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PAF- and bradykinin-induced hyperpermeability of rat venules is independent of actin-myosin contraction

Department of Human Physiology, School of Medicine, University of California, Davis, California 95616

Submitted 9 January 2003 ; accepted in final form 18 March 2003

We tested the hypothesis that acutely induced hyperpermeability is dependent on actin-myosin contractility by using individually perfused mesentery venules of pentobarbital-anesthetized rats. Venule hydraulic conductivity (L_p) was measured to monitor hyperpermeability response to the platelet-activating factor (PAF) 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine or bradykinin. Perfusion with PAF (10 nM) induced a robust transient high L_p [24.3 ± 1.7 x 10^-7 cm/(s·cmH₂O)] that peaked in 8.9 ± 0.5 min and then returned toward control L_p [1.6 ± 0.1 x 10^-7 cm/(s·cmH₂O)]. Reconstruction of venular segments with the use of transmission electron microscopy of serial sections confirmed that PAF induces paracellular inflammatory gaps. Specific inhibition of myosin light chain kinase (MLCK) with 1–10 µM 1-(5-iodonaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine hydrochloride (ML-7) failed to block the PAF L_p response or change the time-to-peak L_p. ML-7 reduced baseline L_p 50% at 40 min of pretreatment. ML-7 also increased the rate of recovery from PAF hyperpermeability measured as the decrease of half-time of recovery from 4.8 ± 0.7 to 3.2 ± 0.3 min. Inhibition of myosin ATPase with 5–20 mM 2,3-butanedione 2-monoxime also failed to alter the hyperpermeability response to PAF. Similar results were found using ML-7 to modulate 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.

bradykinin; platelet-activating factor; inflammatory gaps; vascular endothelium; ML-7; myosin light chain kinase

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