The permeability-reducing effects of prostacyclin and inhibition of Rho kinase do not counteract endotoxin-induced increase in permeability in cat skeletal muscle

Abstract

cAMP stimulation and Rho kinase inhibition are shown to decrease microvascular permeability during noninflammatory conditions, most likely by decreasing contractility of actomyosin filaments in the endothelial cell, but their effects on permeability during inflammatory conditions are not clarified. The objective of this in vivo study, performed on the autoperfused and denervated calf muscle of the cat, was therefore to evaluate to what extent cAMP stimulation and inhibition of Rho kinase reduce permeability at endotoxemia. Change in osmotic reflection coefficient for albumin was used as a measure of altered protein permeability and change in capillary filtration coefficient (CFC) as a measure of altered fluid permeability. After inducing a significant increase in protein and fluid permeability by infusion of lipopolysaccharide (LPS), we determined to what extent the increased permeability was decreased by the cAMP stimulator prostacyclin [1.0 ng/kg/min intravenously (iv)] or the Rho kinase inhibitor Y-27632 [1.05 μg/ml plasma/h intraarterially (ia)]. These doses are known to decrease permeability under noninflammatory conditions. The reflection coefficient for albumin and CFC were determined before and during LPS, and during LPS plus prostacyclin ( n = 6) or LPS plus Y-27632 ( n = 6). The reflection coefficient was reduced by about 30% ( P < 0.05) and CFC was increased by about 25% ( P < 0.05) by LPS, and these permeability parameters were not affected by prostacyclin or Y-27632. We conclude that cAMP stimulation and Rho kinase inhibition reduce permeability by other pathways and mechanisms than those by which permeability is increased during endotoxemia.