Extracellular l-arginine Enhances Relaxations Induced by Opening of Calcium-Activated SKCa Channels in Porcine Retinal Arteriole

Simonsen, Ulf; Winther, Anna K.; Oliván-Viguera, Aida; Comerma-Steffensen, Simón; Köhler, Ralf; Bek, Toke

doi:10.3390/ijms20082032

Cited by 2 publications

(1 citation statement)

References 49 publications

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“…However, the combination of TRAM-34 with UCL1684, a blocker of SK Ca channels, decreased pirfenidone relaxation in mouse coronary arteries (Figure 3D). As these channels are involved in release of endothelium-derived NO (Stankevicius et al, 2011;Simonsen et al, 2019), these results suggest that pirfenidone modifies the release or the effect of NO in the smooth muscle layer. A blocker of voltage-gated K V 7 channels, XE991 (10 −5 M) blocked the pirfenidone relaxation (Figure 3E), and 10 −4 M pirfenidone relaxed the mouse coronary arteries with 14 ± 7% (p < 0.05, n 6) in the presence of XE991.…”

Section: Mechanisms Involved In Pirfenidone Relaxation In Mouse Coron...mentioning

confidence: 83%

Pirfenidone Is a Vasodilator: Involvement of KV7 Channels in the Effect on Endothelium-Dependent Vasodilatation in Type-2 Diabetic Mice

et al. 2021

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Endothelial cell dysfunction and fibrosis are associated with worsening of the prognosis in patients with cardiovascular disease. Pirfenidone has a direct antifibrotic effect, but vasodilatation may also contribute to the effects of pirfenidone. Therefore, in a first study we investigated the mechanisms involved in the relaxant effect of pirfenidone in rat intrapulmonary arteries and coronary arteries from normal mice. Then in a second study, we investigated whether pirfenidone restores endothelial function in the aorta and mesenteric arteries from diabetic animals. From 16–18-week old normal male C57BL/6 mice and normoglycemic (db/db+), and type 2 diabetic (db/db) male and female mice, arteries were mounted in microvascular isometric myographs for functional studies, and immunoblotting was performed. In rat pulmonary arteries and mouse coronary arteries, pirfenidone induced relaxations, which were inhibited in preparations without endothelium. In mouse coronary arteries, pirfenidone relaxation was inhibited in the presence of a nitric oxide (NO) synthase inhibitor, NG-nitro-l-arginine (L-NOARG), a blocker of large-conductance calcium-activated potassium channels (BKCa), iberiotoxin, and a blocker of KV7 channels, XE991. Patch clamp studies in vascular smooth muscle revealed pirfenidone increased iberiotoxin-sensitive current. In the aorta and mesenteric small arteries from diabetic db/db mice relaxations induced by the endothelium-dependent vasodilator, acetylcholine, were markedly reduced compared to db/db + mice. Pirfenidone enhanced the relaxations induced by acetylcholine in the aorta from diabetic male and female db/db mice. An opener of KV7 channels, flupirtine, had the same effect as pirfenidone. XE991 reduced the effect of pirfenidone and flupirtine and further reduced acetylcholine relaxations in the aorta. In the presence of iberiotoxin, pirfenidone still increased acetylcholine relaxation in aorta from db/db mice. Immunoblotting for KV7.4, KV7.5, and BKCa channel subunits were unaltered in aorta from db/db mice. Pirfenidone failed to improve acetylcholine relaxation in mesenteric arteries, and neither changed acetylcholine-induced transient decreases in blood pressure in db/db+ and db/db mice. In conclusion, pirfenidone vasodilates pulmonary and coronary arteries. In coronary arteries from normal mice, pirfenidone induces NO-dependent vasodilatation involving BKCa and KV7 channels. Pirfenidone improves endothelium-dependent vasodilatation in aorta from diabetic animals by a mechanism involving voltage-gated KV7 channels, a mechanism that may contribute to the antifibrotic effect of pirfenidone.

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Section: Mechanisms Involved In Pirfenidone Relaxation In Mouse Coron...mentioning

confidence: 83%

Pirfenidone Is a Vasodilator: Involvement of KV7 Channels in the Effect on Endothelium-Dependent Vasodilatation in Type-2 Diabetic Mice

et al. 2021

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A KCa2.2/2.3 opener reverses ET-1 induced NLRP3 activation in hypertensive mice

Fais,

Comerma-Steffensen,

Pinilla

et al. 2024

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Membrane depolarization is implicated in the activation of the NLRP3 inflammasome. Downregulation of endothelial Ca2+-activated K+channels type 2.3 (KCa2.3) and endothelin-1 (ET-1) upregulation in the corpus cavernosum (CC) are associated with erectile dysfunction. We hypothesized that opening KCa2.2/2.3 channels could reverse erectile dysfunction and NLRP3 activation in hypertensive DOCA/salt mice. Methods: Hypertension was induced in mice using a DOCA/salt model, with unilaterally nephrectomized mice as controls; blood pressure was measured by tail-cuff. Intracavernous pressure (ICP) and CC reactivity were assessed. Western blot analysis for KCa2.3, caspase-1, and interleukin-1β (IL-1β) was performed. Endothelial cells from erectile tissue were isolated and stimulated with ET-1, and KCa2.2/2.3-dependent currents were evaluated via voltage-clamp electrophysiology. Results: DOCA/salt mice exhibited impaired erectile function, increased pro-caspase-1 and caspase-1 expression, and reduced relaxations induced by acetylcholine (ACh), sodium nitroprusside (SNP), and electrical field stimulation (EFS). Treatment with either the endothelin receptor antagonist bosentan or the KCa2.2/2.3 channel opener NS13001 reversed these dysfunctions and reduced ET-1-induced NLRP3 activation in DOCA/salt mice. NS13001 also restored the decreased current observed in primary endothelial cells exposed to ET-1. Apamin, a KCa2.2/2.3 channel blocker, inhibited erectile responses in unilaterally nephrectomized mice and restored erectile responses in DOCA mice. Apamin did not affect EFS-, ACh-, or SNP-induced relaxation in CC from hypertensive DOCA/salt mice. Conclusion: NS13001 reversed ET-1-induced NLRP3 activation and erectile dysfunction in DOCA/salt mice, suggesting that KCa2.2/2.3 channel modulation may restore erectile function in hypertension-related diseases.

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Extracellular l-arginine Enhances Relaxations Induced by Opening of Calcium-Activated SKCa Channels in Porcine Retinal Arteriole

Cited by 2 publications

References 49 publications

Pirfenidone Is a Vasodilator: Involvement of KV7 Channels in the Effect on Endothelium-Dependent Vasodilatation in Type-2 Diabetic Mice

Pirfenidone Is a Vasodilator: Involvement of KV7 Channels in the Effect on Endothelium-Dependent Vasodilatation in Type-2 Diabetic Mice

A KCa2.2/2.3 opener reverses ET-1 induced NLRP3 activation in hypertensive mice

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