ToxSci Advance Access originally published online on October 15, 2008
Toxicological Sciences 2009 107(1):298-305; doi:10.1093/toxsci/kfn218
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An Increased Regional Blood Flow Precedes Mesenteric Inflammation in Rats Treated by a Phosphodiesterase 4 Inhibitor
* Université François-Rabelais de Tours, Centre National de la Recherche Scientifique Formation de Recherche en Evolution 3092, F-37200 Tours, France
Drug Safety R&D, Pfizer, Z.I. Pocé-sur-Cisse, BP 159, F-37401, Amboise, France
1 To whom correspondence should be addressed at Université François-Rabelais de Tours, Centre National de la Recherche Scientifique Formation de Recherche en Evolution 3092 and Department of Pharmacology, Faculty of Pharmacy, 31 Avenue Monge, F-37200 Tours, France. Fax: +33-2-47-36-72-07. E-mail: jean-louis.freslon{at}univ-tours.fr.
Received July 25, 2008; accepted October 7, 2008
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Abstract |
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The study was undertaken to assess the hemodynamic effects induced by a single dose of the phosphodiesterase 4 (PDE4) inhibitor, CI-1044, which is known to cause mesenteric vascular alterations in rats. In the present study, an administration of 160 mg/kg of CI-1044 caused perivascular and interstitial inflammation, with infiltrates of admixed neutrophils and macrophages but without evidence of vascular necrosis (ileum, 15/20 rats; duodenum + jejunum, 7/20 rats). Four hours after administration, blood pressure was decreased (– 13%). A fluorescent microsphere technique demonstrated that, in these conditions, cardiac output was doubled (+ 100%) and total peripheral resistance was decreased (– 54%). The largest increases in blood flow were measured in the duodenum (+ 101%), in the jejunum (+ 110%), and in the ileum (+ 192%). Therefore, the mesentery was the most sensitive organ affected by the drug and, within this area, parts with the highest incidence of vascular alteration were those which had shown the highest increase in flow. In addition, isolated precontracted mesenteric resistance arteries dissected from untreated animals were fully relaxed when incubated with increasing concentrations of CI-1044 up to 2.5 x 10–5M. At this latter concentration, contractile abilities and sensitivities to the physiological agonist noradrenaline (NA) and to the thromboxane analogue U46619 [GenBank] were significantly attenuated (– 28 and – 27%, respectively). This effect could lead to a decreased response to NA and possibly to other agonists in vivo consistent with the vasodilation observed with the microsphere technique. These data provide evidence that the PDE4 inhibitor CI-1044 induces changes of vascular tone that could lead to histological alterations in the mesenteric area.
Key Words: drug-induced vascular injury; mesenteric artery; PDE4 inhibitor; mesenteric blood flow; vasoreactivity.