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Am J Physiol Lung Cell Mol Physiol (April 2, 2004). doi:10.1152/ajplung.00420.2003
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Submitted on December 1, 2003
Accepted on March 25, 2004

Pressor responses to platelet-activating factor and thromboxane are mediated by Rho-kinase

Christian Martin1, Rolf Goeggel1, Anna R. Ressmeyer1, and Stefan Uhlig1*

1 Division of Lung Pharmacology, Research Center Borstel, Borstel, Germany

* To whom correspondence should be addressed. E-mail: suhlig{at}fz-borstel.de.

Platelet-activating factor (PAF) contracts smooth muscle of airways and vessels primarily via release of thromboxane. Contraction of smooth muscle is thought to be mediated either by calcium and inositol trisphosphat (IP3)-dependent activation of the myosin light chain kinase, or alternatively, via the recently discovered Rho-kinase pathway. Here we investigated the contribution of these two pathways to PAF and thromboxane receptor-mediated broncho- and vasoconstriction in two different rat models: the isolated perfused lung (IPL) and precisioncut lung slices. Inhibition of the IP3- receptor (1-10µM Xestospongin C) or inhibition of phosphatidylinositol specific PLC (30µM L-108) did not affect bronchoconstriction but attenuated the sustained vasoconstriction by PAF. Inhibition of myosin light chain kinase (35µM ML-7) or of calmodulin kinase kinase (26µM STO609), which regulates the phosphorylation of the myosin light chain, had only a small effect on PAF or thromboxaneinduced pressor responses. Similarly, calmidazolium (10µM), which inhibits calmodulin dependent proteins, only weakly reduced the airway responses. In contrast, Y27632 (10µM), a Rho-kinase inhibitor attenuated the thromboxane release triggered by PAF, and provided partial respectively complete inhibition against PAF- and thromboxane-induced pressor responses. Taken together, our data indicate that PAF- and thus thromboxane receptormediated smooth muscle contraction depends largely on the Rho-kinase pathway.




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