Inhibitors of phosphodiesterase type 4 (PDE4) are currently exploited as potent drugs for pulmonary diseases. Some PDE4 inhibitors induce necrotizing panarteritis in the mesentery of rats, comparable to spontaneous polyarteritis nodosa in rats and vascular alterations that are induced by various vasoactive compounds, such as fenoldopam and inhibitors of PDE3. The mechanism of toxicity is unknown. In order to investigate the development of arteritis in the splanchnic vasculature of rats, a time-course study was performed with high doses of a compound (BYK169171), specifically inhibiting PDE4. Rats were treated orally for 1-28 days, and alterations in the mesentery were evaluated by histology, morphometry, and immunohistology. As early as 3 days after the onset of treatment, a mesenteritis was found, characterized by macrophage infiltration, fibroblast proliferation, neovascularization, and loss of adipocytes. Incidence and severity of the mesenteritis were low during the first 2 weeks of treatment, but increased with duration of treatment, finally affecting 2/3 of all animals. A segmental necrotizing panarteritis was detected in some rats treated for 21 or 28 days, but always followed a mesenteritis, whereas many animals with mesenteric inflammation did not have vascular lesions. We postulate that PDE4 inhibitors do not cause a primary vasculitis/arteritis in rats, but induce a non-purulent inflammation as the predominant initial toxic effect in the mesentery. This renders their toxic effect distinct from that of PDE3 inhibitors.