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W. F. Graier S. Holzmann B. G. Hoebel W. R. Kukovetz G. M. Kostner 《British journal of pharmacology》1996,119(6):1177-1186
1. Coronary arteries from bovines (BCA) and pigs (PCA) were used for measuring endothelium-dependent relaxation in the presence of L-NG nitroarginine and indomethacin. As some compounds tested have been found to have an inhibitory effect on autacoid-activated endothelial Ca2+ signalling, endothelium-dependent relaxation was initiated with the Ca2+ ionophore A23187. 2. The common compounds for modulating arachidonic acid release/pathway, mepacrine and econazole only inhibited L-NG nitroarginine-resistant relaxation in BCA not in PCA. In contrast, proadifen (SKF 525A) diminished relaxation in BCA and PCA. Mepacrine and proadifen inhibited Hoe-234-initiated relaxation in BCA and PCA, while econazole only inhibited Hoe 234-induced relaxation in PCA. Due to the multiple effects of these compounds, caution is necessary in the interpretation of results obtained with these compounds. 3. The inhibitor of Ca(2+)-activated K+ channels, apamin, strongly attenuated A23187-induced L-NG nitroarginine-resistant relaxation in BCA while apamin did not affect L-NG nitroarginine-resistant relaxation in PCA. 4. Pertussis toxin blunted L-NG nitroarginine-resistant relaxation in BCA, while relaxation of PCA was not affected by pertussis toxin. 5. Thiopentone sodium inhibited endothelial cytochrome P450 epoxygenase (EPO) in PCA but not in BCA, while L-NG nitroarginine-resistant relaxation of BCA and PCA were unchanged. Protoporphyrine IX inhibited EPO in BCA and PCA and abolished L-NG nitroarginine-resistant relaxation of BCA not PCA. 6. An EPO-derived compound, 11,12-epoxy-eicosatrienoic acid (11,12-EET) yielded significant relaxation in BCA and PCA in three out of six experiments. 7. These findings suggest that L-NG nitroarginine-resistant relaxation in BCA and PCA constitutes two distinct pathways. In BCA, activation of Ca(2+)-activated K+ channels via a pertussis-toxin-sensitive G protein and EPO-derived compounds might be involved. In PCA, no selective inhibition of L-NG nitroarginine-resistant relaxation was found. 相似文献
3.
Florian Guthmann Bernd Mayer Doris Koesling Walter R. Kukovetz Eycke Böhme 《Naunyn-Schmiedeberg's archives of pharmacology》1992,346(5):537-541
Summary Soluble guanylyl cyclase partially purified from bovine and human platelets was characterized with antibodies raised against synthetic peptides corresponding to different sequences of the 1- and 1-subunits of the bovine lung enzyme. On immunoblots, the platelet guanylyl cyclase was recognized by the four antisera used, with the exception of an antiserum against the C-terminus of the 1-subunit which did not react with the human platelet but with the bovine platelet 1-subunit. Furthermore the human platelet 1-subunit exhibited a slightly lower molecular mass than the bovine protein. The C-terminal antibodies precipitated native platelet and lung guanylyl cyclase activity. In contrast an antibody against a peptide out of the putative catalytic domain, which is highly conserved between all guanylyl cyclases sequenced so far, did not precipitate native guanylyl cyclase, although it recognized both subunits on immunoblots, suggesting that the respective amino acid sequence is located in an inner site of the protein.Abbreviations GCpep2
YGPEVWEDIKKEA (one letter code)
- GCpep3
SRKNTGTEETEQDEN
- GCpep5
VYKVETVGDKYMTVSGLP
- GCpep8
KKDVEEANANFLGKASGID
- TBS-T
Tris-buffered saline, containing 0.0501o Tween 20
Correspondence to E. Böhme at the above address 相似文献
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Bencyclane (N-[3-(1-benzyl-cycloheptyloxy)-propyl]-N,N-dimethyl-amine-hydrogenfumarate, Fludilat), inhibits phosphodiesterase(PDE)-activity in vitro similarly to several other smooth muscle relaxants. Compared with papaverine this inhibitory effect of bencyclane on PDE is weak despite of its strong relaxant effect on smooth muscle, which is about equal to that of papaverine. 14C-Bencyclane is accumulated 8-fold in the smooth muscle tissue of bovine coronary arteries, indicating that relaxation is caused by 8-fold higher concentrations in the tissue than in the organ bath. A comparison of (corrected) ED50-values for relaxation with Ki-values for PDE-inhibition obtained with several PDE-inhibitors, including bencyclane, yields a significant correlation between both parameters. Since in subsequent studies in isolated tracheal muscle strips bencyclane at maximum relaxing concentrations did not increase cAMP, which was in contrast to the actions of papaverine or aminophylline, it is likely that bencyclane-induced smooth muscle relaxation is unrelated to inhibition of PDE or cAMP. In the same dose range in which bencyclane relaxes smooth muscles it exerts a non-specific antiadrenergic inhibitory effect, possibly due to its local anesthetic action at the cell membrane. It is also possible that the myocardial inhibitory effect of bencyclane is caused by a direct Ca++-antagonistic mechanism (Fleckenstein et al. 1971). 相似文献
6.
Ohne ZusammenfassungMit 4 TextabbildungenHerrn Prof. Dr. H. F. Häusler in Verehrung zum 65. Geburtstag gewidmet. 相似文献
7.
Summary The effect of noradrenaline, norephedrine, oxyfedrine and DMPP on isotonic contractions and release of3H-noradrenaline was studied using isolated perfused guinea-pig hearts.The spontaneous rate of3H-release was linear from 30–70 min after infusion of a tracer dose of 20 Ci noradrenaline. The calculated size of the labeled noradrenaline-pool of the heart was 5–10% of the total noradrenaline-content.Oxyfedrine (10 g) caused strong and long lasting positive inotropic effects but only a weak and transient increase of3H-release. Equimolar doses of 5g 1-norephedrine which is a component of the oxyfedrine molecule had no significant inotropic effect but caused similar increases in3H-release.Noradrenaline (0.5 g, a dose with maximum positive inotropic action) released more3H-activity from the heart than oxyfedrine.DMPP, a ganglion stimulating agent, in doses of 250 g, increased contractions significantly but had very little effect on3H-noradrenaline-release. An additional release of non-labeled noradrenaline is discussed as explanation of the positive inotropic action of DMPP.After repeated administration of DMPP in large doses, the increase in contraction and3H-release was abolished. In this state of tachyphylaxis oxyfedrine also failed to release3H-noradrenaline but retained its full inotropic effect.The results do not provide evidence that a releasing effect on labeled and/or non-labeled endogenous noradrenaline significantly contributes to the positive inotropic action of oxyfedrine. This finding supports the view that oxyfedrine stimulates the heart by adirect action on sympathetic-receptors. 相似文献
8.
To elucidate the role of potassium channel activation in muscarinic inhibition of atrial contractility, we studied the influence of K+ channel blockers on the effects of the muscarinic agonist carbachol in isolated guinea pig auricles. We tested BaCl2, tetraethylammoniumchloride (TEA), and 9-aminotetrahydroacridine (THA), which block K+ channels, for their ability to antagonize the effects of carbachol on atrial contractility and functional refractory period. Due to inhibition of K+ outward currents, BaCl2, TEA, and THA markedly blocked the carbachol-induced shortening of refractory period and, to a lesser extent, antagonized its negative inotropic action. BaCl2, TEA, and THA shifted the concentration-response curve of the negative inotropic action of carbachol to the right; the most pronounced effect was obtained with TEA (DR = 30 at 3 x 10(-3) M). The maximum negative inotropic effect of carbachol, however, was only slightly reduced by the K+ channel blockers, and carbachol clearly inhibited atrial contractility even in the absence of any shortening of refractory period. These results suggest the existence of an additional cholinergic, negative inotropic mechanism, distinctly different from activation of atrial K+ channels. 相似文献
9.
Since the diminished vasodilatation characterizing tolerance to organic nitrates is associated with lower rises in 3', 5'-cyclic guanosine monophosphate (cGMP) levels, the possibility that nitrovasodilators desensitized guanylate cyclase (GC) when pre-incubated with coronary supernatants was studied. In the absence of cysteine, pre-incubation with nitroglycerin (NG) decreased GC-activity during subsequent incubation to 24 +/- 7% of control values, whereas six other nitrovasodilators had much smaller effects. When cysteine was present during pre-incubation, NG-stimulation of GC remained significantly higher (59 +/- 3%; P less than 0.05), whereas the effects of other nitrovasodilators were not significantly changed. We also found that GC-activity, when reduced by pre-incubation with NG could only be restored by readdition of native coronary supernatant, suggesting that the enzyme became inactivated. NG pre-incubation of GC (in contrast to coronary strips) almost completely abolished the direct and thiol-independent stimulatory effect of 3-morpholinosydnonimine (SIN-1) down to 4.5 +/- 0.2%, whereas pre-incubation with other nitrovasodilators reduced the stimulatory response to SIN-1 to only 59 to 98%. Increasing concentrations of NG during pre-incubation dose-dependently (IC50 = 0.13 mM) reduced the activating effect of SIN-1 during incubation. There was also a time dependence in NG-induced inactivation of GC which followed first order kinetics with a calculated half life of 2.5 min in the absence of a thiol. The latter was increased to 4.0 or 19.2 min, respectively, when glutathione or cysteine-methylester were present during pre-incubation.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
10.
Cholesterol-lowering effect of mevinolin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme a reductase, in healthy volunteers. 总被引:16,自引:4,他引:12
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J A Tobert G D Bell J Birtwell I James W R Kukovetz J S Pryor A Buntinx I B Holmes Y S Chao J A Bolognese 《The Journal of clinical investigation》1982,69(4):913-919
Mevinolin reduces cholesterol synthesis by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase. The safety and effectiveness of this agent was evaluated in a double-blind, placebo-controlled study in 59 healthy men (serum cholesterol 3.88--7.76 mmol/liter) in five centers. Subjects maintained their usual diet and activities. Doses of 6.25, 12.5, 25, or 50 mg twice daily for 4 wk produced mean reductions of total serum cholesterol fo 23--27% [vs. placebo (4%), P less than 0.01]. Mean low density lipoprotein cholesterol fell 35--45%, while high density lipoprotein and very low density lipoprotein cholesterol, and triglycerides were not significantly affected. Mean apolipoprotein B fell 27--34%. 50 mg was not significantly more effective than 6.25 mg. Mevinolin was generally well tolerated, and no serious clinical or laboratory abnormalities occurred. One subject (12.5 mg) was withdrawn because of abdominal pain and diarrhea. These results suggest that if long-term safety can be demonstrated, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase are likely to prove useful in the treatment of hypercholesterolemia. 相似文献