Effects of Rho kinase, prostacyclin and L-arginine on microvascular permeability and perfusion

Abstract: This thesis presents some effects of Rho kinase, prostacyclin (PGI2) and nitric oxide (NO) in relation to trauma and inflammation by evaluating their effects on microvascular perfusion and permeability in mouse brain and in cat skeletal muscle. PGI2 and NO are endogenous vasoactive substances produced by the endothelium. They are vasodilators with antiaggregatory/antiadhesive and permeability-reducing properties, and exert their effects via cAMP and cGMP, respectively. Earlier studies indicate that both PGI2 and NO are beneficial by improving perfusion in the traumatized brain. Rho kinase is an intracellular kinase, known to increase the contractility of the endothelial cells and thereby the intercellular distance and may, therefore, be involved in regulation of microvascular permeability. cAMP and cGMP are also suggested to exert their permeability-reducing effects by affecting the intercellular distance between the endothelial cells. PGI2, NO and Rho kinase affect the contractility of smooth muscle cells and thereby contributes to the regulation of vascular resistance. The effects on fluid and protein microvascular permeability of the Rho kinase inhibitor Y-27632 and PGI2 were analysed in cat skeletal muscle. Y-27632 reduced permeability following the surgical trauma, as shown previously for PGI2, but neither PGI2 nor Y-27632 counteracted the endotoxin-induced increase in fluid and protein permeability. These results suggest that mechanisms behind increased permeability during inflammation differ partly from those responsible for normal regulation of permeability. To investigate cerebral hemodynamic effects of brain trauma, a controlled cortical impact injury was evaluated regarding trauma-induced effects on cortical blood flow, number of perfused capillaries, permeability-surface area product, brain oedema and contusion volume. The model was then used to evaluate effects of L-arginine and endogenous PGI2 (using transgenic mice with deficient PGI2 receptor) on these parameters following trauma. L-arginine improved cerebral perfusion in the contusion areas, and endogenous PGI2 is important for cell survival as the contusion was larger in animal with deficient PGI2 receptor.