Premium
Modulation of vascular tone by endothelin‐1: role of preload, endothelial integrity and concentration of endothelin‐1
Author(s) -
Mehta J.L.,
Lawson D.L.,
Yang B.C.,
Mehta P.,
Nichols W.W.
Publication year - 1992
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1992.tb14304.x
Subject(s) - contraction (grammar) , preload , endothelin 1 , chemistry , medicine , endothelium , vasodilation , endocrinology , endothelin receptor , vascular smooth muscle , smooth muscle , hemodynamics , receptor
1 Endothelin‐1 (ET‐1) has been shown to exert both arterial relaxant and constrictor effects. To examine the mechanisms of these divergent effects, rat aortic rings were suspended in an organ bath (baseline preload, 5 g) and exposed to ET‐1 (10 −11 to 10 −7 m ). ET‐1 contracted these rings in a concentration‐dependent fashion. 2 When aortic rings were contracted with noradrenaline (NA) to 1 g of tension, ET‐1 caused further contraction of these rings. In rings precontracted to 2 to 4 g of tension, low concentrations of ET‐1 (10 −11 to 10 −9 m ) caused a significant relaxation, but high concentrations (≥5× 10 −9 m ) caused a marked contraction, indicating both relaxant and contractile effects of ET‐1 depending on the preload and ET‐1 concentration. 3 To determine the mechanism of ET‐1‐induced relaxation, aortic rings were pretreated with the cyclo‐oxygenase inhibitor indomethacin, N G ‐monomethyl‐ l ‐arginine ( l ‐NMMA) an inihibitor of synthesis of endothelium‐derived relaxing factor (EDRF), or oxyhaemoglobin (Hb) which decreases the activity of EDRF, prior to their exposure to ET‐1. Both indomethacin and l ‐NMMA markedly ( P < 0.01) attenuated ET‐1‐induced relaxation, whereas Hb totally abolished it. Removal of the endothelium from aortic rings also abolished ET‐1‐mediated relaxation. 4 The relaxant effect of ET‐1 in NA‐precontracted rings was associated with marked accumulation of guanosine 3′:5′‐cyclic monophosphate (cyclic GMP), whereas ET‐1‐induced contraction of quiescent rings was not. 5 In manually stretched rings (4 g of tension), ET‐1 caused only concentration‐dependent contraction, but no cyclic GMP accumulation. 6 Thus, ET‐1 contracts rat aortic rings with intact endothelium and those which are passively stretched. However, stimulation of rat aortic rings with NA to modest tension alters the contractile effect of ET‐1 to a potent relaxant effect. The ET‐1‐mediated relaxation in this setting appears to be endothelium‐dependent and is related to release of both cyclo‐oxygenase products and EDRF.