Prostacyclin Reduces Microvascular Fluid Conductivity in Cat Skeletal Muscle through Opening of ATP-Dependent Potassium Channels

Abstract

Prostacyclin is suggested to reduce microvascular permeability, but the cellular mechanisms mediating this response in the microvascular endothelial cells are still unknown. Considering that prostacyclin relaxes vascular smooth muscle cells via opening of ATP-dependent potassium channels, and opening of ATP-dependent potassium channels in the endothelial cells is suggested to influence microvascular permeability, this study was designed to test (1) if ATP-dependent potassium channels are involved in the regulation of microvascular hydraulic permeability, (2) if the permeability-reducing effect of prostacyclin is mediated through opening of ATP-dependent potassium channels, and (3) if cAMP is involved in this process. An autoperfused cat calf hindlimb was used as experimental model, and microvascular hydraulic permeability (conductivity) was estimated by a capillary filtration coefficient (CFC) technique. The potassium channel opener PCO-400 (0.5 μg·min^–1 per 100 g muscle, intra-arterially), prostacyclin (1 ng·min^–1 per kg body weight, intravenously) and the cAMP analogue dibutyryl-cAMP (24 μg·min^–1 per 100 g muscle, intra-arterially), decreased CFC to 77, 72 and 69% compared to control, respectively (p < 0.01). The decrease in CFC obtained by these substances was completely restituted after the start of a simultaneous infusion of the ATP-dependent potassium channel blocker glibenclamide (6 μg·min^–1 per 100 g muscle, intra-arterially; p < 0.01). Infusion of glibenclamide alone increased CFC to 107% of control (p < 0.05). In conclusion, the ATP-dependent potassium channels contribute to the regulation of microvascular hydraulic conductivity, and the prostacyclin permeability-reducing effect may act through this mechanism via increase in intracellular cAMP.

Endotoxin increases both protein and fluid microvascular permeability in cat skeletal muscle

“…Recent studies indicate that endotoxin induces cell filament contraction by phosphorylation of myosin light chains, which may involve inhibition of cAMP via the GTP-binding protein Rho (33). It remains to be determined whether an increase in intracellular cAMP by the Rho/Rho kinase-inhibiting substances or by prostacyclin, the latter having previously been shown to reduce hydraulic permeability via intraendothelial filament relaxation (34), also may restore the endotoxin-induced increase in permeability.…”

Prostacyclin Treatment in Severe Traumatic Brain Injury: A Microdialysis and Outcome Study

“…This relative decrease in PGI 2 levels would lead to decreased vasodilation, increased leukocyte adhesion and platelet aggregation, and thus an impaired microcirculation. Beneficial effects of PGI 2 in experimental models of traumatic brain injury and microvascular permeability have been reported (Moller and Grande, 1997, 1999a, 1999bBentzer et al, 1999Bentzer et al, , 2001aBentzer et al, , 2001b. In a study of experimental brain trauma, cerebral cortical blood flow and cortical lesion volume were studied in mice with and without the prostacylin receptor gene (IP þ=þ and IP…”

Prostacylin Treatment in Severe Traumatic Brain Injury - a microdialysis and outcome study

“…This relative decrease in PGI 2 levels would lead to decreased vasodilation, increased leu-kocyte adhesion and platelet aggregation, and thus an impaired microcirculation. Beneficial effects of PGI 2 in experimental models of traumatic brain injury and microvascular permeability have been reported (Moller and Grande, 1997, 1999a, 1999bBentzer et al, 1999Bentzer et al, , 2001aBentzer et al, , 2001b. In a study of experimental brain trauma, cerebral cortical blood flow and cortical lesion volume were studied in mice with and without the prostacylin receptor gene (IP þ=þ and IP À=À ).…”