The Effect of Calcium Antagonists on the Activation of Gu nea Pig Neutrophils

Azuma, Yukio; Tokunaga, Takashi; Takeda, Yoshinobu; Ogawa, Tamotsu

doi:10.1254/jjp.42.243

Cited by 8 publications

(1 citation statement)

References 31 publications

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“…5). It must be pointed out that organic Ca 2ϩ channel blockers have been reported to inhibit various PMN functions elicited by FMLP, bacteria, or latex in vitro and ex vivo (3,13,25,26,53). According to Jaconi et al (22), the mechanism of calcium influx in stimulated PMNs does not appear to involve voltage-operated, receptor-operated, or second messenger-operated Ca 2ϩ channels but correlates with the filling state of intracellular Ca 2ϩ stores and is referred to as capacitative Ca 2ϩ influx (42).…”

Section: Discussionmentioning

confidence: 99%

Role of extracellular calcium in in vitro uptake and intraphagocytic location of macrolides

Mtairag

Abdelghaffar

Douhet

et al. 1995

Antimicrob Agents Chemother

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We compared the uptakes and intracellular locations of four 14-membered-ring macrolides (roxithromycin, dirithromycin, erythromycin, and erythromycylamine) in human polymorphonuclear neutrophils (PMNs) in vitro. Intracellular location was assessed by cell fractionation and uptake kinetics in cytoplasts (granule-poor PMNs). Trapping of dirithromycin within PMN granules (up to 80% at 30 min) was significantly more marked than the intracellular trapping of the other drugs (erythromycylamine, 45% ؎ 5.1%; erythromycin, 42% ؎ 3.7%; roxithromycin, 35% ؎ 3.0%). A new finding was that, in the absence of extracellular calcium, the uptakes of all of the macrolides by PMNs and cytoplasts were significantly impaired, by about 50% (PMN) and 90% (cytoplasts). Furthermore, inorganic Ca 2؉ channel blockers inhibited macrolide uptake in a concentrationdependent manner, with 50% inhibitory concentrations of 1.6 to 2.0 mM and 29 to 35 M, respectively, for Ni The organic Ca 2؉ channel blocker nifedipine had no effect on macrolide uptake, whereas verapamil inhibited it in a time-and concentration-dependent manner. These data show the importance of extracellular Ca 2؉ in macrolide uptake by phagocytes and suggest a link with Ca 2؉ channels or a Ca 2؉ channel-operated mechanism.Infections caused by organisms which survive and multiply within host cells, such as Legionella spp., Chlamydia spp., and Mycobacteria spp., are difficult to cure, partly because of the intracellular locations of these pathogens, which are protected from the antimicrobial activities of non-cell-penetrating agents (20). However, the abilities of antibiotics to enter and concentrate within host cells, generally estimated from the intracellular concentration-to-extracellular concentration ratio, may not actually reflect their overall intracellular bactericidal activities (17). Another factor of importance is the respective intracellular locations of the drug and the pathogen. Possible interactions between the drug and host cell factors (inactivation, binding, synergy) may also result from the particular location of the drug. In addition, intracellular accumulation of antibacterial agents or the mechanism used for this cellular transport may in turn affect host cell metabolism and functions, ultimately modifying the overall course of infectious diseases. Among those cell-penetrating agents, macrolide antibiotics have been much studied (14,27). Many publications examine their intracellular (particularly intraphagocytic) accumulation (for a review, see reference 29) and their possible interference with phagocyte activities (for a review, see reference 28). Despite abundant data, the mechanism underlying macrolide uptake by host cells is poorly understood. Various hypotheses have been put forward. These hypotheses involve liposolubility and active transport systems, particularly those used by nucleosides (18, 21). A likely mechanism for their intracellular accumulation involves the weakly basic nature of macrolides and the possibility of trapping by protonation within ...

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