Pharmacology of the K‐ATP Channel Blocking Morpholinoguanidine PNU‐37883A

Humphrey, Stephen J.

doi:10.1111/j.1527-3466.1999.tb00022.x

Cited by 6 publications

(3 citation statements)

References 106 publications

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“…Both channel types would be expected to be blocked by Ba 2+ in the high micromolar range (>100 μ M ). Nonetheless, PNU‐37883A is considered to be a highly selective inhibitor of the K ATP channel (Humphrey, 1999). It antagonises the vasorelaxant effects of pinacidil, levcromakalim and minoxidil sulphate in rabbit mesenteric artery (IC 50 ∼1 μ M ), while not significantly affecting the vasorelaxant responses to forskolin, nitroglycerin or the Ca 2+ channel blocker, D‐600 (Meisheri et al ., 1993).…”

Section: Discussionmentioning

confidence: 99%

The pore‐forming subunit of the K_ATP channel is an important molecular target for LPS‐induced vascular hyporeactivity in vitro

O’Brien

Thakur

Buckley

et al. 2005

British J Pharmacology

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1 ATP-sensitive K þ (K ATP ) channel activation is implicated in the vascular hyporeactivity occurring in septic shock. However, channel inhibition with the sulphonylurea receptor (SUR) antagonist, glibenclamide (Glib) fails to reverse lipopolysaccharide (LPS)-induced vascular hyporeactivity in vitro. We investigated whether inhibitors that act by binding to the K ATP channel pore could be effective. 2 Ring segments of endothelium-intact rat mesenteric artery were incubated with LPS in culture media for either 6 or 20 h before contractile responses to phenylephrine were assessed in the absence or presence of K ATP channel inhibitors. 3 The pore-forming subunit inhibitors barium chloride (BaCl 2 ; 300 mM) and PNU-37883A (1 mM) significantly reversed hyporeactivity at both time points, although less so at 20 h. In contrast, the SUR inhibitors, Glib (10 mM), tolbutamide (Tolb) (1 mM) and PNU-99963 (1 mM) were ineffective. In LPSincubated tissues, Glib and Tolb antagonised contractions to the thromboxane A2 mimetic, U46619 (9,11-dideoxy-9a, 11a-methanoepoxy prostaglandin F 2a ) (10 À7 M), whereas the pinacidil-derived inhibitor, PNU-99963, did not. 4 Contractions to 60 mM KCl were unaffected by LPS at 6 h, but were significantly depressed by LPS at 20 h, suggesting that K þ -channel-independent pathways contribute to hyporeactivity at the later time point. 5 The inducible nitric oxide synthase (iNOS) inhibitor, 1400 W (10 mM) and Tolb inhibited the production of nitrite induced by LPS, whereas BaCl 2 and PNU-37883A had no effect. 6 In conclusion, K ATP channels contribute to LPS-induced vascular hyporeactivity via the iNOS pathway in rat mesenteric artery. The effectiveness of pore inhibitors over SUR inhibitors of the K ATP channel suggests altered SUR function following LPS administration, which cannot be explained by thromboxane receptor inhibition.

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Section: Discussionmentioning

confidence: 99%

The pore‐forming subunit of the K_ATP channel is an important molecular target for LPS‐induced vascular hyporeactivity in vitro

O’Brien

Thakur

Buckley

et al. 2005

British J Pharmacology

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“…Lastly, the morpholinoguanidine PNU-37883A needs mentioning. Both in vitro and in vivo evidence suggest that this compound is selective for vascular K ATP channels over pancreatic ones and that it acts on the Kir6.1 rather than SUR components [ 132 ].…”

Section: Pharmacological Tools Targeting K Atp Cha...mentioning

confidence: 99%

“…Glibenclamide also inhibited dilation caused by migraine-triggering peptides CGRP [ 65 ] and PACAP [ 147 ] that support K ATP channel activation by phosphorylation via cAMP and PKA [ 148 ]. PNU-37883A effectively inhibited dilatory responses to stimulation with K ATP channel openers in various arteries of different species including the MMA in vitro and in vivo [ 117 , 132 ]. Interestingly, glibenclamide [ 65 ] and PNU-37883A [ 149 ] failed to inhibit arterial dilation caused by NO-donors in some reports whereas others did find a relationship between NO (cGMP) and K ATP channel-mediated arterial dilation [ 45 , 150 ].…”

Section: K Atp Channels and Headachementioning

confidence: 99%

ATP-Sensitive Potassium Channels in Migraine: Translational Findings and Therapeutic Potential

Clement

Guo

Jansen‐Olesen

et al. 2022

Cells

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Globally, migraine is a leading cause of disability with a huge impact on both the work and private life of affected persons. To overcome the societal migraine burden, better treatment options are needed. Increasing evidence suggests that ATP-sensitive potassium (KATP) channels are involved in migraine pathophysiology. These channels are essential both in blood glucose regulation and cardiovascular homeostasis. Experimental infusion of the KATP channel opener levcromakalim to healthy volunteers and migraine patients induced headache and migraine attacks in 82-100% of participants. Thus, this is the most potent trigger of headache and migraine identified to date. Levcromakalim likely induces migraine via dilation of cranial arteries. However, other neuronal mechanisms are also proposed. Here, basic KATP channel distribution, physiology, and pharmacology are reviewed followed by thorough review of clinical and preclinical research on KATP channel involvement in migraine. KATP channel opening and blocking have been studied in a range of preclinical migraine models and, within recent years, strong evidence on the importance of their opening in migraine has been provided from human studies. Despite major advances, translational difficulties exist regarding the possible anti-migraine efficacy of KATP channel blockage. These are due to significant species differences in the potency and specificity of pharmacological tools targeting the various KATP channel subtypes.

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Kir Channel Molecular Physiology, Pharmacology, and Therapeutic Implications

Cui

Cantwell

Zorn

et al. 2021

Pharmacology of Potassium Channels

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Pharmacology of the K‐ATP Channel Blocking Morpholinoguanidine PNU‐37883A

Cited by 6 publications

References 106 publications

The pore‐forming subunit of the K_ATP channel is an important molecular target for LPS‐induced vascular hyporeactivity in vitro

The pore‐forming subunit of the K_ATP channel is an important molecular target for LPS‐induced vascular hyporeactivity in vitro

ATP-Sensitive Potassium Channels in Migraine: Translational Findings and Therapeutic Potential

Kir Channel Molecular Physiology, Pharmacology, and Therapeutic Implications

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Pharmacology of the K‐ATP Channel Blocking Morpholinoguanidine PNU‐37883A

Cited by 6 publications

References 106 publications

The pore‐forming subunit of the KATP channel is an important molecular target for LPS‐induced vascular hyporeactivity in vitro

The pore‐forming subunit of the KATP channel is an important molecular target for LPS‐induced vascular hyporeactivity in vitro

ATP-Sensitive Potassium Channels in Migraine: Translational Findings and Therapeutic Potential

Kir Channel Molecular Physiology, Pharmacology, and Therapeutic Implications

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Product

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The pore‐forming subunit of the K_ATP channel is an important molecular target for LPS‐induced vascular hyporeactivity in vitro

The pore‐forming subunit of the K_ATP channel is an important molecular target for LPS‐induced vascular hyporeactivity in vitro