The pulmonary vasodilator properties of potassium channel opening drugs

Wanstall, Janet C.

doi:10.1016/0306-3623(95)02044-6

Cited by 26 publications

(20 citation statements)

References 65 publications

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“…KCNK3, also called Twik-related acid-sensitive K + channel (TASK1), shares several characteristics with the background K + current, including minimal voltage sensitivity, extracellular pH sensitivity, resistance to classic K + channel inhibitors, and insensitivity to cytoplasmic Ca 2+ . 6 Electrophysiological experiments have demonstrated a loss of function in all identified mutations of the channel. 3 However, additional experiments are required to decipher the pathophysiological role of KCNK3 channels in the development of nonheritable forms of PAH.…”

Section: Clinical Perspective On P 1385mentioning

confidence: 99%

Potassium Channel Subfamily K Member 3 (KCNK3) Contributes to the Development of Pulmonary Arterial Hypertension

et al. 2016

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P ulmonary artery (PA) hypertension (PAH) is a severe and progressive condition characterized by increased mean pulmonary arterial pressure >25 mm Hg at rest, with a normal PA wedge pressure in the absence of chronic respiratory, cardiac, or thromboembolic disease.1 PAH is a complex disease associated with endothelial cell (EC) dysfunction and Background-Mutations in the KCNK3 gene have been identified in some patients suffering from heritable pulmonary arterial hypertension (PAH). KCNK3 encodes an outward rectifier K + channel, and each identified mutation leads to a loss of function. However, the pathophysiological role of potassium channel subfamily K member 3 (KCNK3) in PAH is unclear. We hypothesized that loss of function of KCNK3 is a hallmark of idiopathic and heritable PAH and contributes to dysfunction of pulmonary artery smooth muscle cells and pulmonary artery endothelial cells, leading to pulmonary artery remodeling: consequently, restoring KCNK3 function could alleviate experimental pulmonary hypertension (PH). Methods and Results-We demonstrated that KCNK3 expression and function were reduced in human PAH and in monocrotaline-induced PH in rats. Using a patch-clamp technique in freshly isolated (not cultured) pulmonary artery smooth muscle cells and pulmonary artery endothelial cells, we found that KCNK3 current decreased progressively during the development of monocrotaline-induced PH and correlated with plasma-membrane depolarization. We demonstrated that KCNK3 modulated pulmonary arterial tone. Long-term inhibition of KCNK3 in rats induced distal neomuscularization and early hemodynamic signs of PH, which were related to exaggerated proliferation of pulmonary artery endothelial cells, pulmonary artery smooth muscle cell, adventitial fibroblasts, and pulmonary and systemic inflammation. Lastly, in vivo pharmacological activation of KCNK3 significantly reversed monocrotaline-induced PH in rats. Conclusions-In PAH and experimental PH, KCNK3 expression and activity are strongly reduced in pulmonary artery smooth muscle cells and endothelial cells. KCNK3 inhibition promoted increased proliferation, vasoconstriction, and inflammation. In vivo pharmacological activation of KCNK3 alleviated monocrotaline-induced PH, thus demonstrating that loss of KCNK3 is a key event in PAH pathogenesis and thus could be therapeutically targeted. (Circulation.

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Section: Clinical Perspective On P 1385mentioning

confidence: 99%

Potassium Channel Subfamily K Member 3 (KCNK3) Contributes to the Development of Pulmonary Arterial Hypertension

et al. 2016

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“…These drugs are potent inhibitors of hypoxic pulmonary vasoconstriction both in vivo and in perfused lungs (12). The effects of potassium channel openers on pulmonary artery pressure might depend on the level of hypoxia in individual patients (101,102).…”

Section: Therapy Of Hphmentioning

confidence: 99%

“…This also raises the possibility that the properties of K ATP channels could vary between different vascular beds (102). Unitary potassium currents were identified through 2 types of K-channels with conductance gradients of 50 and 22 pS; these are referred to as LK and MK channels, respectively.…”

Section: Molecular Characteristics Of K Atpmentioning

confidence: 99%

Hypoxic Pulmonary Hypertension (HPH) and Iptakalim, a Novel ATP-sensitive Potassium Channel Opener Targeting Smaller Arteries in Hypertension

Wang¹,

Tang

Zhang

2006

Cardiovascular Drug Reviews

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Hypoxic pulmonary hypertension (HPH) is a serious and potentially devastating chronic disorder of the pulmonary circulation. Attempts to use drugs in the therapy of hypoxic pulmonary hypertension indicated the importance of prevention or reduction of vasoconstriction as well as of the reversal of remodeling within the cardiovascular system. Iptakalim (2,3-dimethyl-N-(1-methylethyl)-2-butylamine), a novel ATP-sensitive potassium channel opener, has the desired effects on hypoxic pulmonary arteries. Iptakalim decreases the elevated mean pressure in pulmonary arteries, and attenuates remodeling in the right ventricle, pulmonary arteries and airways. Moreover, iptakalim has selective antihypertensive effects: it significantly lowers arterial pressure in hypertensive animals, but has little if any effect in normotensive animals. In HPH iptakalim has selective effects on smaller arteries. Long-term iptakalim therapy decreases expression of sulfonylurea receptor 2 and of mRNA of inwardly rectifying potassium channel in smaller arteries of spontaneously hypertensive rats. Iptakalim inhibits the effects of endothelin-1, reduces the intracellular calcium concentration and inhibits the cell cycle in smooth muscle cells of pulmonary arteries. There is no evidence for the development of tolerance to the longlasting antihypertensive action of iptakalim. At therapeutic doses iptakalim has no effects on the central nervous, respiratory, digestive, or endocrine systems. It has a broad therapeutic range, so that it can be safely used in the therapy of HPH.

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“…This is reflected in the vasoconstrictor effect of agents causing membrane depolarization [1][2][3] and the vasodilator action of drugs causing hyperpolarization. 4,5 There is general agreement that the resting potential of PASMCs is determined largely by a noninactivating K ϩ conductance (I KN ) that is sensitive to inhibition by 4-aminopyridine, albeit at relatively high (Ͼ1 mmol/L) concentrations. 6 Thus, both the resting potential and I KN are abolished when pipette K ϩ is replaced with equimolar Cs ϩ , whereas equimolar substitution of Cs ϩ for extracellular K ϩ has little effect.…”

mentioning

confidence: 99%

Two-Pore Domain K Channel, TASK-1, in Pulmonary Artery Smooth Muscle Cells

Gurney

Osipenko

MacMillan

et al. 2003

Circulation Research

170

171

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Abstract-Pulmonary vascular tone is strongly influenced by the resting membrane potential of smooth muscle cells, depolarization promoting Ca 2ϩ influx, and contraction. The resting potential is determined largely by the activity of K ϩ -selective ion channels, the molecular nature of which has been debated for some time. In this study, we provide strong evidence that the two-pore domain K ϩ channel, TASK-1, mediates a noninactivating, background K ϩ current (I KN ), which sets the resting membrane potential in rabbit pulmonary artery smooth muscle cells (PASMCs). TASK-1 mRNA was found to be present in PASMCs, and the membranes of PASMCs contained TASK-1 protein. Both I KN and the resting potential were found to be exquisitely sensitive to extracellular pH, acidosis inhibiting the current and causing depolarization. Moreover, I KN and the resting potential were enhanced by halothane (1 mmol/L), inhibited by Zn 2ϩ (100 to 200 mol/L) and anandamide (10 mol/L), but insensitive to cytoplasmic Ca 2ϩ . These properties are all diagnostic of TASK-1 channels and add to previously identified features of I KN that are shared with TASK-1, such as inhibition by hypoxia, low sensitivity to 4-aminopyridine and quinine and insensitivity to tetraethylammonium ions. It is therefore concluded that TASK-1 channels are major contributors to the resting potential in pulmonary artery smooth muscle. They are likely to play an important role in mediating pulmonary vascular responses to changes in extracellular pH, and they could be responsible for the modulatory effects of pH on hypoxic pulmonary vasoconstriction.

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The pulmonary vasodilator properties of potassium channel opening drugs

Cited by 26 publications

References 65 publications

Potassium Channel Subfamily K Member 3 (KCNK3) Contributes to the Development of Pulmonary Arterial Hypertension

Potassium Channel Subfamily K Member 3 (KCNK3) Contributes to the Development of Pulmonary Arterial Hypertension

Hypoxic Pulmonary Hypertension (HPH) and Iptakalim, a Novel ATP-sensitive Potassium Channel Opener Targeting Smaller Arteries in Hypertension

Two-Pore Domain K Channel, TASK-1, in Pulmonary Artery Smooth Muscle Cells

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