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

Wang, Hai; Tang, Yuan; Zhang, Yingli

doi:10.1111/j.1527-3466.2005.tb00174.x

Cited by 15 publications

(12 citation statements)

References 99 publications

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“…7,10,11 Iptakalim can attenuate right ventricular remodeling induced by pulmonary hypertension, protect the endothelium, and prevent progression of cardiac hypertrophy to failure induced by pressure overload. 6,12 Natakalim is a derivative of iptakalim and selectively opens the SUR2B/Kir6.1 channel subtype. 13,14,15,16 Based on these lines of evidence, we hypothesized that natakalim may reduce pressure overloadinduced heart failure via protecting against endothelial dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Activation of SUR2B/Kir6.1 Subtype of Adenosine Triphosphate-sensitive Potassium Channel Improves Pressure Overload-induced Cardiac Remodeling via Protecting Endothelial Function

Tang¹,

Long²,

Wang³

et al. 2010

Journal of Cardiovascular Pharmacology

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We sought to explore new strategies targeting SUR2B/Kir6.1, a subtype of adenosine triphosphate (ATP)-sensitive potassium channels (KATP), against pressure overload-induced heart failure. The effects of natakalim, a SUR2B/Kir6.1 selective channel opener, on progression of cardiac remodeling were investigated. Pressure overload-induced heart failure was induced in Wistar rats by abdominal aortic banding. The effects of natakalim (1, 3, and 9 mg·kg⁻¹·d⁻¹ for 10 weeks) on myocardial hypertrophy and heart failure, cardiac histology, vasoactive compounds, and gene expression were assessed. Ten weeks after the onset of pressure overload, natakalim treatment potently inhibited cardiac hypertrophy and prevented heart failure. Natakalim remarkably inhibited the changes of left ventricular hemodynamic parameters and reversed the increase of heart mass index, left ventricular weight index, and lung weight index. Histological examination demonstrated that there was no significant hypertrophy or fibrosis in pressure-overloaded hearts of natakalim-treated rats. Ultrastructural examination of hearts revealed well-organized myofibrils with mitochondria grouped along the periphery of longitudinally oriented fibers in rats from the natakalim group. The content of serum nitric oxide and plasma prostacyclin was increased, whereas that of plasma endothelin-1 and cardiac tissue hydroxyproline and atrial and B-type natriuretic peptide messenger RNA was downregulated in natakalim-treated rats. Natakalim at 0.01-100 µM had no effects on isolated working hearts derived from Wistar rats; however, natakalim had endothelium-dependent vasodilatory effects on the isolated tail artery helical strips precontracted with norepinephrine. These results indicate that natakalim reduces heart failure caused by pressure overloading by activating the SUR2B/Kir6.1 KATP channel subtype and protecting against endothelial dysfunction.

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Section: Introductionmentioning

confidence: 99%

Activation of SUR2B/Kir6.1 Subtype of Adenosine Triphosphate-sensitive Potassium Channel Improves Pressure Overload-induced Cardiac Remodeling via Protecting Endothelial Function

Tang¹,

Long²,

Wang³

et al. 2010

Journal of Cardiovascular Pharmacology

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“…Iptakalim is an adenosine triphosphate-sensitive potassium channel opener that is approved for use in treating hypertension in China (Wang et al , 2005a; Wang et al , 2005b). Along with its action on potassium channels, iptakalim has several other neuropharmacological effects that suggest that it could be used to treat nicotine dependence.…”

Section: Introductionmentioning

confidence: 99%

Iptakalim attenuates self-administration and acquired goal-tracking behavior controlled by nicotine

et al. 2013

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Iptakalim is an ATP-sensitive potassium channel opener, as well as an α4β2-containing nicotinic acetylcholine receptor (nAChR) antagonist. Pretreatment with iptakalim diminishes nicotine-induced dopamine (DA) and glutamate release in the nucleus accumbens. This neuropharmacological profile suggests that iptakalim may be useful for treatment of nicotine dependence. Thus, we examined the effects of iptakalim in two preclinical models. First, the impact of iptakalim on the interoceptive stimulus effect of nicotine was evaluated by training rats in a discriminated goal-tracking task that included intermixed nicotine (0.4 mg/kg, SC) and saline sessions. Sucrose was intermittently presented in a response-independent manner only on nicotine sessions. On intervening test days, rats were pretreated with iptakalim (10, 30, 60 mg/kg, IP). Results revealed that iptakalim attenuated nicotine-evoked responding controlled by the nicotine stimulus in a dose-dependent manner. In a separate study, the impact of iptakalim on the reinforcing effects of nicotine was investigated by training rats to lever-press to self-administer nicotine (0.03 mg/kg/infusion). Results revealed that pretreatment with iptakalim (1, 3, 6 mg/kg, IV) decreased nicotine intake (i.e., less active lever responding). Neither behavioral effect was due to a non-specific motor effect of iptakalim, nor to an ability of iptakalim to inhibit DA transporter (DAT) or serotonin transporter (SERT) function. Together, these finding support the notion that iptakalim may be an effective pharmacotherapy for increasing smoking cessation and better understanding its action could contribute medication development.

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“…We further explored, giving mitoKATP-specific inhibitors in vivo , pulmonary arterial pressure and pathological changes in reversible pulmonary hypertension rats (16). In this way, we completely explained the mechanism of mitoKATP regulating HIF-1α/miR-210/ISCU signaling axis and the formation of a positive feedback loop in chronic PAH, providing theoretical basis for filtering new chronic hypoxic PAH therapeutic targets.…”

Section: Discussionmentioning

confidence: 99%

MitoKATP regulating HIF/miR210/ISCU signaling axis and formation of a positive feedback loop in chronic hypoxia-induced PAH rat model

Lü

Huang

Geng

et al. 2017

Experimental and Therapeutic Medicine

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In the present study, we studied the mechanism of mitochondrial ATP-sensitive potassium (mitoKATP) channels regulating hypoxia-inducible factor (HIF)-1α/microRNA (miR)-210/mitochondrial iron-sulfur protein integrin (ISCU) signaling axis and forming a positive feedback loop in chronic hypoxia-induced pulmonary arterial hypertension (PAH) by using in vivo animal model. Two hundred healthy adult SPF Sprague-Dawley rats were randomly divided into five groups: Control, a mimic miR-210 agent (mimic-210) intervention, a miR-210 inhibitor (anti-210) intervention, a chronic PAH and an anti-210 intervention PAH groups, with 40 rats in each group. After the chronic PAH rat model was successfully established, the rats were intervened with mimic-210 and anti-210. The pulmonary artery smooth muscle cells (PASMCs) of rats in each group were acutely isolated and the activity of mitoKATP and mitochondria-derived oxygen free radicals reactive oxygen species (ROS) was detected. RT-qPCR was used to detect the gene of HIF-1α/miR-210/ISCU and western blot analysis was used to detect the protein of HIF-1α and ISCU. The gene and protein expression were detected again after mitoKATP-specific opener diazoxide and blocker 5-HD was given via tail vein and took effect on each group of rats, respectively. Additionally, the indicators were detected again after ISCU recombinant protein was given via tail vein and ISCU small interfering RNA (siRNA) via nasal feeding and took effect on each group of rats, respectively. It was found that the activity of mitoKATP and ROS and the gene and protein levels of HIF-1α/miR-210/ISCU of the mimic-210 group were significantly higher than those of the control group while that of the anti-210 group was significantly reduced (P<0.05). The indicators in the chronic PAH group were significantly higher than those of the control group while those of the anti-210 intervention PAH group were significantly reduced (P<0.05). The indicators of all the groups were increased after being given mitoKATP specific opener diazoxide. The indicators of all the groups were significantly reduced after receiving blocker 5-HD (P<0.05). The indicators of all the groups were significantly reduced after given ISCU recombinant protein. The indicators of all the groups increased following ISCU siRNA, and there was a statistically significant difference (P<0.05). In conclusion, the mechanism of mitoKATP regulating the HIF-1α/miR-210/ISCU signaling axis and formation of a positive feedback loop exists in the PAH rat model.

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

Cited by 15 publications

References 99 publications

Activation of SUR2B/Kir6.1 Subtype of Adenosine Triphosphate-sensitive Potassium Channel Improves Pressure Overload-induced Cardiac Remodeling via Protecting Endothelial Function

Activation of SUR2B/Kir6.1 Subtype of Adenosine Triphosphate-sensitive Potassium Channel Improves Pressure Overload-induced Cardiac Remodeling via Protecting Endothelial Function

Iptakalim attenuates self-administration and acquired goal-tracking behavior controlled by nicotine

MitoKATP regulating HIF/miR210/ISCU signaling axis and formation of a positive feedback loop in chronic hypoxia-induced PAH rat model

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