Functional effects of the KCNQ modulators retigabine and XE991 in the rat urinary bladder

Rode, Frederik; Svalø, Julie; Sheykhzade, Majid; Rønn, Lars Christian B.

doi:10.1016/j.ejphar.2010.03.050

Cited by 56 publications

(60 citation statements)

References 24 publications

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“…1, A and B), consistent with the previous reports by our group and others using immunohistochemistry (Afeli et al, 2013;Anderson et al, 2013). K V 7 channel activators and inhibitors such as retigabine and XE991 have provided a useful pharmacological approach for elucidating K V 7 channel roles in urinary bladder function Sheldon et al, 2002;Streng et al, 2004;Rode et al, 2010;Svalø et al, 2012Svalø et al, , 2013Svalø et al, , 2015Petkov, 2012;Afeli et al, 2013;Anderson et al, 2013). However, retigabine and XE991 do not effectively distinguish among K V 7.2-K V 7.5 and K V 7.1-K V 7.5 channel subtypes, respectively.…”

Section: Discussionsupporting

confidence: 79%

The Novel K_V7.2/K_V7.3 Channel Opener ICA-069673 Reveals Subtype-Specific Functional Roles in Guinea Pig Detrusor Smooth Muscle Excitability and Contractility

Provence

Malysz

Petkov

2015

J Pharmacol Exp Ther

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The physiologic roles of voltage-gated K V 7 channel subtypes (K V 7.1-K V 7.5) in detrusor smooth muscle (DSM) are poorly understood. Here, we sought to elucidate the functional roles of K V 7.2/K V 7.3 channels in guinea pig DSM excitability and contractility using the novelWe employed a multilevel experimental approach using Western blot analysis, immunocytochemistry, isometric DSM tension recordings, fluorescence Ca 21 imaging, and perforated whole-cell patch-clamp electrophysiology. Western blot experiments revealed the protein expression of K V 7.2 and K V 7.3 channel subunits in DSM tissue. In isolated DSM cells, immunocytochemistry with confocal microscopy further confirmed protein expression for K V 7.2 and K V 7.3 channel subunits, where they localize within the vicinity of the cell membrane. ICA-069673 inhibited spontaneous phasic, pharmacologically induced, and nerve-evoked contractions in DSM isolated strips in a concentration-dependent manner. The inhibitory effects of ICA-069673 on DSM spontaneous phasic and tonic contractions were abolished in the presence of the K V 7 channel inhibitor XE991 [10,10-bis(4-pyridinylmethyl)-9 (10H)-anthracenone dihydrochloride]. Under conditions of elevated extracellular K 1 (60 mM), the effects of ICA-069673 on DSM tonic contractions were significantly attenuated. ICA-069673 decreased the global intracellular Ca 21 concentration in DSM cells, an effect blocked by the L-type Ca 21 channel inhibitor nifedipine. ICA-069673 hyperpolarized the membrane potential and inhibited spontaneous action potentials of isolated DSM cells, effects that were blocked in the presence of XE991. In conclusion, using the novel K V 7.2/ K V 7.3 channel activator ICA-069673, this study provides strong evidence for a critical role for the K V 7.2-and K V 7.3-containing channels in DSM function at both cellular and tissue levels.

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Section: Discussionsupporting

confidence: 79%

The Novel K_V7.2/K_V7.3 Channel Opener ICA-069673 Reveals Subtype-Specific Functional Roles in Guinea Pig Detrusor Smooth Muscle Excitability and Contractility

Provence

Malysz

Petkov

2015

J Pharmacol Exp Ther

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“…Kv7 channels have an important physiological role in vascular tissues, [11][12][13][14][15][16][17][18][19][20][21] as well as nonvascular tissues, [43][44][45] in addition to their established role in neurons, cardiomyocytes, and epithelia. In each vascular tissue studied previously, quantitative polymerase chain reaction and protein analysis revealed that KCNQ1, KCNQ4, and KCNQ5 were predominant, with a minimal contribution from KCNQ2 and KCNQ3.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Kv7.4 Channel Activity in Primary and Secondary Hypertension

Jepps

Chadha²,

Davis³

et al. 2011

Circulation

141

150

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Background-Voltage-gated potassium (K ϩ ) channels encoded by KCNQ genes (Kv7 channels) have been identified in various rodent and human blood vessels as key regulators of vascular tone; however, nothing is known about the functional impact of these channels in vascular disease. We ascertained the effect of 3 structurally different activators of Kv7.2 through Kv7.5 channels (BMS-204352, S-1, and retigabine) on blood vessels from normotensive and hypertensive animals. Methods and Results-Precontracted thoracic aorta and mesenteric artery segments from normotensive rats were relaxed by all 3 Kv7 activators, with potencies of BMS-204352ϭS-1Ͼretigabine. We also tested these agents in the coronary circulation using the Langendorff heart preparation. BMS-204352 and S-1 dose dependently increased coronary perfusion at concentrations between 0.1 and 10 mol/L, whereas retigabine was effective at 1 to 10 mol/L. In addition, S-1 increased K ϩ currents in isolated mesenteric artery myocytes. The ability of these agents to relax precontracted vessels, increase coronary flow, or augment K ϩ currents was impaired considerably in tissues isolated from spontaneously hypertensive rats (SHRs). Of the 5 KCNQ genes, only the expression of KCNQ4 was reduced (Ϸ3.7 fold) in SHRs aorta. Kv7.4 protein levels were Ϸ50% lower in aortas and mesenteric arteries from spontaneously hypertensive rats compared with normotensive vessels. A similar attenuated response to S-1 and decreased Kv7.4 were observed in mesenteric arteries from mice made hypertensive by angiotensin II infusion compared with normotensive controls. Conclusions-In 2 different rat and mouse models of hypertension, the functional impact of Kv7 channels was dramatically downregulated. (Circulation. 2011;124:602-611.)Key Words: hypertension Ⅲ vasodilation Ⅲ KCNQ potassium channels Ⅲ gene expression P rimary hypertension is characterized by raised total peripheral resistance caused by increased arterial tone. 1 Evidence suggests increased vascular tone during hypertension is a result of a more depolarized membrane potential, which has been associated with a rise in intracellular calcium (Ca 2ϩ ). 2,3 As such, an understanding of the K ϩ channels that stabilize the resting membrane potential is crucial for delineating the pathogenesis of hypertension. Clinical Perspective on p 611KCNQ1-5 genes encode for voltage-gated K ϩ channels (Kv7.1 through Kv7.5, respectively) that have an established physiological role in neurons, 4 -7 cardiomyocytes, 8 cochlea, 9 and some epithelia. 10 There is now a growing appreciation that Kv7 channels are important regulators of smooth muscle contractility in rodent and human blood vessels. [11][12][13] In all blood vessels studied, KCNQ1 and KCNQ4 expression appears to dominate, 11,12,14 -18 although our laboratory has shown a truncated variant of KCNQ5 is also readily expressed. 15,19 Modulation of these channels provokes profound changes in vascular smooth muscle membrane potential and consequently vascular tone. [13][14][15][16][17]20 Thus, the non...

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“…RTG received FDA's black box warning mainly because of its link to retinal abnormalities and blue skin discoloration that might be permanent and irreversible (Brickel et al, 2012;Faulkner and Burke 2013). Additionally, RTG has been reported to cause bladder dysfunction, including dysuria and urinary hesitation, which may be related to the potentiation of KCNQ5 expressed in the bladder (Streng et al, 2004;Rode et al, 2010). Therefore, our rationale for developing RTG derivatives was to enhance its brain-toplasma ratio and improve its anticonvulsant potency.…”

Section: Introductionmentioning

confidence: 99%

P-Retigabine: An N-Propargyled Retigabine with Improved Brain Distribution and Enhanced Antiepileptic Activity

Zhou

Zhang

et al. 2014

Mol Pharmacol

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Retigabine (RTG,methyl] amino] phenyl] carbamate]) is a first-in-class antiepileptic drug that acts by potentiating neuronal KCNQ potassium channels; however, it has less than optimal brain distribution. In this study, we report that P-RTG (ethyl N-[2-amino-4-((4-fluorobenzyl) (prop-2-ynyl)amino)phenyl]carbamate), an RTG derivative that incorporates a propargyl group at the N position of the RTG linker, exhibits an inverted brain distribution compared with RTG. The brain-to-plasma concentration ratio of P-RTG increased to 2.30 compared with 0.16 for RTG. However, the structural modification did not change the drug's potentiation potency, subtype selectivity, or RTG molecular determinants on KCNQ channels. In addition, in cultured hippocampal neurons, P-RTG exhibited a similar capability as RTG for suppressing both induced and spontaneous action potential firing. Notably, P-RTG antiepileptic activity in the maximal electroshock (MES)-induced mouse seizure model was significantly enhanced to a value 2.5 times greater than that of RTG. Additionally, the neurotoxicity of P-RTG in the rotarod test was comparable with that of RTG. Collectively, our results indicate that the incorporation of a propargyl group significantly improves the RTG brain distribution, supporting P-RTG as a promising antiepileptic drug candidate. The strategy for improving brain-to-plasma distribution of RTG might be applicable for the drug development of other central nervous system diseases.

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Functional effects of the KCNQ modulators retigabine and XE991 in the rat urinary bladder

Cited by 56 publications

References 24 publications

The Novel K_V7.2/K_V7.3 Channel Opener ICA-069673 Reveals Subtype-Specific Functional Roles in Guinea Pig Detrusor Smooth Muscle Excitability and Contractility

The Novel K_V7.2/K_V7.3 Channel Opener ICA-069673 Reveals Subtype-Specific Functional Roles in Guinea Pig Detrusor Smooth Muscle Excitability and Contractility

Downregulation of Kv7.4 Channel Activity in Primary and Secondary Hypertension

P-Retigabine: An N-Propargyled Retigabine with Improved Brain Distribution and Enhanced Antiepileptic Activity

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Functional effects of the KCNQ modulators retigabine and XE991 in the rat urinary bladder

Cited by 56 publications

References 24 publications

The Novel KV7.2/KV7.3 Channel Opener ICA-069673 Reveals Subtype-Specific Functional Roles in Guinea Pig Detrusor Smooth Muscle Excitability and Contractility

The Novel KV7.2/KV7.3 Channel Opener ICA-069673 Reveals Subtype-Specific Functional Roles in Guinea Pig Detrusor Smooth Muscle Excitability and Contractility

Downregulation of Kv7.4 Channel Activity in Primary and Secondary Hypertension

P-Retigabine: An N-Propargyled Retigabine with Improved Brain Distribution and Enhanced Antiepileptic Activity

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Product

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The Novel K_V7.2/K_V7.3 Channel Opener ICA-069673 Reveals Subtype-Specific Functional Roles in Guinea Pig Detrusor Smooth Muscle Excitability and Contractility

The Novel K_V7.2/K_V7.3 Channel Opener ICA-069673 Reveals Subtype-Specific Functional Roles in Guinea Pig Detrusor Smooth Muscle Excitability and Contractility