Effects of iptakalim hydrochloride, a novel K_ATP channel opener, on pulmonary vascular remodeling in hypoxic rats

Abstract

To investigate whether pulmonary artery remodeling could be prevented or not in hypoxic pulmonary hypertensive rats by treatment, the effects of iptakalim hydrochloride, a novel K_ATPCO, were evaluated. Iptakalim hydrochloride was orally administered at the doses of either 1.5 mg/kg/day or 0.75 mg/kg/day before their 4-week exposure to hypoxia (10% oxygen). It was demonstrated that iptakalim hydrochloride could reverse all pathological indices of pulmonary arterial remodeling and significantly reduce right ventricular hypertrophy in hypoxic rats. The reversal of hypoxic indices was dose-dependent, in which the higher dose of iptakalim hydrochloride reversed pathological indices more effectively than the lower dose did. This was further confirmed electrophysiologically using whole cell patch-clamp technique, which revealed that the outward potassium currents could be enhanced by iptakalim hydrochloride, and the decrease of K⁺ current density and increase of membrane capacitance could be reversed by chronic iptakalim hydrochloride treatment. These findings implied that iptakalim hydrochloride could play its role through activating plasmalemmal K⁺ channels of pulmonary arterial SMCs. The results indicated that iptakalim hydrochloride had anti-remodeling properties of pulmonary artery in hypoxic pulmonary hypertensive rats. It is therefore suggested that K_ATPCOs might be promising in the treatment of patients with hypoxic, and even possibly other forms of, pulmonary hypertension.

Introduction

Iptakalim hydrochloride, a novel compound, has been confirmed by substantial pharmacological, biochemical, and electrophysiological studies as well as receptor-combining test as a newly selective ATP-sensitive potassium channel opener (K_ATPCO) (Wang, 2003). Chronic hypoxic pulmonary hypertension (HPH) is associated with vasoconstriction and structural remodeling of pulmonary vessels including narrowing of the arterial lumen and loss of distal functional arteries. Pulmonary vascular remodeling is one of the key pathological features contributing to the rise in pulmonary artery pressure in pulmonary hypertension. Drugs in current use for the treatment of pulmonary hypertension consist mainly of vasodilators, which oppose the other key pathological feature of this disease, i.e. abnormal pulmonary vasoconstriction. Since abnormal vasoconstriction becomes progressively less important and vascular remodeling progressively more important as the disease advances, an alternative, and possibly more fruitful, approach may be to target pulmonary vascular remodeling.

The plasmalemmal K⁺ channels in pulmonary arterial SMCs may play a unique and important role in the regulation of pulmonary vasoconstriction and vascular remodeling to hypoxia (Mandegar and Yuan, 2002). Some researches have shown that acute hypoxia could selectively inhibit voltage-gated K⁺(Kv) channel function, whereas chronic hypoxia down-regulates Kv channel expression (Sweeney and Yuan, 2000, Platoshyn et al., 2001, Wang et al., 1997).

K⁺ channels are involved in the initiation of the tissue response to hypoxia in a variety of O₂-sensitive tissues, such as the carotid body, the ductus arteriosus, and the neuroepithelial body (Archer et al., 2000).Although there is evidence in the carotid body that the K⁺ channels protein might sense hypoxia (Ganfornina and Lopez-Barneo, 1991), this has not been shown in pulmonary arterial SMCs. The redox theory suggests that hypoxia induces a shift of the redox status of SMCs toward a more reduced state (Weir and Archer, 1995). The O₂ sensor might respond to hypoxia by the production of redox signals that, in turn, would inhibit K⁺ channels (Michelakis et al., 1997). Mitochondrial electron transport chain inhibitors mimic hypoxia and decrease activated oxygen species (AOS) production in pulmonary arterial SMCs (Archer et al., 1993). In addition, hypoxia inhibits the flow of electrons in the electron transport chain and results in a cytoplasmic accumulation of electron donors such as reduced glutathione and/or nicotinamide-adenine dinucleotide phosphate (NADPH), leading to K⁺ channels inhibition. Growth-stimulating hormone (reduced glutathione) inhibits K⁺ channels in pulmonary arterial SMCs (Weir and Archer, 1995).

A reduction in the activity of K⁺ channels in pulmonary arterial SMCs, with the resultant membrane depolarization, may be involved in the development of chronic hypoxic pulmonary hypertension by mediating pulmonary vasoconstriction and vascular remodeling. Therefore, K⁺ channels in pulmonary arterial SMCs represent potential therapeutic targets for control of pulmonary hypertension (Cole and Clement-Chomienne, 2003). Opening of potassium channels is a physiologic mechanism for reversing hypoxia-induced membrane depolarization, and thereby reversing depolarization-induced vascular contraction and remodeling. Iptakalim hydrochloride, as a potassium channel opener, is a potential agent theoretically effective in treatment of pulmonary vascular remodeling, pulmonary hypertension in HPH. The present study was undertaken to determine whether changes in pulmonary vascular structure in hypoxic pulmonary hypertensive rats could be prevented by iptakalim hydrochloride.