Vascular effects and mechanism of action of endothelin-1 in
isolated perfused pig skin.
Pang, Cho Y., Richard Z. Yang, Peter Neligan, Ning Xu, Christine Chiu,
Anguo Zhong, and Christopher R. Forrest.
Research Institute, The Hospital for Sick Children; and Departments
of Surgery and Physiology, University of Toronto, Toronto, Ontario,
Canada M5G 1X8
APStracts 2:0334A, 1995.
We investigated the vascular effects and mechanism of action of
endothelin-1 (ET-1) in the skin by intra-arterial infusion of ET-1
and its precursor big ET-1 via a direct cutaneous artery in isolated
perfused pig skin flaps (6 x 16 cm). The vascular contractivity was
studied by monitoring the perfusion pressure in the skin flap. There
was evidence to indicate local conversion of big ET-1 to ET-1 in the
pig skin. It was also observed that ET-1 was a potent long-lasting
vasoconstrictor with a potency of about 10 and 300-fold higher than
big ET-1 and norepinephrine, respectively. The vasoconstrictor action
of ET-1 was blocked (p<0.01) by a selective ETA receptor
antagonist (BQ 123 and BQ 610, 10-7M), and enhanced (p<0.05) by
a nitric oxide synthase inhibitor (NG-monomethyl-L-arginine and Nw
-nitro-L-arginine methyl ester, 10-5M). ET-1-induced increase in
perfusion pressure was attenuated (p<0.05) by an L-type Ca2+
channel antagonist (nitrendipine, verapamil and nifedipine, 10-5M)
and by removal of Ca2+ from the perfusate. ET-1-induced increase in
perfusion pressure was also attenuated (p<0.05) by a
phospholipase C (PLC) inhibitor (neomycin, 10-2M), a protein kinase C
(PKC) inhibitor (chelerythrine and H7, 10-5M) and an intracellular
Ca2+ chelator (BAPTA, 10-5M). Furthermore, it was observed that the
concentration-dependent (5 x 10-8 to 10-5M) increase in perfusion
pressure induced by phorbol 12, 13 - dibutyrate, a PKC activator, was
not affected by verapamil (10-5M) or removal of Ca2+ from the
perfusate. Taken together, these observations suggest that the
vasoconstrictor mechanism of ET-1 in the pig skin involved activation
of ETA receptors, L-type Ca2+ channels, PLC and PKC and the
vasoconstrictor effect caused by activation of PKC was independent of
L-type Ca2+ channels.
Received 3 May 1995; accepted in final form 13 July 1995.
APS Manuscript Number A470-5.
Article publication pending Journal of Applied Physiology.
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 30 July 1995.