An increased regional blood flow precedes mesenteric inflammation in rats treated by a phosphodiesterase 4 inhibitor.

Abstract

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(-5)M. At this latter concentration, contractile abilities and sensitivities to the physiological agonist noradrenaline (NA) and to the thromboxane analogue U46619 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.

• Authors: Sevil Korkmaz, Véronique Maupoil, Cécile Sobry, Chloé Brunet, Stephan Chevalier, Jean-Louis Freslon
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 107 Issue 1 Pg. 298-305 (Jan 2009) ISSN: 1096-0929 [Electronic] United States
• PMID: 18922941 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Azepines
• Phosphodiesterase 4 Inhibitors
• Niacinamide
• 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
• CI 1044
• Norepinephrine

Topics

• 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid (metabolism)
• Analysis of Variance
• Animals
• Azepines (administration & dosage, pharmacology)
• Blood Pressure (drug effects)
• Cardiac Output (drug effects)
• Duodenum (drug effects, metabolism)
• Heart (drug effects, physiology)
• Hemodynamics (drug effects)
• Ileum (drug effects, metabolism)
• Inflammation (metabolism)
• Jejunum (drug effects, metabolism)
• Male
• Mesenteric Arteries (drug effects, metabolism)
• Muscle, Skeletal (drug effects, metabolism)
• Necrosis (metabolism)
• Niacinamide (administration & dosage, analogs & derivatives, pharmacology)
• Norepinephrine (metabolism)
• Phosphodiesterase 4 Inhibitors
• Rats
• Rats, Sprague-Dawley
• Splanchnic Circulation (drug effects)