Endothelium-dependent vascular activities of endothelin-like peptides in the isolated superior mesenteric arterial bed of the rat
Article first published online: 19 JUL 2012
1990 British Pharmacological Society
British Journal of Pharmacology
Volume 101, Issue 1, pages 81–88, September 1990
How to Cite
Douglas, S. A. and Hiley, C. R. (1990), Endothelium-dependent vascular activities of endothelin-like peptides in the isolated superior mesenteric arterial bed of the rat. British Journal of Pharmacology, 101: 81–88. doi: 10.1111/j.1476-5381.1990.tb12093.x
- Issue published online: 19 JUL 2012
- Article first published online: 19 JUL 2012
- Received January 26, 1990; Revised March 30, 1990; Accepted April 26, 1990
- 1The vasoconstrictor activities of endothelin-2, endothelin-3, sarafotoxin S6b, human proendothelin1–38 and mouse vasoactive intestinal contractor (VIC) were studied in the isolated Krebs-Henseleit perfused mesenteric arterial bed of the rat in the presence and absence of the endothelium. The vasoconstrictor properties of endothelin-1 were studied in control preparations and in preparations treated with methylene blue or Nω-nitro-l-arginine methyl ester (NAME). Finally, the direct vasodilator properties of endothelin-2, endothelin-3 and sarafotoxin S6b were studied in preparations preconstricted with methoxamine.
- 2In the presence of an intact endothelium, all of the peptides caused dose-dependent increases in perfusion pressure and sarafotoxin S6b was a full agonist relative to the other peptides studied (maximum increase in perfusion pressure, Rmax = 106 ± 11mmHg). Endothelin-1, endothelin-2 and VIC were more potent vasoconstrictors (ED50 93.0 ± 40.0, 90.8 ± 20.5 and 106 ± 63 pmol, respectively) than endothelin-3 and sarafotoxin S6b, which were found to be equipotent (ED50 values 411 ± 195 and 345 ± 86 pmol, respectively). A full dose-response relationship could not be constructed for proendothelin, but the highest dose used (4 nmol) increased the perfusion pressure by 15.4 ± 1.6mmHg.
- 3Destruction of the endothelium with the zwitterionic detergent 3-[(3-cholamidopropyl)-dimethylammonio]-l-propanesulphonate (CHAPS) significantly enhanced the pressor activity of all 5 peptides. The Rmax for sarafotoxin S6b was not significantly altered by removal of the endothelium but its potency was significantly increased (ED50 = 115 ± 15 pmol). Although their Rmax values were significantly increased, endothelin-2 and VIC were still partial agonists relative to sarafotoxin S6b in CHAPS-pretreated preparations; their potencies were unchanged (ED50 values 118 ± 53 and 416 ± 196 pmol, respectively). Removal of the endothelium significantly reduced the potency of endothelin-3 (ED50, 6.3 ± 2.2 nmol) but this peptide then exhibited full agonist activity (Rmax = 106 ± 14 mmHg). After endothelial cell destruction, the pressor responses to proendothelin were increased; 4 nmol gave a response of 38.8 ± 5.5 mmHg.
- 4Exposure of preparations to either 100 μm NAME (Rmax = 42.6 ± 2.4 mmHg and ED50 = 57.5 ± 13.7 pmol) or 10 μm methylene blue (Rmax = 36.0 ± 5.1 mmHg and ED50 = 81.5 ± 26.1 pmol) significantly enhanced the maximum pressor responses to endothelin-1 (control: Rmax = 22.5 ± 2.6mmHg; ED50 = 93.0 ± 40.0 pmol). The values in the presence of NAME or methylene blue were not significantly different from those found previously for endothelin-1 after removal of the endothelium with CHAPS.
- 5Endothelin-2, endothelin-3 and sarafotoxin S6b all caused vasorelaxation in preparations which had been precontracted with 100 μm methoxamine. This action was endothelium-dependent as it was abolished by perfusing the mesentery with CHAPS. Endothelin-3 and sarafotoxin S6b caused relaxation at much lower doses than were needed with endothelin-1 and endothelin-2.
- 6The endothelium significantly modulates the vasoconstrictor activity of all the endothelin-like peptides studied, including the precursor peptide proendothelin (which was the least potent of the peptides). This modulation is likely to be due to the release of endothelium-derived relaxing factor, since similar results to destruction of the endothelium were obtained when endothelin-1 was investigated in the presence of either methylene blue or NAME (an inhibitor of nitric oxide formation) in the perfusion fluid. The vasodilator effects of the peptides were also endothelium-dependent. There was a different order of potency for vasoconstriction and vasodilatation supporting the suggestion that there are sub-types of receptor for the endothelin-like peptides in the vasculature; one type on the vascular smooth muscle and a second type on the endothelium.