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* To whom correspondence should be addressed. E-mail: gnadamson{at}ucdavis.edu.
We tested the hypothesis that acutely induced hyperpermeability is dependent on actin-myosin contractility using individually perfused mesentery venules of pentobarbitol anesthetized rats. Venule hydraulic permeability (Lp) was measured to monitor hyperpermeability response to platelet activating factor (PAF) or bradykinin (BK). Perfusion with PAF (10 nM) induced a robust transient high Lp (24.3 ± 1.7 x 10-7 cm/(s x cmH2O)) that peaked in 8.9 ± 0.5 min and then returned toward control Lp (1.6 ± 0.1 x 10-7 cm/(s x cmH2O)). Reconstruction of venular segments using transmission electron microscopy of serial sections confirmed that PAF induces paracellular inflammatory gaps. Specific inhibition of myosin light chain kinase (MLCK) by ML-7 (1-10 µM) failed to block the PAF Lp response or change the time to peak Lp. ML-7 reduced baseline Lp 50% at 40 min of pretreatment. ML-7 also increased the rate of recovery from PAF hyperpermeability measured as decrease of half-time of recovery from 4.8 ± 0.7 to 3.2 ± 0.3 min. Inhibition of myosin ATPase with BDM (5-20 mM) also failed to alter the hyperpermeability response to PAF. Similar results were found using ML-7 to modulate BK responses. These experiments indicate that an actin-myosin contractile mechanism modulated by MLCK does not contribute significantly to the robust initial increase in permeability of rat venular microvessels exposed to two common inflammatory mediators. The results are consistent with paracellular gap formation by local release of endothelial-endothelial cell adhesion structures in the absence of contraction by the actin-myosin network.
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