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The potential of the potassium channel activator cromakalim and its active enantiomer BRL 38227 as inhaled bronchodilators has been evaluated in the guinea-pig, in comparison with nifedipine, salbutamol and aminophylline. Inhaled cromakalim and BRL 38227 prolonged the time before histamine-induced collapse in conscious guinea-pigs, BRL 38227 (ED50 250 to 500 micrograms/mL, roughly 10 to 20 micrograms per animal) being twice as potent as cromakalim. In anaesthetized guinea-pigs, BRL 38227 (inhaled and i.v.) and aminophylline (i.v.) caused similar percentage inhibitions of the increase in airways resistance and decrease in dynamic lung compliance elicited by histamine, whereas salbutamol (inhaled and i.v.) was more effective against resistance. Inhaled BRL 38227 and salbutamol were more potent against inhaled than against i.v. histamine. BRL 38227 inhibited the effects of i.v. and inhaled histamine by 67-78% when nebulized from solutions of 250 and 31 micrograms/mL respectively, but the lowest concentration that lowered blood pressure significantly was 500 micrograms/mL. In contrast, nifedipine had no effect on compliance and caused only a marginal (21%) inhibition of resistance at a dose (200 micrograms/kg i.v.) which lowered blood pressure by 44%. These results show that BRL 38227 is an effective bronchodilator when given by inhalation. It differs from salbutamol in its effects on airways dynamics, and its effect on lung compliance cannot be attributed to a pulmonary vasodilator effect. Furthermore, L-type calcium channels are not significantly involved in histamine-induced bronchoconstriction or therefore in the bronchodilator effect of BRL 38227.
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PMID:Evaluation of the potassium channel activator BRL 38227 as an inhaled bronchodilator in the guinea-pig: contrast with nifedipine and salbutamol. 180 2

1. The potential of the potassium channel activator, cromakalim (BRL 34915), as a bronchodilator has been evaluated in guinea-pig models in comparison with nifedipine. Some effects of the compounds on guinea-pig tracheal spirals have been studied in an attempt to elucidate their different efficacies in vivo. 2. When given by the intraduodenal route to anaesthetized guinea-pigs, cromakalim (3 and 10 mg kg-1) inhibited 5-hydroxytryptamine (5-HT)-induced bronchospasm for at least 60 min. When given by the i.v. route, the dose of cromakalim producing 50% inhibition of the 5-HT response was 84 micrograms kg-1. Nifedipine failed to show any protective effect up to 100 micrograms kg-1, i.v. and was lethal at higher dose levels. 3. Cromakalim protected conscious guinea-pigs from asphyxic collapse in response to histamine aerosol. The maximal effect occurred 60 min following oral dosing, with 2.5 mg kg-1 providing complete protection for almost half of the animals. Nifedipine had only a weak protective effect even at a high dose level of 50 mg kg-1, p.o. 4. Cromakalim prolonged the time before convulsive cough in response to an antigen challenge in actively sensitized guinea-pigs. Its minimum protective dose was 1 mg kg-1, p.o. Nifedipine (50 mg kg-1, p.o.) was ineffective. 5. Cromakalim inhibited both spontaneous and prostaglandin E2-induced tone in guinea-pig isolated tracheal spirals with IC50 values, relative to the maximum inhibition achieved by isoprenaline (10(-3)M), of 1.1 x 10(-6)M and 8.9 x 10(-7)M, respectively. Its maximal effect was 89% of that produced by isoprenaline. Removal of the epithelium did not influence its activity. Studies using the two enantiomers showed that the activity of cromakalim resided almost entirely in the (-)-enantiomer. 6. Nifedipine (2 x 10-SM) achieved only 49% of the relaxant effect of 10 -3M isoprenaline in isolated tracheal spirals. Addition of cromakalim (10- 5 M) at the end of the nifedipine concentrationresponse experiment caused further relaxation to 94% of the effect of isoprenaline. 7. It is concluded that cromakalim has greater potential than nifedipine as a bronchodilator. It appears that opening of potassium channels, with consequent hyperpolarization and stabilization of the membrane potential, prevents calcium entering the cytosol through routes that are unaffected by calcium entry blockers.
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PMID:Evaluation of the potassium channel activator cromakalim (BRL 34915) as a bronchodilator in the guinea-pig: comparison with nifedipine. 320 91

1. BRL 55834, a novel potassium channel activator, has been compared with levcromakalim (BRL 38227) for its relaxant effects in vivo on the airways and vasculature of the guinea-pig and rat. 2. When administered intravenously 2 min prior to challenge, BRL 55834 and levcromakalim each inhibited histamine-induced increases in airways resistance (Raw) in the anaesthetized guinea-pig, with BRL 55834 showing a 4.5 fold greater potency than levcromakalim (ED25 = 2.5 micrograms kg-1 and 11.3 micrograms kg-1 respectively). By contrast, both compounds had similar hypotensive potencies (ED18 = 8.5 micrograms kg-1 and 6.5 micrograms kg-1 respectively). 3. In the same guinea-pig model, intraduodenally administered BRL 55834 (100 and 250 micrograms kg-1) and levcromakalim (500 micrograms kg-1) each protected against histamine-induced changes in Raw and dynamic lung compliance (Cdyn), both compounds showing a rapid onset of action that persisted for more than 50 min. The lower dose of BRL 55834 had a similar bronchodilator effect to that of levcromakalim, yet both doses of BRL 55834 elicited substantially smaller effects than levcromakalim on mean arterial blood pressure. 4. In the anaesthetized rat, BRL 55834 and levcromakalim each evoked a dose-related inhibition of inhaled methacholine-induced changes in Raw and Cdyn when given i.v., with BRL 55834 showing some four fold greater potency than levcromakalim (BRL 55834: Raw ED35 = 3.7 micrograms kg-1, Cdyn ED35 = 5.9 micrograms kg-1; levcromakalim: Raw ED35 = 16 micrograms kg-1, Cdyn ED35 = 23.5 micrograms kg-1). As in the guinea-pig,BRL 55834 had a reduced propensity to lower mean arterial blood pressure (ED11 = 8 microg kg-1 for BRL55834, 11 +/- 3% being its maximum effect; ED11= 16 microg kg-1, maximum effect= 34 +/- 6% for levcromakalim.5. When administered intraduodenally to anaesthetized rats, BRL 55834 (10, 20 and 100 microg kg-1)evoked rapid and dose-related inhibitions of methacholine-induced Raw and Cdyn changes which persisted for over 30 min. At the lower and middle dose there was little effect on mean arterial blood pressure(<10% fall). Levcromakalim (500 microg kg-1) by contrast elicited transient airways responses that diminished rapidly after 5 min, while the effects on blood pressure were well maintained (>20% at 65 min). Levcromakalim (100 microg kg-1) did not affect airways responses but also evoked a marked and sustained fall in blood pressure.6. BRL 55834, administered per os, prolonged the time to histamine-induced dyspnoea in conscious guinea-pigs. The greatest effect of BRL 55834 was observed when it was administered 60 min prior to challenge, a dose of 0.20 mg kg-1 doubling the mean time to collapse. A similar level of protection was afforded by levcromakalim (1.25 mg kg-1), with maximal activity occurring between 30 and 60 min.7. The present studies in guinea-pigs and rats indicate that BRL 55834 is the first potassium channel activator to exhibit greater bronchodilator potency than levcromakalim but reduced tendency to lower arterial blood pressure. It is suggested that BRL 55834 may have greater potential than levcromakalim as a bronchodilator for therapeutic use in man.
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PMID:Comparison of the airways relaxant and hypotensive potencies of the potassium channel activators BRL 55834 and levcromakalim (BRL 38227) in vivo in guinea-pigs and rats. 840 25

To elucidate the potential role of mitochondria in Taxol-induced cytotoxicity, we studied its direct mitochondrial effects. In Percoll-gradient purified liver mitochondria, Taxol induced large amplitude swelling in a concentration-dependent manner in the microM range. Opening of the permeability pore was also confirmed by the access of mitochondrial matrix enzymes for membrane impermeable substrates in Taxol-treated mitochondria. Taxol induced the dissipation of mitochondrial membrane potential (DeltaPsi) determined by Rhodamine123 release and induced the release of cytochrome c from the intermembrane space. All these effects were inhibited by 2.5 microM cyclosporine A. Taxol significantly increased the formation of reactive oxygen species (ROS) in both the aqueous and the lipid phase as determined by dihydrorhodamine123 and resorufin derivative. Cytochrome oxidase inhibitor CN(-), azide, and NO abrogated the Taxol-induced mitochondrial ROS formation while inhibitors of the other respiratory complexes and cyclosporine A had no effect. We confirmed that the Taxol-induced collapse of DeltaPsi and the induction of ROS production occurs in BRL-3A cells. In conclusion, Taxol-induced adenine nucleotide translocase-cyclophilin complex mediated permeability transition, and cytochrome oxidase mediated ROS production. Because both cytochrome c release and mitochondrial ROS production can induce suicide pathways, the direct mitochondrial effects of Taxol may contribute to its cytotoxicity.
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PMID:Direct effect of Taxol on free radical formation and mitochondrial permeability transition. 1149 88