作者: Sakai, Daniel M. ; Howard, Shenise L. ; Quandt, Jane E. ; Grimes, Janet A. ; Schmiedt, Chad W. ; Wallace, Mandy L. ; Barletta, Michele ; Reed, Rachel A.

AbstractObjectiveTo compare the effects of two doses of doxapram intravenous injection and carbon dioxide inhalation on the cardiovascular and laryngeal functions of anesthetized hounds.Study DesignExperimental study.AnimalsSix healthy adult dogs.MethodsIn a Latin‐square design, the mean arterial blood pressure (MABP) and heart rate (HR) were recorded continuously. The inspiratory normalized glottic gap areas (iNGGA) were measured before and after each stimulation with 0.55 mg/kg of doxapram (L‐DOX), 2.2 mg/kg of doxapram (H‐DOX), or 90 s of inhalation of 10% carbon dioxide in oxygen (I‐CO2). The stimulations were tested in duplicate or triplicate. Video clips of the laryngeal movement were scored by board‐certified surgeons masked to the treatment.ResultsThe MABP increased with L‐DOX and H‐DOX up to 81% (both p < .001 compared to I‐CO2), and persisted during the other stimulations (both p < .001). An intermittent tachycardic effect of up to 79% increase in HR was observed with doxapram. The HR following H‐DOX was higher than L‐DOX and I‐CO2 (both p < .016). Neither hypertension nor tachycardia was observed with I‐CO2. The iNGGA increased with all treatments (p < .001). The iNGGA was greater with H‐DOX than L‐DOX and I‐CO2 (both p < .007). All treatments received higher scores (all p < .001) with acceptable inter‐ and intra‐observers Krippendorff's alphas.ConclusionAll treatments were effective respiratory stimulants in anesthetized dogs; however, doxapram caused hypertension and tachycardia.Clinical SignificanceCarbon dioxide inhalation might improve arytenoid motion without cardiovascular effects in dogs during clinical airway examinations.

2020-02-01·Acta Physiologica2区 · 医学

Effects of the ventilatory stimulant, doxapram on human TASK‐3 (KCNK9, K2P9.1) channels and TASK‐1 (KCNK3, K2P3.1) channels

2区 · 医学

Article

作者: Veale, Emma L. ; MacIntyre, D. Euan ; Mathie, Alistair ; Cunningham, Kevin P.

AbstractAimsThe mode of action by which doxapram acts as a respiratory stimulant in humans is controversial. Studies in rodent models, have shown that doxapram is a more potent and selective inhibitor of TASK‐1 and TASK‐1/TASK‐3 heterodimer channels, than TASK‐3. Here we investigate the direct effect of doxapram and chirally separated, individual positive and negative enantiomers of the compound, on both human and mouse, homodimeric and heterodimeric variants of TASK‐1 and TASK‐3.MethodsWhole‐cell patch clamp electrophysiology on tsA201 cells was used to assess the potency of doxapram on cloned human or mouse TASK‐1, TASK‐3 and TASK‐2 channels. Mutations of amino acids in the pore‐lining region of TASK‐3 channels were introduced using site‐directed mutagenesis.ResultsDoxapram was an equipotent inhibitor of human TASK‐1 and TASK‐3 channels, compared with mouse channel variants, where it was more selective for TASK‐1 and heterodimers of TASK‐1 and TASK‐3. The effect of doxapram could be attenuated by either the removal of the C‐terminus of human TASK‐3 channels or mutations of particular hydrophobic residues in the pore‐lining region. These mutations, however, did not alter the effect of a known extracellular inhibitor of TASK‐3, zinc. The positive enantiomer of doxapram, GAL‐054, was a more potent antagonist of TASK channels, than doxapram, whereas the negative enantiomer, GAL‐053, had little inhibitory effect.ConclusionThese data show that in contrast to rodent channels, doxapram is a potent inhibitor of both TASK‐1 and TASK‐3 human channels, providing further understanding of the pharmacological profile of doxapram in humans and informing the development of new therapeutic agents.

2000-01-01·Biological and Pharmaceutical Bulletin4区 · 医学

Potentiation of Acetaminophen Hepatotoxicity by Doxapram in Mouse Primary Cultured Hepatocytes.

4区 · 医学

Article

作者: Takayanagi, Motoaki ; Kanno, Shuuichi ; Sasaki, Ken-Ichi ; Ishikawa, Masaaki ; Takayanagi, Yoshio

The augmentation by doxapram (DOP) of the reduction in viability and of the apoptosis of cells induced by acetaminophen (AA) was examined in mouse primary cultured hepatocytes. Loss of viability on exposure to AA and/or DOP in cultured hepatocytes was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and the apoptosis of cultured hepatocytes was detected by nuclear morphologic observation and from a ladder-like DNA fragmentation pattern. The combination of AA (5 mM) and DOP (10, 20, 50 or 100 microM) potentiated the reduction in cell viability and increased the oxidative stress. Hepatocytes exposed for 24 h to AA (5 mM) plus DOP (100 microM), showed atrophy of nuclei, including chromatin condensation and a ladder-like DNA fragmentation pattern, characteristic of apoptosis. Benzyl-oxycarbonyl-Asp-CH2OC (O)-2,6-dichlorobenzene (Z-Asp-CH2-DCB, 50 microM), an inhibitor for caspases, improved the viability and ladder-like DNA fragmentation in cells exposed to DOP (200 or 500 microM) alone or AA ( 5 mM) plus DOP (100 microM). However, loss of viability on exposure to a high concentration of AA (10 mM) and ladder-like DNA fragmentation were not affected by Z-Asp-CH2-DCB. These results indicated that the synergistic increase in oxidative stress, activation of caspases and DNA fragmentation induced by DOP potentiated the hepatotoxicity of AA.

100 项与 (+)-Doxapram 相关的药物交易

登录后查看更多信息