Inhibitory and facilitatory presynaptic effects of endothelin on sympathetic cotransmission in the rat isolated tail artery

1 The present study was undertaken to determine the modulatory effects of the endothelin peptides on the neurogenically-induced release of endogenous noradrenaline (NA) and the cotransmitter adenosine 5'-triphosphate (ATP) from the sympathetic nerves of endothelium-free segments of the rat isolated tail artery. The electrical field stimulation (EFS, 8 Hz, 0.5 ms, 3 min) evoked overflow of NA and ATP, in the absence of endothelins, was 0.035+/-0.002 pmol mg(-1) tissue and 0.026+/-0.002 pmol mg(-1) tissue, respectively. 2 Endothelin-l (ET-1; 1-30 nM) significantly reduced the EFS evoked overflow of both NA and ATP. The maximum inhibitory effect was produced by a peptide concentration of 10 nM, the amount of NA overflow being 0.020+/-0.002 pmol mg(-1) and that of ATP overflow 0.015+/-0.001 pmol mg(-1). Higher peptide concentrations (100 and 300 nM) reversed the EFS-evoked overflow of NA to control levels and that of ATP to above control levels. The inhibitory effect of ET-1 (10 nM) was resistant to the selective ETA receptor antagonist cyclo-D-Trp-D-Asp(ONa)-Pro-D-Val-Leu (BQ-123) but was prevented by ETB receptor desensitization with sarafotoxin S6c (StxS6c) or by ETB receptor blockade with N, cis-2,6-dimethylpiperidinocarbonyl-L-gmethylleucyl-D-1-methoxycarbonyltryptophanyl-D-norleucine (BQ-788). 3 StxS6c, upon acute application, exerted a dual effect on transmitter release. At concentrations of 0.001-0.3 nM the peptide significantly reduced the EFS;evoked NA overflow, whereas at concentrations of 1-10 nM it caused a significant increase in the evoked overflow of both ATP and NA. Both the maximum inhibitory effect of StxS6c at a concentration of 0.003 nM (approximately 85% reduction of NA overflow and 40% of ATP overflow) and the maximum facilitatory effect of the peptide at a concentration of 3 nM (approximately 400% increase of ATP overflow and 200% of NA overflow) were completely antagonized by either BQ-788 or by StxS6c-induced ETB receptor desensitization. 4 ET-3 (10-100 nM) did not affect the EFS evoked overflow of either ATP or NA, but at a concentration of 300 nM significantly potentiated the release of both transmitters (0.118 +/- 0.02 pmol mg(-1) tissue ATP overflow and 0.077+/-0.004 pmol mg(-1) NA overflow). This effect was prevented either by BQ-123 or by BQ-788. 5 In summary, the endothelin peptides exerted both facilitatory and inhibitory effects on the neurogenically-induced release of the sympathetic cotransmitters ATP and NA in the rat tail artery. Both transmitters were modulated in parallel indicating that the endothelins do not differentially modulate the release of NA and ATP in this tissue.