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online © Copyright 2003 The British Pharmacological Society |
030P
University of Surrey Summer Meeting June 2003 |
Tamoxifen-induced vasorelaxation in the rat aorta
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Tamoxifen has been shown to
cause vasorelaxation in porcine, rabbit and rat arteries (Figtree et al., 2000; Hutchison et al., 2001). In the present study, we
have investigated the involvement of nitric oxide (NO), cyclo-oxygenase
(COX) products, as well as Ca2+ channels
in vasorelaxation to tamoxifen in rat isolated thoracic aorta.
Male Wistar rats (225-250g) were stunned by a blow to the back of the
head, and then killed by exsanguination. Thoracic aortae were removed
and placed in organ baths containing Krebs-Henseleit solution, and were
mounted as 2-3mm rings for isometric recording (Tep-areenan et al.,
2003). The rings were then set to a resting tension of 10mN and allowed
to equilibrate for 1h. Following the equilibration period, the rings were
contracted with methoxamine (100µM). The role of NO was investigated
by carrying out some experiments in the presence of 300µM NG-nitro-L-arginine
methyl ester (L-NAME), and the involvement of prostanoids was investigated
using indomethacin (10µM). In some preparations, the effects of
tamoxifen were investigated against calcium influx; briefly aortae were
bathed in calcium-free buffer and then contractile responses to CaCl2
were determined in the presence of 60mM K+
(Tep-areenan et al., 2003).
Tamoxifen (3nM to 3mM) caused concentration-related relaxations (pEC50=5.67±0.25,
mean ± s.e.mean; maximal relaxation (Rmax)=121±10%;
n=6). Both L-NAME and indomethacin reduced tamoxifen-induced vasorelaxation
(L-NAME: R=47.7±1.6%, P<0.001, n=5; indomethacin:Rmax=52.8±2.7%,
P<0.001, n=6, ANOVA). Combination of 10µM indomethacin
and 300µM L-NAME had no effect on vasorelaxation to tamoxifen (pEC50=6.33±0.18;
Rmax=80.4±5.4%;
n=6) compared to control. 1µM cycloheximide, a protein synthesis
inhibitor did not modify tamoxifen-induced responses in the presence of
indomethacin. Pre-incubation with 10µM tamoxifen did not affect
CaCl2-induced contractile responses on
re-introduction. However, contractile responses to calcium were reduced
in the presence of 100µM tamoxifen, such that at the highest concentration
of CaCl2 (30mM) used, the
contractile response was significantly (P<0.001) reduced (0.4±0.3mN)
compared to the control value (3.9 ± 1.0mN, n=8 in control)
In conclusion, the present findings demonstrate that tamoxifen causes
non-genomic vasorelaxation, mediated mainly by COX- and NO-dependent pathways.
However, when both pathways are blocked there was no significant inhibition
of relaxation, possibly pointing to the participation of another mechanism
which becomes upregulated. At higher concentrations, tamoxifen acts as
a calcium channel antagonist.
Figtree, G.A., Webb, C.M., Collins, P. (2000). J. Pharmacol. Exp. Ther.,
295, 519-523.
Hutchison, S.J., Chou, T.M., Chatterjee, K., et al.. (2001). J.
Cardiovasc. Pharmacol., 38, 657-665.
Tep-areenan, P., Kendall, D.A. & Randall, M.D. (2003). Eur. J.
Pharmacol. 465, 125-132.