Interaction of endothelin-1 and nitric oxide in endothelial barrier failure in the cat hindlimb

Objective: To determine the interactions of endothelin-1 (ET-1) and nitric oxide (NO) in the regulation of endothelial barrier function in skeletal muscle. Methods: The protein sieving coefficient (1 - sigma(f)) was measured as an index of microvascular permeability in the isolated, perfused cat hindlimb preparation The measurement mas made to determine 1) the effects of ET-1 and NO on basal permeability by blocking rile ET, receptor with BQ123 and NO production with the NO-synthase inhibitors L-NAME or L-NMMA; 2) if elevated NO (SNAP) affects permeability: and 3) the interaction of ET-I and NO by ascertaining if NO-synthase inhibition or elevated NO can block; the ET-l-induced permeability increases. Additionally, vascular resistance was determined under these conditions Co see if increased microvascular pressures ol increased shear stress might play a role in the permeability changes. Results: Blocking either the ETA receptor or basal NO production did not affect basal permeability. Likewise, raising NO levels did not affect this permeability. Blocking the ETA receptor blocked the ability of ET-1 ro cause a profound barrier failure. Increased NO also could block this ET-l-induced effect. Blocking the ETA receptor or elevating NO blocked the 2.5-fold increase in vascular resistance induced by ET-1. Conclusions: Since the ETA receptor does not reside on skeletal muscle endothelium, it is not likely that ET-1 acts directly on the endothelium to produce its effects. It could act through 1) increases in shear stress secondary to an ET-1-induced vasoconstriction: 2) ET-1-induced increases in microvascular pressure sufficient to cause an inflammatory reaction:, or 3) stimulation of other cell types such as leukocytes, to release inflammatory; mediators that could damage the endothelium.