Arteries and veins desensitize differently to endothelin.
Hypertension is accompanied by increased arterial endothelin-1 (ET-1) and decreased arterial contraction to ET-1. By contrast, veins remain responsive to ET-1 in hypertension. Isometric contraction was used to test the hypothesis that veins do not desensitize to ET-1 to the extent of arteries, possibly because of the presence of functional ETA and ETB receptors on veins and only functional ETA receptors on arteries. Contraction to ET-1 after exposure to ET-1 (100 nmol/L) was abolished in aortae, while in veins 36.3 +/- 0.2% of maximal contraction to ET-1 remained. Aortae were unresponsive to the ETA receptor agonist ET-1(1-31) (100 nmol/L) after ET-1 exposure, while 21.9 +/- 0.6% of maximum venous contraction to ET-1 (1-31) remained. In a similar manner, the venous ETB receptor did not lose responsiveness to the ETB receptor agonist sarafotoxin 6c (S6c, 100 nmol/L); aortae did not contract to S6c. In ET-1-desensitized veins, the ETB receptor antagonist BQ-788 (100 nmol/L) decreased maximum contraction to ET-1, but did not alter potency (-log EC50 control = 8.14 +/- 0.01 mol/L; BQ-788 = 8.13 +/- 0.04 mol/L). The ETA receptor antagonist atrasentan (100 nmol/L) blocked remaining venous contraction to ET-1 (control = 8.05 +/- 0.05 mol/L; atrasentan = unmeasurable). Maintained responsiveness to ET-1 in veins occurs primarily via the ETA receptor, while in arteries the ETA receptor is responsible for desensitization to ET-1.
Thakali
Keshari
K
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824-1317, USA. thakalik@msu.edu
Fink
Gregory D
GD
Watts
Stephanie W
SW
D000818:Animals; D019332:Endothelin-1 / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000187:drug effects; D013895:Thoracic Arteries / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*; D014683:Vena Cava, Superior / Q000187:drug effects
D019332:Endothelin-1; D017466:Receptors, Endothelin; D009638:Norepinephrine