Drugs online research references
Pulm Pharmacol. 1990;3(1):1-7.
Signal transduction in endothelin-induced contraction of rabbit pulmonary vein.
Steffan M, Russell JA.
Department of Physiology, State University of New York, Buffalo 14214.
The effect of porcine endothelin (endothelin 1) on rings of isolated rabbit pulmonary vein was studied using tissue bath techniques. Endothelin was found to be a potent constrictor of these vessels, producing concentration-dependent contractions with an EC50 value of 3.2 +/- 0.6 x 10(-9) M. Contractions were not significantly affected by the Ca2+ channel antagonists verapamil, nifedipine, or nicardipine. Contractions were greatly attenuated by 3 mM LaCl3 (85.8 +/- 8.0% relaxation) and were diminished in Ca(2+)-free media (51 +/- 9% of control). The protein kinase C (PKC) inhibitor H7 (20 microM) potently and reversibly inhibited endothelin-induced contractions by 82 +/- 6% when used as post-treatment. Incubation of tissues with 20 microM H7 did not significantly affect either the strength of contractions induced with endothelin or the time required for contraction to reach plateau, but these contractions were poorly sustained compared to controls. The phospholipase C (PLC) inhibitor neomycin (10 mM) inhibited endothelin-induced contractions and it also affected the rate of force development. The phospholipase A2 (PLA2) inhibitor quinacrine had no significant effect on endothelin-induced contractions. Extracellular Ca2+ appears to enter the cell via non-potential dependent channels that can be blocked by La3+. Moreover, the potent vasoconstrictor properties of endothelin on rabbit pulmonary veins involves activation of both PLC and PKC, but not PLA2. PKC is intimately associated with maintaining the tonic phase of smooth muscle contraction.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2135207&dopt=Abstract
Life Sci. 1989;44(20):1429-36.
Specific receptors for endothelin on membranes from human placenta. Characterization and use in a binding assay.
Fischli W, Clozel M, Guilly C.
Pharmaceutical Research Department, F. Hoffmann-La Roche & Co., Ltd., Basel, Switzerland.
High-affinity binding sites for endothelin have been found in a human placenta membrane preparation. 125I-endothelin bound to placenta membranes at 20 degrees C with an association half-time of 30 min, whereas the binding was only slowly reversed with a dissociation half-time of 250 min. In saturation experiments, a single class of high-affinity binding sites was identified with an apparent dissociation constant (KD) of 24 pM and a maximal density of 240 fmol per mg of protein. The binding of 125I-endothelin was half-maximally inhibited by cold endothelin at a concentration (IC50) of 140 pM. In contrast, no inhibition was found at 10(-4) M for a variety of vasoactive peptides such as angiotensin II, vasopressin, neuropeptide Y, substance P, CGRP, bradykinin, leucine enkephalin or dynorphin A. Similarly, the binding was modulated neither by the calcium channel blockers nifedipine, verapamil or diltiazem, nor by the calcium channel agonist Bay k 8644. There was also no effect with the structurally-related bee venom apamin. Using this membrane preparation, endothelin-like activity could be measured in the medium of cultured human endothelial cells by competition binding technique.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2542708&dopt=Abstract
J Pharmacol Exp Ther. 1989 Aug;250(2):548-55.
Cellular mechanisms of endothelin in rabbit aorta.
Ohlstein EH, Horohonich S, Hay DW.
Department of Pharmacology, Smith Kline & French Laboratories, King of Prussia, Pennsylvania.
The present studies were designed to investigate the cellular actions of endothelin in rabbit aorta. Endothelin produced concentration-dependent contraction of rabbit isolated aortic rings which was independent of the endothelium; the EC50 values were 6.1 and 5.6 nM for endothelium-intact and endothelium-denuded vascular rings, respectively. Endothelin (1 nM) did not induce the release or inhibit the effect of endothelium-derived relaxing factor in precontracted aortic rings. Removal of calcium from the external bathing medium reduced the maximal contractile response induced by endothelin (0.1 microM) by only 12%; however, addition of ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid (0.1 mM) to the calcium-free medium produced a marked inhibition (approximately 75%) of endothelin-induced contraction. The dihydropyridine calcium channel antagonists nicardipine (1 microM) or nifedipine (1 microM), and also diltiazem (1 microM), had little or no effect on endothelin concentration-response curves. Contraction produced by endothelin (30 nM) was not associated with an alteration in the levels of cyclic 3',5'-adenosine monophosphate or cyclic 3',5-guanosine monophosphate in either endothelium-intact or endothelium-denuded aortic rings. Endothelin (1 nM-0.1 microM) produced concentration-dependent stimulation of phosphatidylinositol (Pl) turnover in aortic rings when exposed to tissues for periods greater than or equal to 15 min. Endothelin-induced stimulation of Pl turnover was unaffected by nicardipine (0.1 microM). In calcium-free medium (+0.1 mM ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid) basal Pl turnover was reduced; however, endothelin (1 nM-0.1 microM) produced similar percentage increases over basal levels to those observed in the presence of calcium.(ABSTRACT TRUNCATED AT 250 WORDS)
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2547938&dopt=Abstract
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