Anilide tertiary carbinols: a novel series of K+ channel openers

Grant, T.; Ohnmacht, Cyrus J.; Howe, Burton B.

doi:10.1016/0165-6147(94)90082-5

Cited by 29 publications

(18 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The serotonin-induced contraction was completely inhibited (Fig. 3A) by 5 M ZM 226600, a potent opener of ATP-dependent K ϩ channels (Grant et al, 1994), suggesting a pivotal contribution of these channels to the mechanism of ileal relaxation. The lack of effect of 1 M TTX on the serotonin-induced contraction (Fig.…”

Section: Organ Bath Experimentsmentioning

confidence: 97%

The Inhibitory Effect of Adrenomedullin in the Rat Ileum: Cross-Talk with β₃-Adrenoceptor in the Serotonin-Induced Muscle Contraction

Kravtsov

Hwang²,

Tang³

2003

J Pharmacol Exp Ther

View full text Add to dashboard Cite

In contrast to vascular muscles, the contribution of a hypotensive peptide adrenomedullin (AM) to the regulation of visceral smooth muscles is obscure. The content, synthesis, and effects of AM on the muscular tone in rat ileum were explored. It was found that there was immunoreactive AM (301 pg/mg of protein) and AM mRNA expression (162 fg/pg actin mRNA) in the ileum and that AM evoked relaxation in ileal strips (K i ϭ 0.85 nM) precontracted with serotonin. Antagonists of both AM (AM ) and calcitonin gene-related peptide ) receptors did not affect this AM-induced relaxation, whereas it was suppressed by a selective blocker of ␤ 3 -adrenoreceptor (SR 59230A). The AM-induced relaxation was accompanied by a production of cAMP. Antagonists of protein kinases A (KT 5720 and H-7) and an inhibitor of the ATP-dependent K ϩ -channels (glibenclamide) attenuated the effect of AM. We suggest that AM is a local regulator of the ileal tone, with an inhibitory action on muscle contraction. AM may activate the ␤ 3 -adrenoceptors, resulting in protein kinase A activation, which in turn opens the ATP-dependent K ϩ -channels.The hypotensive peptide, adrenomedullin (AM), was originally purified from both adrenal medulla and pheochromocytoma Kitamura and Eto, 1997;Jougasaki and Burnett, 2000). Two unique structures, a 6-amino acid ring with a disulfide bond and a C-terminal amide in the molecule of AM Hinson et al., 2000;Jougasaki and Burnett, 2000), are likely to determine its vasorelaxation properties. AM shares structural homology with the calcitonin gene-related peptide (CGRP), indicating that AM probably belongs to the CGRP superfamily (Kitamura and Eto, 1997;Hinson et al., 2000;Poyner et al., 2002). The signal transduction pathways have been studied in the greatest detail in the vasculature. A large body of experimental data shows AM synthesis in smooth muscle cells (Kitamura and Eto, 1997;Nishimura et al., 1997) and suggests that AM-induced vasodilation may be mediated by a specific receptor functionally coupled to adenylate cyclase (Eguchi et al., 1994a;Kitamura and Eto, 1997;Nussdorfer et al., 1997;Jougasaki and Burnett, 2000;Poyner et al., 2002). AM-specific receptors are not only found in smooth muscle cells, but also in endothelium cells (Kamitani et al., 1999). It has been reported that the binding of AM to the endothelial receptor can trigger the nitric oxide (NO)-cGMP pathway (Ikeda et al., 1996). Therefore, it is now widely accepted that at least two mechanisms appear to underlie the AM-induced relaxation in vascular muscles: 1) a direct action on vascular smooth muscle cells to increase cAMP (Eguchi et al., 1994a,b;Shimekake et al., 1995;Kitamura and Eto, 1997;Yoshimoto et al., 1998) and 2) an indirect action on endothelial cells to stimulate NO synthesis (Shimekake et al., 1995;Hinson et al., 2000;Jougasaki and Burnett, 2000).The results of mRNA blot analysis reported 10 years ago (Sakata et al., 1993) and later confirmed (Nishimura et al., 1997;Cameron and Fleming, 1998;Sakata et al., 1998) imply that r...

show abstract

Section: Organ Bath Experimentsmentioning

confidence: 97%

The Inhibitory Effect of Adrenomedullin in the Rat Ileum: Cross-Talk with β₃-Adrenoceptor in the Serotonin-Induced Muscle Contraction

Kravtsov

Hwang²,

Tang³

2003

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…They were derived from a series of potent anti-androgenic propanamides such as hydroxyflutamide 22 [66]. Some of these anti-androgens exhibited unwanted hypotensive effects which were later attributed to KCO properties [67,68].…”

Section: Bladder-selective Tertiary Carbinolsmentioning

confidence: 99%

Second-Generation KATP Channel Openers

Mannhold¹,

Leclerc²

2005

MRMC

View full text Add to dashboard Cite

show abstract

“…A series of novel KATPCOS (anilide tertiary carbinols, e.g. ZD 6169) have been reported to act selectively on urinary bladder smooth muscle, without producing significant cardiovascular effects, after oral administration to rats [88]; these agents may have potential for treating patients with urge incontinence. Observations in animal models with KATPCOS have yet to be supported by clinical trials, as initial studies in humans were disappointing.…”

Section: Urinary Bladdermentioning

confidence: 99%

Is there a Therapeutic Future for ‘Potassium Channel Openers’?

Lawson

1996

Clinical Science

View full text Add to dashboard Cite

1. Potassium channels, which control cell electrical activity, are among the most regulated of all ion channels in biology. Promotion of activity in K+ channels by a wide range of physiological factors tends to stabilize cell function. 2. The discovery of synthetic molecules (e.g. cromakalim) that 'directly' open ATP-sensitive K+ channels has led to a new direction in pharmacology. ATP-sensitive K+ channel-opening properties have subsequently been demonstrated in a diverse range of chemical structures (synthetic and endogenous). 3. The existence of so many different subtypes of K+ channels has been an impetus in the search of new potassium channel openers with different channel selectivities and thus biological profiles. 4. The decrease in cell excitability following K+ channel opening implies a broad clinical potential in a number of pathological conditions for K+ channel openers. Preclinical and clinical evidence supports therapeutic roles of K+ channel openers in disorders of a wide range of biological cells. 5. Although lack of selectivity of current compounds remains a major hurdle, advances in K+ channel openers and K+ channel pharmacology are encouraging. Differences already observed in the pharmacology of K+ channel openers are important factors for the development of second-generation compounds, when tissue selectivity is sought. 6. The availability of subtype-selective K+ channel openers will facilitate detailed study, through a combined effort of electrophysiology, functional pharmacology and molecular biology, leading to focused therapeutic approaches for defined pathological conditions.

show abstract

Anilide tertiary carbinols: a novel series of K+ channel openers

Cited by 29 publications

References 6 publications

The Inhibitory Effect of Adrenomedullin in the Rat Ileum: Cross-Talk with β₃-Adrenoceptor in the Serotonin-Induced Muscle Contraction

The Inhibitory Effect of Adrenomedullin in the Rat Ileum: Cross-Talk with β₃-Adrenoceptor in the Serotonin-Induced Muscle Contraction

Second-Generation KATP Channel Openers

Is there a Therapeutic Future for ‘Potassium Channel Openers’?

Contact Info

Product

Resources

About

Anilide tertiary carbinols: a novel series of K+ channel openers

Cited by 29 publications

References 6 publications

The Inhibitory Effect of Adrenomedullin in the Rat Ileum: Cross-Talk with β3-Adrenoceptor in the Serotonin-Induced Muscle Contraction

The Inhibitory Effect of Adrenomedullin in the Rat Ileum: Cross-Talk with β3-Adrenoceptor in the Serotonin-Induced Muscle Contraction

Second-Generation KATP Channel Openers

Is there a Therapeutic Future for ‘Potassium Channel Openers’?

Contact Info

Product

Resources

About

The Inhibitory Effect of Adrenomedullin in the Rat Ileum: Cross-Talk with β₃-Adrenoceptor in the Serotonin-Induced Muscle Contraction

The Inhibitory Effect of Adrenomedullin in the Rat Ileum: Cross-Talk with β₃-Adrenoceptor in the Serotonin-Induced Muscle Contraction