Vn. Mutafovayambolieva et Dp. Westfall, INHIBITORY AND FACILITATORY PRESYNAPTIC EFFECTS OF ENDOTHELIN ON SYMPATHETIC COTRANSMISSION IN THE RAT ISOLATED TAIL ARTERY, British Journal of Pharmacology, 123(1), 1998, pp. 136-142
1 The present study was undertaken to determine the modulatory effects
of the endothelin peptides on the neurogenically-induced release of e
ndogenous noradrenaline (NA) and the cotransmitter adenosine 5'-tripho
sphate (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 o
f 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) signi
ficantly reduced the EFS evoked overflow of both NA and ATP. The maxim
um 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 le
vels and that of ATP to above control levels. The inhibitory effect of
ET-1 (10 nM) was resistant to the selective ETA receptor antagonist c
yclo-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 recep
tor blockade with N, eucyl-D-1-methoxycarbonyltryptophanyl-D-norleucin
e (BQ-788). 3 StxS6c, upon acute application, exerted a dual effect on
transmitter release. At concentrations of 0.001-0.3 nM the peptide si
gnificantly reduced the EFS;evoked NA overflow, whereas at concentrati
ons 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 p
eptide at a concentration of 3 nM (approximately 400% increase of ATP
overflow and 200% of NA overflow) were completely antagonized by eithe
r 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, b
ut at a concentration of 300 nM significantly potentiated the release
of both transmitters (0.118 +/- 0.02 pmol mg(-1) tissue ATP overflow a
nd 0.077+/-0.004 pmol mg(-1) NA overflow). This effect was prevented e
ither by BQ-123 or by BQ-788. 5 In summary, the endothelin peptides ex
erted both facilitatory and inhibitory effects on the neurogenically-i
nduced 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.