Changes in toxicity and Ah receptor agonist activity of suspended particulate matter during flood events at the rivers Neckar and Rhine — a mass balance approach using in vitro methods and chemical analysis

Background The use of alpha-2 adrenergic agonists for analgesia is limited due to a narrow therapeutic window. Definition of the role of alpha receptor subtypes in alpha agonist mediated analgesia may identify strategies to separate the analgesic from sedative and cardiovascular effects. Methods Analgesic activity of brimonidine, clonidine, and tizanidine was investigated in wild-type C57B/6, alpha-2A, and alpha-2C knockout mice with allodynia induced by N-methyl-D-aspartate or sulprostone. The alpha receptor selectivity of the alpha agonists was assessed using functional in vitro recombinant assays. Results Brimonidine, clonidine, and tizanidine reduced N-methyl-D-aspartate- and sulprostone-induced allodynia in wild-type mice, but not alpha-2A knockout mice. In alpha-2C knockout mice, brimonidine and tizanidine reduced allodynia in both models, whereas clonidine only reduced N-methyl-D-aspartate-induced allodynia. In vitro, clonidine and tizanidine activated alpha-1 and alpha-2 receptors with similar potencies, whereas brimonidine was selective for alpha-2 receptors. In alpha-2C knockout mice with sulprostone-induced allodynia, blockade of clonidine's alpha-1 receptor agonist activity restored clonidine's analgesic efficacy. In wild-type mice, the analgesic potency of intrathecal clonidine and tizanidine was increased 3- to 10-fold by coadministration with the alpha-1A-selective antagonist 5-methylurapidil without affecting sedation. Following intraperitoneal administration, the therapeutic window was negligible for clonidine and tizanidine, but greater for brimonidine. 5-Methylurapidil enhanced the therapeutic window of intraperitoneal clonidine and tizanidine approximately 10-fold. Conclusions Alpha-1A receptor agonist activity can counterbalance alpha-2 receptor agonist-induced analgesia. Greater alpha-2 selectivity may enhance the therapeutic window of alpha-2 agonists in the treatment of pain.

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AH receptor agonist activity in human blood measured with a cell-based bioassay: Evidence for naturally occurring AH receptor ligands in vivo

Journal of Exposure Science & Environmental Epidemiology ◽

10.1038/sj.jes.7500607 ◽

2007 ◽

Vol 18 (4) ◽

pp. 369-380 ◽

Cited By ~ 21

Author(s):

Kevin T Connor ◽

Mark A Harris ◽

Melanie R Edwards ◽

Robert A Budinsky ◽

George C Clark ◽

...

Keyword(s):

Human Blood ◽

Receptor Agonist ◽

Ah Receptor ◽

Agonist Activity ◽

Receptor Ligands ◽

Naturally Occurring ◽

A Cell

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Ambient particulate matter induces relaxation of rat aortic rings in vitro

Human & Experimental Toxicology ◽

10.1191/096032701678227677 ◽

2001 ◽

Vol 20 (5) ◽

pp. 259-265 ◽

Cited By ~ 19

Author(s):

A M Knaapen ◽

G J den Hartog ◽

A Bast ◽

P JA Borm

Keyword(s):

Smooth Muscle ◽

Particulate Matter ◽

Muscle Function ◽

Ultrafine Particles ◽

Epidemiological Studies ◽

Suspended Particulate ◽

Smooth Muscle Function ◽

Underlying Mechanisms

Epidemiological studies have shown an association between ambient levels of particulate matter (PM) and increased mortality from cardiovascular diseases. However, the underlying mechanisms are still not clear. We hypothesised that PM, when translocated after inhalation, could affect vascular smooth muscle function. Therefore, total suspended particulate matter (TSP) was sampled and investigated for its ability to affect aortic muscle contraction. Both TSP and TSP supernatant (TSP-sup) induced a concentration-dependent relaxation of phenylephrine (PE)-precontracted aortic rings. Relaxation induced by 100 jg/ml TSP was 51.5 t 3.1% of total contraction. At 60 and 100 Hg/ ml, relaxation induced by TSP was significantly higher compared to TSP-sup. Ultrafine TiO2, used as a model to investigate the role of ultrafine particles, did not show an effect. Soluble iron, present in TSP suspensions, seems not to be involved, as chelating with deferoxamine did not affect TSP-induced relaxation. However, TSP effects were inhibited by Trolox, suggesting a role of oxidants. Nudation of aortic rings showed that effects of TSP were only partly endothelium-dependent, while preincubation with LNAME increased TSP-induced relaxation. From these data, we conclude that both the particle core and soluble components of TSP can affect the smooth muscle function, leading to changes in the vascular contractile response.

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