Inhalation of the BKCa-Opener NS1619 Attenuates Right Ventricular Pressure and Improves Oxygenation in the Rat Monocrotaline Model of Pulmonary Hypertension

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.

MicroRNA-mediated downregulation of K+ channels in pulmonary arterial hypertension

“…Our findings are consistent with the observations in animal models of pulmonary hypertension (7,71,77). BK Ca channel activator NS1619 was able to reduce right ventricular systolic pressure, a surrogate of pulmonary arterial systolic pressure, in rats with monocrotaline-induced pulmonary hypertension (54). KCNMB1 is a regulatory subunit that modulates the electrophysiological property of the pore-forming subunit (e.g., KCNMA1) of the large-conductance Ca 2ϩactivated and voltage-dependent K ϩ channels (BK Ca channels) (13).…”

Tsantan Sumtang Alleviates Chronic Hypoxia-Induced Pulmonary Hypertension by Inhibiting Proliferation of Pulmonary Vascular Cells

“…BK Ca channels, with seven transmembrane domains and a calcium-binding zone (bowl), are fairly structurally distinctive, even among the K Ca channel family [32–36]. BK Ca channels have also been suggested as probable remedial targets for circulatory diseases based on their ability to adjust vascular tension [21, 33, 36].…”

BK Channels in Rat and Human Pulmonary Smooth Muscle Cells are BKα‐β1 Functional Complexes Lacking the Oxygen‐Sensitive Stress Axis Regulated Exon Insert

“…37 Medications for PH have been introduced and refined to optimize patient outcomes, but resistance to vasodilator drugs remains a key challenge, largely related to structural remodeling of the pulmonary vasculature. 38,39 A BKCO (NS1619) was recently reported to ameliorate monocrotaline-induced PH in rats, 40 which is a promising result, but unfortunately NS1619 also exhibits several off-target effects, including inhibition of L-type voltage-gated Ca 2+ channels, 41 making it difficult to credit the BK channel alone for the therapeutic effect. Earlier investigations have demonstrated that sarcolemmal K + efflux in PASMCs establishes a negative membrane potential, which inactivates voltage-dependent Ca 2+ channels to lower pulmonary vascular tone.…”