Drugs online research references
Eur J Pharmacol. 1989 Jun 20;165(2-3):223-30.
Tissue selectivity of endothelin.
Borges R, Von Grafenstein H, Knight DE.
Division of Biomedical Sciences, King's College, University of London, U.K.
The effects of endothelin, a potent endogenous vasoconstrictor peptide, were examined in a range of vascular and non-vascular tissues. At concentrations that cause vasoconstriction in portal vein and aorta, the peptide strongly contracted rat uterus, trachea and vas deferens, but not guinea pig ileum. Nifedipine, a dihydropyridine calcium anatgonist, partially inhibited these contractions. Endothelin had no inotropic or chronotropic effect on the isolated rat heart. The peptide did not modulate secretion at the neuromuscular junction, from adrenal medullary cells or neutrophils, nor affect secretion or aggregation of platelets. The tissue responsiveness to endothelin was not the same as the tissue distribution of dihydropyridine receptors. This supports the idea that endothelin interacts with a specific receptor distinct from dihydropyridine sensitive calcium channels. The contractile effect of endothelin on non vascular smooth muscle suggests that the concept of endothelium dependent modulation of vascular smooth muscle tone may be extended to include epithelium dependent modulation of non vascular tissues.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2550250&dopt=Abstract
Am J Physiol. 1998 Oct;275(4 Pt 2):R1066-74.
Role and mechanism of endothelin-B receptors in mediating ET-1-induced vasoconstriction in pig skin.
Pang CY, Zhang J, Xu H, Lipa JE, Forrest CR, Neligan PC.
The Hospital for Sick Children Research Institute, University of Toronto, Toronto, Ontario, Canada M5G 1X8.
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.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9756535&dopt=Abstract
Br J Pharmacol. 2000 Nov;131(6):1055-64.
Lack of involvement of endothelin-1 in angiotensin II-induced contraction of the isolated rat tail artery.
Jiang Y, Triggle CR.
Department of Pharmacology & Therapeutics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
1. The contribution of endothelin-1 (ET-1) to angiotensin II (Ang II)-mediated contraction of the isolated rat tail artery was assessed with measurements of tension, and cytosolic calcium ([Ca(2+)](i)). The distribution of the AT(1) receptor was studied with RT - PCR and immunohistochemistry. 2. Ang II induced an endothelium-independent contraction (pEC(50) 7.95+/-0.06 and E(max): 0.46 g+/-0.05 with endothelium vs 7.81+/-0.02 and 0.41 g+/-0.07 without endothelium; P>0.05). Ang II (0.003 - 0.3 microM)-induced a non-sustained contraction of endothelium-intact preparations which was not antagonized by BQ-123 (1 microM), but was inhibited by losartan (10 nM). In addition, the maximal contraction induced by ET-1 (0.1 microM) could be further increased by the addition of 0.1 microM Ang II. 3. Ang II (0.001 - 0.3 microM) elevated [Ca(2+)](i) in single vascular smooth muscle cells (VSMCs) in a dose-dependent manner (pEC(50) 9.12+/-0.26) and the Ang II-induced increases in [Ca(2+)](i) were not affected by a Ca(2+)-free solution, but were abolished by pretreatment with caffeine (5 mM). Ang II did not increase [Ca(2+)](i) in endothelial cells. ET-1 (0.1 microM) increased [Ca(2+)](i) in single VSMCs in a normal Ca(2+) containing physiological saline solution (PSS), but not in a Ca(2+)-free solution. 4. Ang II-induced contraction was insensitive to inhibition by nifedipine (0.1 microM), an antagonist of L-type voltage-gated Ca(2+) channels, and SK&F96365 (10 microM), which blocks non-selective cation channels, whereas that to ET-1 was inhibited by SK&F69365. 5. RT - PCR data indicate the expression of AT(1A) and AT(1B) on both VSMCs and endothelial cells, but immunohistochemical evidence illustrates that the AT(1) is located primarily on VSMCs. 6. These results indicate that endothelium-derived ET-1 is not involved in the Ang II-mediated vasoconstriction of the rat tail artery and that Ang II- and ET-1-mediated VSM contractions utilize distinct pathways.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11082111&dopt=Abstract
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