Pressor responses to platelet-activating factor and thromboxane are mediated by Rho-kinase.
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 trisphosphate (IP(3))-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 precision-cut lung slices. Inhibition of the IP(3) receptor (1-10 microM xestospongin C) or inhibition of phosphatidylinositol-specific PLC (30 microM L-108) did not affect bronchoconstriction but attenuated the sustained vasoconstriction by PAF. Inhibition of myosin light chain kinase (35 microM ML-7) or of calmodulin kinase kinase (26 microM STO609), which regulates the phosphorylation of the myosin light chain, had only a small effect on PAF- or thromboxane-induced pressor responses. Similarly, calmidazolium (10 microM), which inhibits calmodulin-dependent proteins, only weakly reduced the airway responses. In contrast, Y-27632 (10 microM), a Rho-kinase inhibitor, attenuated the thromboxane release triggered by PAF and provided partial or complete inhibition against PAF- and thromboxane-induced pressor responses, respectively. Together, our data indicate that PAF- and thus thromboxane receptor-mediated smooth muscle contraction depends largely on the Rho-kinase pathway.
Martin
C
C
Division of Pulmonary Pharmacology, Research Center Borstel, 23845 Borstel, Germany.
Göggel
R
R
Ressmeyer
A-R
AR
Uhlig
S
S
D000577:Amides / Q000494:pharmacology; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008168:Lung / Q000098:blood supply*; D010972:Platelet Activating Factor / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013931:Thromboxanes / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*; D054460:rho-Associated Kinases
D000577:Amides; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D010972:Platelet Activating Factor; D011725:Pyridines; D013931:Thromboxanes; C108830:Y 27632; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases