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Phosphodiesterase‐4‐inhibition stabilizes microvascular endothelial barrier functions and microcirculation in a model of polymicrobial sepsis

In sepsis breakdown of endothelial barrier functions contributes to disturbed microcirculation, organ failure and death. Increased cAMP levels have been demonstrated to protect endothelial barrier functions in inflammation. In the present study effects of systemically intravenously applied phosphodiesterase‐IV‐inhibitor rolipram (PD‐IV‐I) on microvascular endothelial barrier functions and microcirculation were tested in a rodent model of polymicrobial sepsis using the colon‐ascendens stent peritonitis (CASP) model. Animals with CASP showed clinical and laboratory signs of sepsis and peritonitis with increased IL‐6‐levels compared to sham‐operated animals. In postcapillary mesenteric venules PD‐IV‐I led to stabilisation of endothelial barrier properties as revealed by extravasation of intravenously applied FITC‐albumin. Only low‐dose application of 0,3 mg/h of PD‐IV‐I led to barrier protective effects in the CASP model whereas high‐dose therapy of 1,2 mg/h PDI‐IV‐I had adverse effects. Accordingly microcirculatory flow in mesenteric venules was only improved under low‐dose PD‐IV‐I therapy. Severe side effects of PD‐IV‐I application on blood pressure and cardiac output were not observed. The present data provide further evidence that systemic application of PD‐IV‐I can become a clinically relevant and applicable approach to stabilize endothelial barrier functions in sepsis.