Abstract
BackgroundRight heart failure is a fatal consequence of chronic pulmonary hypertension (PH). The development of PH is characterized by increased proliferation of vascular cells, in particular pulmonary artery smooth muscle cells (PASMCs) and pulmonary artery endothelial cells. In the course of PH, an escalated right ventricular (RV) afterload occurs, which leads to increased perioperative morbidity and mortality. BKCa channels are ubiquitously expressed in vascular smooth muscle cells and their opening induces cell membrane hyperpolarization followed by vasodilation. Moreover, BK activation induces anti-proliferative effects in a multitude of cell types. On this basis, we hypothesized that treatment with the nebulized BK channel opener NS1619 might be a therapy option for pulmonary hypertension and tested this in rats.Methods(1) Rats received monocrotaline injection for PH induction. Twenty-four days later, rats were anesthetized and NS1619 or the solvent was administered by inhalation. Systemic hemodynamic parameters, RV hemodynamic parameters, and blood gas analyses were measured before as well as 30 and 120 minutes after inhalation. (2) Rat PASMCs were stimulated with PDGF-BB in the presence and absence of NS1619. AKT, ERK1 and ERK2 activation were investigated by western blot analyses, and relative cell number was determined 48 hours after stimulation.ResultsInhalation of a 12 µM and 100 µM NS1619 solution significantly reduced RV pressure without affecting systemic arterial pressure. Blood gas analyses demonstrated significantly reduced carbon dioxide and improved oxygenation in NS1619-treated animals pointing towards a considerable pulmonary shunt-reducing effect. In PASMC’s, NS1619 (100 µM) significantly attenuated PASMC proliferation by a pathway independent of AKT and ERK1/2 activation.ConclusionNS1619 inhalation reduces RV pressure and improves oxygen supply and its application inhibits PASMC proliferation in vitro. Hence, BK opening might be a novel option for the treatment of pulmonary hypertension.
Highlights
Pulmonary hypertension (PH) is a serious disease with a fatal progressive course and a risk of perioperative morbidity and mortality
Since potassium channels modulate the vascular tone [6] and the cellular proliferative state [7], we investigated the impact of the BK channel opener NS1619 on right ventricular and systemic hemodynamic performance and blood gases in the rat monocrotaline pulmonary hypertension (PH) model as well as on pulmonary artery smooth muscle cells (PASMCs) proliferation in cell culture
Inhalation of NS1619 In this study, we explored whether the BK channel opener
Summary
Pulmonary hypertension (PH) is a serious disease with a fatal progressive course and a risk of perioperative morbidity and mortality. Pharmacological treatment improved in recent years, the survival of patients suffering from PH is limited by right heart failure and arrhythmias [1]. New therapeutic strategies to improve the survival of patients suffering from this disease are still required. Right heart failure is a fatal consequence of chronic pulmonary hypertension (PH). BK activation induces antiproliferative effects in a multitude of cell types. On this basis, we hypothesized that treatment with the nebulized BK channel opener NS1619 might be a therapy option for pulmonary hypertension and tested this in rats
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