Endothelin-1 decreases microvessel permeability after endothelial activation.
BACKGROUND
Endothelin-1 (ET-1) is a potent vasoconstrictor that is released during shock and sepsis. We hypothesized that ET-1 plays a role in the modulation of the elevated microvascular permeability state of the activated endothelium.


METHODS
Hydraulic permeability (Lp) was measured using the modified Landis micro-occlusion technique. The effect of different ET-1 doses on Lp was determined by obtaining paired measures of Lp at baseline and after the vessels were perfused with ET-1 at doses of 2.0 pg/mL (n = 6), 20 pg/mL (n = 6), 200 pg/mL (n = 6), or 2,000 pg/mL (n = 6). To evaluate the effects of ET-1 in the activated endothelium, additional vessels were perfused with either 10 micromol/L adenosine triphosphate (ATP) (n = 6) or 1 nmol/L bradykinin (n = 6). The vessels were then perfused with 200 pg/mL ET-1 followed by the final L determination.


RESULTS
ET-1 significantly decreased Lp at doses of 20 pg/mL (p = 0.03), 200 pg/mL (p = 0.03), and 2,000 pg/mL (p = 0.01). Endothelial activation with ATP and bradykinin increased Lp to 4.21 +/- 0.39 (p < 0.0001) and 2.72 +/- 0.24 (p = 0.001), respectively. ET-1 significantly decreased the Lp to 1.99 +/- 0.48 after activation with ATP (p = 0.004). ET-1 also decreased the Lp to 1.10 +/- 0.19 after activation with bradykinin (p = 0.001). Units for Lp are x10(-7) cm x s(-1) x cm H2O(-1).


CONCLUSIONS
In this model, ET-1 attenuated the increase in microvascular permeability that can be seen in inflamed vessels. In addition to its vasopressor function, ET-1 may be of benefit in pathophysiologic states by decreasing third-space fluid loss. This receptor-mediated function of ET-1 may be amenable to pharmacologic manipulation.
Victorino
Gregory P
GP
Department of Surgery, University of California-East Bay, Oakland, California 94602, USA. victorinog@surgery.ucsf.edu
Newton
Christopher R
CR
Curran
Brian
B
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D019332:Endothelin-1 / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects
D019332:Endothelin-1; D000244:Adenosine Diphosphate; D001920:Bradykinin