KATPChannel Openers for the Treatment of Airways Hyperreactivity

Buchheit, Karl Heinz; Fozard, John R.

doi:10.1006/pupt.1999.0183

Cited by 17 publications

(11 citation statements)

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“…Of the other three main groups of K + channel, it is only the adenosine triphosphate (ATP)-dependent variants (K ATP ) [107][108][109] that are currently believed to be functionally important in ASM [90,110,111]. However, although K ATP channel openers oppose bronchoconstriction, attenuate airways hyperreactivity and may play a role in b 2 -adrenocepotormediated relaxation of vascular smooth muscle, the effect of selective agonists, per se, on these channels in human ASM is not well studied [112][113][114].…”

Section: Role Of Other Potassium Channelsmentioning

confidence: 99%

Beyond the dogma: novel β₂-adrenoceptor signalling in the airways

Giembycz

Newton²

2006

Eur Respir J

132

118

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b 2 -Adrenoceptor agonists evoke rapid bronchodilatation and are the mainstay of the treatment of asthma symptoms worldwide. The mechanism of action of this class of compounds is believed to involve the stimulation of adenylyl cyclase and subsequent activation of the cyclic adenosine monosphosphate (cAMP)/cAMP-dependent protein kinase cascade.This classical model of b 2 -adrenoceptor-mediated signal transduction is deeply entrenched, but there is compelling evidence that agonism of b 2 -adrenoceptors can lead to the activation of multiple effector pathways, which now compels researchers in academia and the pharmaceutical industry alike to think beyond the traditional dogma. Therefore, the regulation by b 2 -adrenoceptor agonists of responses, including airways smooth muscle tone and the secretory capacity of the epithelium and pro-inflammatory/immune cells, may be highly complex, involving both cAMPdependent and -independent mechanisms that, in many cases, may act in concert.In this article, the current status of b 2 -adrenoceptor-mediated signalling in the airways is reviewed in the context of understanding mechanisms that may underlie both the beneficial and detrimental effects of these drugs in asthma symptom management.

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Section: Role Of Other Potassium Channelsmentioning

confidence: 99%

Beyond the dogma: novel β₂-adrenoceptor signalling in the airways

Giembycz

Newton²

2006

Eur Respir J

132

118

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“…In conclusion, the present data show that when given locally to the airways in both guinea pigs and monkeys, KCO912 suppresses AHR at doses devoid of cardiovascular effects and has a significantly better 'therapeutic window' than representative earlier generation K ATP channel openers defined in the same models (Buchheit and Fozard 1999;Fozard and Manley 2001). Given the pivotal role of AHR in the pathophysiology of asthma and the preclinical profile of KCO912, this compound was selected for clinical evaluation.…”

Section: Discussionmentioning

confidence: 82%

“…K ATP channel openers can prevent and/or reverse experimental AHR in animals (reviewed by Buchheit and Fozard 1999;Fozard and Manley 2001). Moreover, both antibronchoconstrictor effects and attenuation of the early morning fall in FEV 1 (Forced Expiratory Volume in 1 s) in nocturnal asthma have been observed in clinical studies with cromakalim (Baird et al 1988;Williams et al 1990).…”

Section: Introductionmentioning

confidence: 99%

KCO912: a potent and selective opener of ATP-dependent potassium (K ATP ) channels which suppresses airways hyperreactivity at doses devoid of cardiovascular effects

Buchheit¹,

Manley

Quast

et al. 2002

Naunyn-Schmiedeberg's Archives of Pharmacology

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ATP-sensitive potassium (K(ATP)) channel openers can obviate experimental airways hyperreactivity (AHR) and have shown therapeutic benefit in asthma. However, the clinical potential of such compounds has been compromised by cardiovascular side-effects. We report here the pharmacological properties of (3 S,4 R)-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(2-oxo-1-piperidinyl)- N-phenyl-2 H-1-benzopyran-6-sulphonamide (KCO912), a K(ATP) channel opener which suppresses AHR at doses devoid of cardiovascular effects.Specific interaction of KCO912 with the native vascular channel and the sulphonylurea receptor subunit (SUR2B) of the vascular K(ATP) channel was shown in radioligand binding assays. In rat aortic strips, KCO912 inhibited specific binding of [3H]P1075 and [3H]glibenclamide with up to 100% efficacy and with p Ki values of 8.28 and 7.96, respectively. In HEK cells transfected with the recombinant vascular K(ATP) channel (Kir6.1 + SUR2B), the compound elicited a concentration-dependent outward current (pEC50 6.8) and in preloaded rat aortic rings it induced a concentration-dependent glibenclamide-sensitive 86Rb+ efflux (pEC50 7.51). Following intratracheal (i.t.) administration of KCO912 to guinea pigs, AHR induced by immune complexes or ozone was rapidly (<5 min) reversed (ED50 values 1 microg/kg and 0.03 microg/kg, respectively). Changes in blood pressure were seen only at doses =100 microg/kg yielding 'therapeutic ratios' of 100 and 3333, respectively. In addition, KCO912 reversed AHR induced by lipopolysaccharide (LPS; ED50 0.5 microg/kg i.t.) and a dose of 1 microg/kg i.t. fully reversed AHR induced by subchronic treatment with salbutamol. At doses which suppressed AHR, KCO912 had no anti-bronchoconstrictor effects in normoreactive guinea pigs. In spontaneously hyperreactive rhesus monkeys, KCO912, given by inhalation, inhibited methacholine-induced bronchoconstriction (ED50 1.2 microg/kg) but had no significant effects on blood pressure or heart rate at all doses tested (therapeutic ratio >100). In rats given 3 mg/kg of KCO912 by inhalation, the ratio of the area under the concentration-time curve (AUC) for lung to the AUC in blood was 190 and the compound was rapidly cleared (initial t1/2 approximately 30 min). Thus, the wide therapeutic window following administration of KCO912 to the lung seems likely to reflect slow or incomplete passage of KCO912 from the lung into the systemic circulation coupled with rapid removal from the systemic circulation.Thus, when given locally to the airways in both guinea pigs and monkeys, KCO912 suppresses AHR at doses devoid of cardiovascular effects and has a significantly better therapeutic window than representative earlier generation K(ATP) channel openers defined in the same models. Given the pivotal role of AHR in the pathophysiology of asthma and the preclinical profile of KCO912, this compound was selected for clinical evaluation.

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“…Based on the medicinal use of M. alba in asthma and potential therapeutic use of K + channel openers in this disorder (Buchheit and Fozard, 1999;Pelaia et al, 2002;294 Bangladesh J Pharmacol 2012;7: 289-298 A 100 Sheng and Jian, 2005), the extract was studied for possible bronchodilatory effect in anaesthetized rats, where M. alba dose-dependently suppressed the carbachol-evoked bronchospasm, like that caused by cromakalim. The plant extract was then studied in isolated trachea to investigate the possible modes of brochodilatory action.…”

Section: Discussionmentioning

confidence: 99%