Further analysis of the mechanisms underlying the tracheal relaxant action of SCA40

Cook, Susan; Archer, Katie E.; Martin, A.; Buchheit, Karl Heinz; Fozard, John R.; Müller, Thomas; Miller, A.J.; Elliott, Keith; Foster, Robert W.; Small, R.C.

doi:10.1111/j.1476-5381.1995.tb14918.x

Cited by 39 publications

(26 citation statements)

References 20 publications

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“…However, they suggest that the interaction of SCA40 with the guinea pig trachea in vitro might be more complex than previously assumed. Thus, we found that suppression of the spontaneous tone of guinea pig trachea by SCA40 can be described by a biphasic rather than the monophasic concentration-response curves, as described by Cook et al 1995. The reason for this discrepancy is unclear.…”

Section: In Vitro Effectsmentioning

confidence: 64%

“…Previous data have shown SCA40 to suppress both the spontaneous tone (Cook et al 1995) and the tone induced by various spasmogens McHarg et al 1994) in the isolated guinea pig trachea. The results of the current study confirm this property of SCA40.…”

Section: In Vitro Effectsmentioning

confidence: 99%

“…Since BK Ca channels are considered to play a major role in the regulation of vascular tone (Nelson 1993), the cardiovascular effects of SCA40 were deemed to be consistent with the proposed mechanism of action. However, the ability of SCA40 to open BK Ca channels has been disputed by others who suggested that the ralaxant effect of SCA40 in vitro might be due to blockade of phosphodiesterase type III and IV (Cook et al 1995).…”

mentioning

confidence: 99%

“…Clearly, there is a need for new symptomatic antiasthma drugs acting by a mechanism different from badrenoceptor activation. The ability of SCA40 to relax isolated airway smooth muscle Cook et al 1995) prompted us to investigate its potential anti-asthma effects in vitro and in vivo in comparison with salbutamol; some of the in vivo results for salbutamol were taken from a previous paper . To limit systemic cardiovascular effects of SCA40, the in vivo experiments were performed following intratracheal administration.…”

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confidence: 99%

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In vitro and in vivo effects of SCA40 on guinea pig airways

Buchheit

Hofmann

Pfannkuche

1997

Naunyn-Schmiedeberg's Arch Pharmacol

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SCA40 (6-bromo-8-methylaminoimidazo [1,2-a]-pyrazine-2-carbonitrile), a compound which had been described as an opener of Ca(2+)-dependent large conductance potassium channels (BKCa channels), was investigated in comparison with salbutamol for in vitro and in vivo bronchospasmolytic effects and for the ability to reverse airways hyperreactivity in guinea pigs. SCA40 reduced the spontaneous tone of isolated guinea pig tracheal rings with a biphasic concentration-response curve (first phase: pD2 = 8.0, EMax = 29.7% of maximal effect; second phase: pD2 = 6.4, EMax = 72.6%). The salbutamol curve was monophasic (pD2 = 8.0, EMax = 100%). Total lung resistance (RL) was determined in anaesthetized, ventilated guinea pigs. Bronchoconstriction, measured as an increase in RL, was elicited in normoreactive animals by i.v. infusion of bombesin (100 ng/kg/min) or by i.v. injection of histamine (1.8-5.6 micrograms/kg). Airways hyperreactivity was induced by acute i.v. administration of pre-formed immune complexes. Intravenous bolus injections of histamine (2.4 micrograms/kg) were used to define the sensitivity of the airways prior to and after the exposure to immune complex. Following intratracheal (i.t.) administration, SCA40 reversed bombesin-induced bronchoconstriction with an ED50 of 43 micrograms/kg (EMax = 57%). The ED50 for salbutamol was 0.8 microgram/kg i.t. (EMax = 78%). Histamine-induced bronchoconstriction in hyperreactive guinea pigs was inhibited by SCA40 with an ED50 of 13 micrograms/ kg i.t. (EMax = 82%). Salbutamol completely inhibited histamine-induced bronchospasm with an ED50 of 9 ng/kg i.t. In normoreactive guinea pigs, SCA40 prevented histamine-induced bronchoconstriction with an ED50 of 100 micrograms/kg i.t.; for salbutamol the ED50 in this test was 0.48 microgram/kg i.t. Thus, for both SCA40 and salbutamol, the effects obtained at low doses in hyperreactive guinea pigs represent a true reversal of airways hyperreactivity, whereas at higher doses, anti-hyperreactive and bronchospasmolytic properties may account for the observed effects. In conclusion, SCA40 relaxes guinea pig airways smooth muscle in vitro and in vivo, and it partly reverses airways hyperreactivity. With respect to both potency and efficacy, SCA40 is markedly less active than the beta-adrenoceptor agonist salbutamol.

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Section: In Vitro Effectsmentioning

confidence: 64%

Section: In Vitro Effectsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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In vitro and in vivo effects of SCA40 on guinea pig airways

Buchheit

Hofmann

Pfannkuche

1997

Naunyn-Schmiedeberg's Arch Pharmacol

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“…On the other hand, only a poor correlation between membrane hyperpolarization and relaxation has been noted in relaxation caused by fJ-adrenoceptor activation (Cook et al, 1993). Furthermore, there is evidence that the inhibitory action of charybdotoxin on isoprenaline-induced relaxation is due to an increase in Ca2+ influx through voltage-gated Ca2+ channels after membrane depolarization caused by the toxin (Huang et al, 1993 ;Cook et al, 1995 Bridsh Joumal of Phamacology (1995Phamacology ( ) 116, 2738Phamacology ( -2742 Tension and membrane potential recordings…”

Section: Introductionmentioning

confidence: 99%

Relaxant actions of isoprenaline on guinea‐pig isolated tracheal smooth muscle

Ito

Takagi

Tomita

1995

British J Pharmacology

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1 The effects of isoprenaline on membrane potential and intracellular Ca2" concentration ([Ca2+]i) in guinea-pig isolated tracheal muscle were studied by use of intracellular micro-electrodes and fura-2 signals respectively. Measurements of membrane potential were carried out in the presence of spontaneously-generated muscle tone, whereas fura-2 signals were measured during contraction produced by exogenous prostaglandin E2 (100 nM). The potency of isoprenaline in causing relaxation was the same in these two different situations.2 Isoprenaline (0.01 gM) produced relaxation accompanied by 5 mV hyperpolarization. A combination of tetraethylammonium (TEA, 10 mM) and verapamil (3 gM) did not alter the effects of isoprenaline.Removal of external K' did not increase the degree of hyperpolarization produced by isoprenaline.3 In the presence of TEA (10 mM) and verapamil (3 gM), isoprenaline (0.03-1 M) reduced [Ca2+], concentration-dependently. A similar degree of inhibition was observed when isoprenaline was applied during the maintained contraction induced by prostaglandin E2 and against the contraction evoked by the addition of Ca21 to tissues bathed in a Ca2+-free medium and pretreated with both isoprenaline and prostaglandin E2.4 It is concluded that activation of TEA-sensitive Ca2+-dependent K'channels does not play a significant role in isoprenaline-induced relaxation. We propose that, in the guinea-pig tracheal muscle, isoprenaline may produce relaxation mainly by inhibiting a receptor-operated pathway for Ca21 influx across the plasma membrane which is normally activated by prostaglandins.

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Nitration in the imidazo[1,2‐a]pyrazine series. Experimental and computational results

Vitse

Bonnet

Bompart

et al. 1997

Journal of Heterocyclic Chem

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Nitration was carried out on a series of imidazo[1,2‐a]pyrazine derivatives. The reactivities of diversely substituted derivatives and of all positions of substitution were analysed and experimental results compared with 13‐nmr data and semi empirical calculations (AMI). Although the unsubstituted heterocycle is highly resistant to nitration, electron‐donating groups such as alkoxy or alkylamino on position 8 enhance the reactivity of the imidazo[1,2‐a]pyrazine derivatives towards electrophilic substitution and, more specifically, nitration. The 13‐nmr experiments, electronic distributions and Molecular Electrostatic Potential isodensity surfaces calculated on the neutral forms are in good agreement with experimental results indicating position 3 is the most reactive position towards nitration.

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Further analysis of the mechanisms underlying the tracheal relaxant action of SCA40

Abstract: 1 SCA40 (nM-1I0 LM), isoprenaline (1-300 nM) and levcromakalim (100 nM-10-IM) each produced concentration-dependent suppression of the spontaneous tone of guinea-pig isolated trachea. Propranolol

Cited by 39 publications

References 20 publications

In vitro and in vivo effects of SCA40 on guinea pig airways

In vitro and in vivo effects of SCA40 on guinea pig airways

Relaxant actions of isoprenaline on guinea‐pig isolated tracheal smooth muscle

Nitration in the imidazo[1,2‐a]pyrazine series. Experimental and computational results

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