Role and mechanism of endothelin-B receptors in mediating ET-1-induced vasoconstriction in pig skin.
We investigated the functional importance and signal transduction pathways of endothelin (ET)-B receptors in mediating ET-1-induced vasoconstriction in pig skin. Skin vasoconstriction was studied by monitoring the perfusion pressure of isolated perfused pig skin flaps (6 x 16 cm) at a constant flow rate. Intra-arterial infusion of the ETA/B receptor agonist ET-1, the ETB receptor agonists sarafotoxin 6C (S6c) and BQ-3020, or the thromboxane A2 mimetic U-46619 (n = 4 or 5) caused a concentration-dependent skin vasoconstriction. The vasoconstrictor potency of ET-1 (EC50 3.1 x 10(-9) M) was lower (P < 0.05) than that of S6c (EC50 1.8 x 10(-9) M) and similar to that of BQ-3020 (EC50 2.6 x 10(-9) M). The vasoconstrictor potency of ET-1, S6c, and BQ-3020 was at least 300-fold higher than that of U-46619 (EC50 0.9 x 10(-6) M). The skin vasoconstrictor effect of ET-1 (10(-9)-10(-8) M) was partially inhibited by 10(-5) M BQ-123, an ETA receptor antagonist. Further inhibition was achieved with the combination of 10(-5) M BQ-123 and BQ-788 (an ETB receptor antagonist) or with an ETA/B receptor antagonist (10(-5) M bosentan or PD-145065) (n = 5; P < 0.05). In addition, the skin vasoconstrictor effect of the ETB receptor agonist BQ-3020 was completely blocked by 5 x 10(-6) M BQ-788 and partially inhibited by 5 x 10(-6) M of the phospholipase C (PLC) inhibitor 2-nitro-4-carboxyl-N,N-diphenylcarbamate (NCDC), an L-type Ca2+ channel antagonist (nifedipine), a protein kinase C (PKC) inhibitor (chelerythrine), or removal of Ca2+ from the perfusate (n = 4 or 5; P < 0.05). The vasoconstrictor effect of S6c was also partially blocked by 5 x 10(-6) M of NCDC, nifedipine, or chelerythrine or by removal of Ca2+ from the perfusate (n = 4; P < 0. 01). We conclude that ETB receptors play a central role in mediating ET-1-induced vasoconstriction in pig skin, and the mechanism probably involves L-type Ca2+ channels, PLC, and PKC.
Pang
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CY
The Hospital for Sick Children Research Institute, University of Toronto, Toronto, Ontario, Canada M5G 1X8.
Zhang
J
J
Xu
H
H
Lipa
J E
JE
Forrest
C R
CR
Neligan
P C
PC
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D000077300:Bosentan; D019332:Endothelin-1 / Q000008:administration & dosage / Q000494:pharmacology / Q000502:physiology*; D016232:Endothelins / Q000737:chemistry / Q000494:pharmacology; D007261:Infusions, Intra-Arterial; D008969:Molecular Sequence Data; D009638:Norepinephrine / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000502:physiology*; D012867:Skin / Q000098:blood supply*; D013449:Sulfonamides / Q000494:pharmacology; D013524:Surgical Flaps; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
D000959:Antihypertensive Agents; D019332:Endothelin-1; D016232:Endothelins; D009842:Oligopeptides; D010446:Peptide Fragments; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; C075771:BQ 3020; C082887:PD 145065; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000077300:Bosentan; D009638:Norepinephrine