel blocker XE991. The effects of URO-K10 were confirmed in human PA. URO-K10 also exhibited antiproliferative effects in human PASMC. Unlike retigabine and flupirtine, URO-K10-induced pulmonary vasodilation was not affected by morpholino-induced knockdown of the KCNE4 regulatory subunit. Noteworthy, the pulmonary vasodilator efficacy of this compound was considerably increased under conditions mimicking the ionic remodelling (as an in vitro model of PAH) and in PA from monocrotaline-induced pulmonary hypertensive rats. Taking all together, URO-K10 behaves as a KCNE4-independent KV7 channel activator with much increased pulmonary vascular effects compared to classical KV7 channel activators. Our study identifies a promising new drug in the context of PAH.

Case Studies in Physiology: Physiological and clinical effects of temporary diaphragm pacing in two patients with ventilator-induced diaphragm dysfunction.

Ventilator-induced diaphragm dysfunction (VIDD) is increasingly recognized as an important side-effect of invasive ventilation in critically ill patients and is associated with poor outcomes. Whether patients with VIDD benefit from temporary diaphragm pacing is uncertain. Intramuscular diaphragmatic electrodes were implanted for temporary stimulation with a pacing device (TransAeris System) in two patients with VIDD. The electrodes were implanted via laparoscopy (first patient) or via bilateral thoracoscopy (second patient). Stimulation parameters were titrated according to tolerance. Diaphragm thickening fraction by ultrasound, maximum inspiratory pressure (Pimax) and diaphragm electromyography (EMGdi) signal analysis were used to monitor the response to diaphragm pacing. Both patients tolerated diaphragm pacing. In the first patient, improvements in diaphragm excursions were noted once pacing was initiated and diaphragm thickening fraction did not further deteriorate over time. The diaphragm thickening fraction improved in the second patient, and Pimax as well as EMGdi analysis suggested improved muscle function. This patient could be fully weaned from the ventilator. These case reports present the first experience with temporary diaphragm pacing in critically ill patients with VIDD. Our results should be taken cautiously given the reduced sample size, but provide the proof of concept to put forward the hypothesis that a course of diaphragm pacing may be associated with improved diaphragmatic function. Our findings of the tolerance to the procedure and the beneficial physiological effects are not prove of safety and efficacy, but may set the ground to design and conduct larger studies.NEW & NOTEWORTHY Diaphragmatic electrode implantation and temporary diaphragm pacing have not been previously used in ICU patients with VIDD. Patients were monitored using a multimodal monitoring approach including ultrasound of the diaphragm, measurement of maximum inspiratory pressure and EMG signal analysis. Our results suggest that diaphragm pacing may improve diaphragmatic function, with the potential to prevent and treat VIDD in critically ill patients. Safety and efficacy of this intervention is yet to be proven in larger studies.