下载免费PDF全文 2 NG, up to a concentration of 10-5 M, modified neither the membrane potential nor the membrane resistance. Increased concentrations of NG (> 2.8 × 10-5 M) hyperpolarized the membrane, reduced the membrane resistance and enhanced the rectifying property of the membrane measured by depolarization pulses. These phenomena observed with a high concentration of NG are the result of an increase in the K-conductance of the membrane.
3 NG (2.8 × 10-5 M) did not modify the membrane potential displaced by various concentrations of excess [K]o. In low [K]o, NG (2.8 × 10-5 M) hyperpolarized the membrane to a greater extent than that observed in Krebs solution. The effects of NG (10-6 to 2.8 × 10-5 M) on the membrane potential were not modified by simultaneous application of 2 × 10-6 M acetylcholine (ACh).
4 NG (2.8 × 10-6 M) consistently raised the mechanical threshold required for tension development and suppressed the amplitude of the contraction evoked by excess [K]o, ACh or electrical depolarization of the membrane. The dose-response curve shifted to the right in the presence of NG noncompetitively in all the conditions employed to develop the tension.
5 When the tissue was immersed in Ca-free (EGTA) solution, ACh (5 × 10-6 M) evoked a contraction even after the tissue had lost the ability to contract to repetitive applications of 118 mM [K]o in Ca-free (EGTA) solution. However, the tissue finally failed to contract to repetitively applied ACh. At this stage, 2.5 mM [Ca]o evoked a small contraction, after which the response was briefly restored to 5 × 10-6 M ACh. This transient response to ACh was reduced by NG (5.6 × 10-6 M) when NG was added either simultaneously with ACh or with the previous Ca application. However, the inhibition was greater in the former than the latter case.
6 Cysteine (1 to 2 mM), without modifying the membrane potential or membrane resistance, partly restored the contraction evoked by excess [K]o or ACh which had been reduced by NG.
7 The mechanism of action of NG on the smooth muscle cell of the coronary artery of the pig is postulated to be due to a nonselective suppression of the Ca-mobilization from the store site with no noticeable change in the membrane properties.
相似文献 下载免费PDF全文 2 Mianserin and ORG GC 94 produced a concentration-dependent increase of more than two fold in the electrically evoked overflow and the contractile response and, at the highest concentration, slightly increased resting release. These effects were largely unchanged in the presence of a concentration of cocaine effective in blocking noradrenaline uptake (1.1 × 10-5 M).
3 The ability of phentolamine (1 × 10-5 M) to increase both the evoked overflow of tritium and the contractile response was greatly reduced when these parameters were already elevated by the presence of mianserin or ORG GC 94.
4 The inhibitory effect of exogenous (—)-noradrenaline on evoked overflow was greatly reduced in the presence of mianserin or ORG GC 94 (4 × 10-6 M).
5 The inhibitory effect of clonidine on the twitch response of the mouse vas deferens was antagonized by mianserin and ORG GC 94 in a competitive manner (pA2 values 7.3 and 7.1 respectively).
6 Maprotiline, desipramine and nortriptyline (> 3 × 10-6 M) produced a parallel fall in both evoked tritium overflow and in the contractile response and increased the resting overflow at higher concentrations. These effects were largely unchanged in the presence of cocaine (1.1 × 10-5 M).
7 Doxepin, imipramine and iprindole all increased resting overflow at high concentrations (2 × 10-5 M) but produced only small changes in evoked overflow and in the contractile response at lower concentrations.
8 It is concluded that mianserin and ORG GC 94 produce a blockade of presynaptic α-adrenoceptors which could contribute to an antidepressant effect but that this type of action is not common to all antidepressants.
相似文献 下载免费PDF全文 2 Each procedure reduced carbachol-induced tone; sympathetic and NANC nerve stimulation were equipotent but both were less effective than sympathomimetic drugs, of which Iso was the better. Both Iso and NA, but not sympathetic nerve stimulation, inhibited the contractions produced by pelvic nerve stimulation in a concentration-dependent manner. Against ACh-induced contractions, only Iso was effective. The effects of NANC nerve stimulation on the motor responses to pelvic nerve stimulation or to ACh were not investigated.
3 The inhibitory effects of sympathetic nerve stimulation, of Iso and of NA were reduced by propranolol (3 × 10-6 M) but unaffected by phentolamine (3 × 10-5 M).
4 In the presence of high (45 mM) concentrations of KCl, Iso and NA produced a concentration-dependent inhibition of tone that was antagonized by propranolol (3 × 10-6 M).
5 Methoxamine (4 × 10-7 to 4 × 10-5 M) and phenylephrine (5 × 10-7 to 5 × 10-5 M) which interact mainly with α1-adrenoceptors, produced only small, transient reductions in carbachol-induced tone which were subject to tachyphylaxis, unlike those produced by Iso and NA. These inhibitory effects were antagonized by phentolamine (3 × 10-6 M) or azapetine (3 × 10-6 M).
6 Phenylephrine (5 × 10-4 M) and high doses (3 × 10-5 M or greater) of NA enhanced the contractile response to pelvic nerve stimulation and, on occasion, produced muscle contraction. These effects were antagonized by phentolamine (3 × 10-6 M).
7 These results suggest that inhibition of the rectococcygeus, a muscle which has no intramural nerve plexus, can be inhibited by stimulation of extrinsic NANC nerves, the transmitter for which is unknown and by sympathetic nerve stimulation via α- and β-adrenoceptors located postsynaptically on the muscle. Excitatory α-adrenoceptors may also be present.
相似文献 下载免费PDF全文 2 Atropine (1 × 10-9 -1 × 10-6M) alone, in the presence of hexamethonium (1 × 10-4M), or phentolamine (1 × 10-6M), inhibited responses to acetylcholine but not to (-)-noradrenaline. The inhibitory effect with the higher concentrations of atropine (1 × 10-8 - × 10-6M), was seen as an increase in the slopes of the concentration-response curves. Atropine (1 × 10-8M) alone inhibited the responses to methacholine and carbachol without altering the slopes of the concentration-response curves.
3 Homatropine (1 × 10-6M) alone had no effect on responses to (-)-noradrenaline and inhibited responses to acetylcholine and methacholine. The inhibitory effect on responses to acetylcholine but not to methacholine, included an increase in the slopes of the concentration-response curves.
4 Neostigmine (1 × 10-6M) alone had no effect on responses to (-)-noradrenaline and potentiated responses to acetylcholine and methacholine. The potentiating effect included an increase in the slopes of the concentration-response curves.
5 In the presence of neostigmine (1 × 10-6M), atropine (1 × 10-9M - 1 × 10-6M) caused a parallel concentration-dependent shift of the concentration-response curves to acetylcholine. The pA2 values, in the presence of neostigmine, were independent of the concentration of atropine and of the agonist (acetylcholine, methacholine, or carbachol) used. In the presence of neostigmine (1 × 10-6M), homatropine (1 × 10-6M) also failed to alter the slopes of the concentration-response curves to acetylcholine and was approximately 100 times less potent than atropine as an antimuscarinic agent.
6 These results illustrate that, in the rat anococcygeus muscle, it is necessary to inhibit acetylcholinesterase before determining the relative potencies of antagonists at muscarinic receptors.
相似文献 下载免费PDF全文 2 The prolongation of APD and the positive inotropic effect of AP-A (1 × 10-8 M) were augmented by lowering the driving frequency from 2.0 to 0.2 Hz, resulting in an apparent negative staircase of contractile force in this frequency range. When the preparation was driven at an extremely low frequency (0.017 Hz), AP-A did not increase the contractile force, but caused a considerable prolongation of APD.
3 Verapamil (1 × 10-6 M) and nifedipine (1 × 10-6 M) had no apparent influence on the APD prolongation by AP-A (5 × 10-9 M, 1 × 10-8 M). The positive inotropic effect of AP-A was also relatively well maintained even in the presence of these calcium antagonistic drugs when the preparation was driven at a lower frequency (0.2 Hz).
4 Tetrodotoxin (TTX 2 × 10-6 M) and lidocaine (1 × 10-4 M) markedly inhibited both the APD prolongation and the positive inotropic effect of AP-A (1 × 10-8 M).
5 In the presence of ryanodine (2 × 10-6 M), an agent which is known to interfere with calcium release from the intracellular activator pool, AP-A (1 × 10-8 M) failed to cause its positive inotropic effect in spite of the marked prolongation of APD.
6 These results suggest that the effects of AP-A on cardiac muscle are primarily mediated by the fast sodium inward current. Thus, delayed inactivation of sodium inward current may cause APD prolongation, and probably induces an alteration of intracellular calcium kinetics reflected by an increase of contractile force.
相似文献 下载免费PDF全文 2 In rat stomach strips, NT elicited a dose-dependent contractile effect in concentrations varying between 1.3 × 10-9 and 5.4 × 10-7 M.
3 The contractile effect of NT (1.3 and 5.4 × 10-8 M) in this tissue was not modified by atropine (3.4 × 10-7 M), methysergide (2.0 × 10-6 M), a mixture of cimetidine (8.0 × 10-6 M) and diphenhydramine (7.8 × 10-6 M), indomethacin (1.4 × 10-5 M), 8-Leu-angiotensin II (1.0 × 10-6 M), glucagon (2.0 × 10-6 M) or somatostatin (3.0 × 10-7 M).
4 Rat stomach strips desensitized by bradykinin (6.1 × 10-6 M) or substance P (7.4 × 10-6 M) maintained their sensitivities to NT (1.3 and 5.4 × 10-8 M).
5 In guinea-pig atria, NT produced a dose-dependent positive inotropic action in concentrations varying between 5.4 × 10-10 and 2.7 × 10-7 M.
6 The inotropic effect of NT (2.7 × 10-9 M) was not influenced by methysergide (2.8 × 10-6 M), atropine (3.4 × 10-7 M), practolol (1.5 × 10-5 M), 8-Leu-angiotensin II (1.0 × 10-6 M), or indomethacin (1.4 × 10-5 M), but it was reduced by 37% by cimetidine (4.0 × 10-5 and 2.0 × 10-4 M). A combination of cimetidine (4.0 × 10-5 M) and diphenhydramine (3.9 × 10-6 M) did not produce a greater inhibition of NT than cimetidine alone.
7 Atria desensitized by bradykinin (6.1 × 10-6 M) or glucagon (2.0 × 10-6 M) maintained their sensitivities to NT (2.7 × 10-9 M). Substance P was inactive both as an agonist or antagonist of NT.
8 These results suggest the existence of specific NT receptors in rat stomach strips and guinea-pig atria.
9 The data derived from our structure-activity study suggest that the minimum structure required for the full stimulation of NT receptors in these two preparations is H-Arg9-Pro10-Tyr11-Ile12-Leu13-OH. The sequence PyroGlu1-Leu2-Tyr3-Glu4-Asn5-Lys6-Pro7-Arg8- and the amino acids Ile12 and Leu13 appear to contribute mainly to the affinity or binding of NT to its receptor. The chemical groups responsible for the full activation (intrinsic activity) of NT receptors seem to be located in the sequence -Arg9-Pro10-Tyr11.
相似文献 下载免费PDF全文 2 Boiling decidual tissue abolished the inhibitory influence on myometrial PGI2 output. Preincubation of decidua with 5,8,11,14-eicosatetraynoic acid (ETA) (30 μg/ml) also suppressed decidual inhibitory activity but indomethacin (30 μg/ml) was ineffective.
3 Incubation of decidual and myometrial tissue with arachidonic acid (AA) 10 μg/ml did not increase the inhibition of myometrial PGI2 synthesis, even if the decidua were pre-incubated with indomethacin.
4 Myometrial PGI2 production was reduced if the chopped tissue was pre-incubated with soya bean lipoxidase for 10 min at 4°C. This reduction was reversed if the lipoxidase was incubated with ETA (30 μg/ml) for 30 min at 37°C before addition to the myometrial tissue.
5 Perfusion of the uterus to remove blood elements removed the inhibitory action that the decidua exerted upon myometrial PGI2 production. PGI2 synthesis by separated decidual and whole uterine tissue was markedly elevated.
6 The addition of rat blood platelets (0.75 × 109/ml) to incubations of perfused decidual tissue reduced PGI2 output and restored the inhibitory action that the decidua exerted on myometrial PGI2 synthesis.
7 It is concluded that a lipoxygenase enzyme contained in blood platelets trapped within the decidual vasculature produces a hydroperoxy acid which inhibits decidual PGI2 production or myometrial PGI2 synthesis when the tissues are incubated together. It is suggested that perfusion is a pre-requisite before study of PGI2 synthesis in highly vascularised tissues.
8 The pathophysiological importance of such platelet lipoxygenase products is discussed.
相似文献2 The vasodilator effect of histamine was potentiated by papaverine (6.1 × 10-7 M) and IBMX (4.4 × 10-5 M) but inhibited dose-dependently by verapamil (5.1 and 51.0 × 10-7 M).
3 Adenosine-induced vascular relaxations were greatly increased in the presence of papaverine (6.1 × 10-7 M) but significantly reduced in the presence of IBMX (4.4 × 10-5 M) or verapamil (5.1 and 51.0 × 10-7 M).
4 The vasodilatation produced by isoprenaline was increased in the presence of IBMX (4.4 × 10-5 M) or papaverine (6.1 × 10-7 M), but inhibited by verapamil (5.1 and 51.0 × 10-7 M).
5 The vascular relaxant effects of nitroglycerine and papaverine were inhibited in the presence of IBMX (4.4 × 10-5 M) or verapamil (5.1 and 51.0 × 10-7 M). Papaverine (6.1 × 10-7 M) also antagonized nitroglycerine-induced vascular relaxation.
6 The vasodilator effect of IBMX was greatly reduced in the presence of papaverine (6.1 × 10-7 M) or verapamil (5.1 and 51.0 × 10-7 M).
7 The vascular relaxant effect of verapamil was reduced proportionally by raising the extracellular Ca2+ concentration from 1.25 to 5.0 mM while those elicited by histamine, adenosine, isoprenaline, nitroglycerine, papaverine and IBMX were not modified by this procedure.
8 These results were taken as an indication that several vasodilators (e.g. histamine, adenosine, isoprenaline, nitroglycerine, papaverine and IBMX), but not a Ca2+ antagonist such as verapamil, produce a fraction of their vasodilator effects by promoting Ca2+ extrusion from and/or Ca2+ sequestration into the vascular smooth muscle cells, via a cyclic adenosine 3′,5′-monophosphate-dependent mechanism.
相似文献 下载免费PDF全文 2 Cph ≥ 10-6M reduced the amplitude of normal spontaneous contractions and concurrently decreased the number of action potentials occurring with each slow-wave of depolarization (sucrose-gap recordings). These inhibitory effects of Cph were antagonized by increasing the medium [Ca] three fold to 7.68 mM.
3 Intracellular recordings showed that Cph ≥ 2 × 10-6M decreased the amplitude and extended the duration of the action potential. These effects were only partially reversible in normal medium whereas large overshooting action potentials were again seen in 7.68 mM Ca medium.
4 High frequency mechanical activity was produced by inclusion of veratridine 5 × 10-6M in the perfusate. Low concentrations of Cph (≥ 10-7M) reduced the amplitude of such contractions at a faster rate than they did normal spontaneous contractions.
5 At concentrations between 10-7 and 10-6M, Cph fully reduced the tonic component of contractions elicited in 112 mM isotonic KCl whilst having little or no effect on either (i) the initial phasic KCl contraction or (ii) the `repolarization contracture' normally produced on wash-out of the KCl or (iii) the spontaneous contractions before and after KCl treatment. In contrast, at Cph 2 × 10-6M, the repolarization contracture, as well as the isotonic KCl contraction, was totally blocked whereas spontaneous contractions were still unaffected. Progressively higher Cph concentrations inhibited all components of this contractile cycle.
6 Dose-response curves for the rate of drug-induced relaxation of tonic contractures produced in hypertonic 42.7 mM high-potassium medium, showed the calcium antagonistic potency of Cph to be intermediate between that of chlorpromazine and D600. The minimum Cph concentration for effect lay between 1 and 5 × 10-7M, and the effects of Cph 2 × 10-6M (approximately the ID50) were totally antagonized by 12.8 mM Ca.
7 By means of a lanthanum wash procedure, Cph ≥ 2 × 10-6M was found to decrease the 45Ca uptake occurring into strips of taenia coli in normal medium, although the maximum effect (at Cph 10-5M) amounted to only 25% inhibition of the uptake occurring into control strips (also found with D600). The increased uptake occurring in hypertonic 44.7 mM high-potassium medium was inhibited in a dose-dependent manner by Cph 1 × 10-7M.
8 The results are consistent with an action of Cph in reducing the flow of Ca2+ through voltage-dependent Ca channels in the smooth muscle cell membrane. It is suggested that the interaction of Cph molecules with such sites is dependent upon membrane potential as well as drug concentration.
相似文献 下载免费PDF全文 2 The muscular contraction caused by the narcotic analgesics exhibited stereospecificity, with levorphanol being about 50 times more potent than dextrorphan and (-)-methadone 4 times more potent than (+)-methadone. In addition, the rank order in potency of a homologous series of N-alkyl substituted norketobemidones demonstrated that the activity of these compounds in eliciting contractile responses corresponded to that for analgesic efficacy in the rat and also correlated to the ability of these derivatives to inhibit the muscular twitch evoked by electrical stimulation of the guinea-pig ileum.
3 Naloxone blocked the contractile response of the opiates following competitive kinetics; the naloxone pA2 values for morphine, etorphine, levorphanol and methadone were very close, in spite of the marked differences in potency of these agents.
4 The contractile effect of morphine on the rat colon was abolished by incubation of the tissues with tetrodotoxin 2.0 × 10-7 M or by decreasing the external Ca2+ level 100 fold. Increasing the external Ca2+ concentration caused an apparent non-competitive antagonism of the response to morphine.
5 Pretreatment of the tissues with hexamethonium 8.3 × 10-5 M caused a modest antagonism of the morphine effect while atropine 5.8 × 10-7 M did not significantly modify the morphine contractile effect. In contrast, methysergide 10-5 M caused a 10 fold increase in the morphine EC50.
6 Colons from rats rendered tolerant-dependent on morphine were markedly less sensitive to the contractile effects of morphine than those from placebo-treated controls. Tolerance to morphine was also accompanied by an increased sensitivity to the contractile effects of 5-hydroxytryptamine (5-HT).
7 A marked increase in the spontaneous muscular activity of segments of the terminal colon of rats chronically treated with morphine was found to occur upon removal of the residual morphine in the tissues by repetitive washings. The spontaneous activity was arrested by applications of morphine, suggesting that physical dependence can be demonstrated in vitro in this particular preparation.
8 It is concluded that the opiate-induced contractile response is mediated via stereospecific, naloxone-sensitive, opiate receptors and that the muscular response involves the activation of a 5-HT neurone in the nerve terminals of the colon.
相似文献 下载免费PDF全文 2 At low concentrations (between 5 × 10-10 and 10-9 M) At II induces an acceleration of spontaneous action potential (AP) discharge without change in the resting membrane potential. The frequency and size of the associated contractions are simultaneously augmented. Under these conditions the size of the spikes is not affected, thus suggesting that At II triggers the release of Ca2+ from internal stores.
3 The increase in AP discharge rate produced by low concentrations of At II results from an acceleration of the pacemaker potential. Furthermore, in the presence of 10 mM tetraethylammonium (TEA), there is an acceleration of the repolarizing phase of AP.
4 Ouabain (10-3 M) inhibits the increase in rhythmic activity induced by low concentrations of At II (in the presence of 10 mM TEA), thus suggesting that the Na-K pump is directly or indirectly involved in this action of the peptide.
5 At higher concentrations, At II produces a concentration-dependent depolarization with an EC50 of 1.2 × 10-8 M and a maximum of 10-7 M. The associated contraction has an EC50 of 3.3 × 10-8 M and a maximum of 3 × 10-7 M.
6 Ouabain (3 × 10-3 M) depolarizes the cell membrane. Under these conditions, At II (10-7 M) has a slight depolarizing effect, but it still produces a large tonic contraction.
7 It is concluded, that At II acts on different steps of excitation-contraction coupling, depending on the concentration. At low levels, the peptide mainly accelerates spike discharge, through a mechanism involving the Na-K pump. At higher concentrations, At II depolarizes the cell membrane. The contraction is then activated by the influx of Ca2+ due to secondary AP discharge and the release of Ca2+ from intracellular stores. Pharmacomechanical coupling has an important role in the triggering of contractions both at high and at low concentrations of At II.
相似文献 下载免费PDF全文 2 The amplitudes of nerve-mediated and drug-induced responses were considerably potentiated by substance P (SP) in the dose range 10-12 to 10-7 M. Higher concentrations of SP were directly spasmogenic. The sensitizing property of SP was dose-dependent and was usually well maintained, but always disappeared quickly on washing the preparation. In some experiments SP facilitated the twitch, but not the subsequent phase of the electrically-induced contraction or the response to externally applied noradrenaline.
3 Phentolamine (10-6 M) failed to block this effect of SP, but itself potentiated the nerve-mediated twitch, and completely abolished the sustained secondary contraction.
4 Desmethylimipramine (10-6 M) enhanced the delayed contraction but not the immediate contraction.
5 The uptake of tritiated noradrenaline (3 × 10-7 M) by vasa was inhibited by desmethylimipramine (10-6 M) and increased by nialamide (3 × 10-5 M), but was not modified by SP (10-6 M).
6 Nerve-mediated release of accumulated radioactivity was accelerated by phentolamine, but not by SP or desmethylimipramine.
7 These findings suggest that SP sensitizes the muscle cells to depolarizing stimuli but that it has no facilitatory effect on sympathetic neural elements.
相似文献 下载免费PDF全文 2 5-HT contracted the dog isolated femoral artery and saphenous vein over the concentration-range 1.0 × 10-8 to 5.0 × 10-6 mol/l.
3 In the femoral artery methysergide and cyproheptadine were potent, competitive and specific antagonists of the contractile responses to 5-HT, with pA2 values of 8.52 and 8.55 respectively.
4 In the saphenous vein, methysergide was only a weak antagonist of 5-HT. In addition, it was an agonist over the concentration-range 5.0 × 10-8 to 1.0 × 10-5 mol/l. Cyproheptadine was a weak and unsurmountable antagonist of contractile responses to 5-HT and methysergide.
5 Contractile responses to 5-HT and methysergide in the saphenous vein were not antagonized by morphine (3.0 × 10-5 mol/l), indomethacin (5.0 × 10-5 mol/l), phentolamine (5.0 × 10-7 mol/l), propranolol (1.0 × 10-6 mol/l), atropine (1.0 × 10-6 mol/l), mepyramine (1.0 × 10-6 mol/l) or cimetidine (1.0 × 10-5 mol/l).
6 In the external carotid and lingual arteries the pattern of activity obtained with methysergide and cyproheptadine was the same as that in the femoral artery, while in the auricular artery the pattern of activity was the same as that in the saphenous vein.
7 The results are consistent with the hypothesis that there are two types of receptor mediating 5-HT-induced vasoconstriction in dog vasculature. One type, characterized by the pattern of activity obtained in the femoral artery, is like the previously described `D-receptor'. The other type, characterized by the pattern of activity obtained in the saphenous vein, has not been described before. The verification of this hypothesis requires the identification of a specific antagonist of 5-HT and methysergide in the saphenous vein.
相似文献 下载免费PDF全文 2 The membrane potentials of smooth muscle cells in the rat and guinea-pig were -44.4 mV and -47.6 mV, respectively. In both species the smooth muscle cells generated spikes as burst discharges.
3 In the guinea-pig portal vein, NG (2.8 × 10-8 M) produced biphasic potential changes, an initial transient hyperpolarization followed by depolarization. The hyperpolarization suppressed and depolarization enhanced spike activities.
4 From the changes in the membrane potential produced by NG in various concentrations of [K]o, [Na]o or [Ca]o, it is postulated that the hyperpolarization is due to an increase in the K-permeability and the depolarization is due to an increase in the Na-permeability of the membrane.
5 NG (2.8 × 10-5 M) had no effect on the membrane activity of the rat portal vein.
6 NG consistently suppressed mechanical activities generated in both tissues. The minimum concentration required to suppress the mechanical activity was lower in the guinea-pig than in the rat portal vein.
7 NG suppressed the contraction due to noradrenaline more than that evoked by excess [K]o in both species.
8 From these experiments, it is concluded that NG relaxes the muscular bed of portal veins of both species. In the rat portal vein, suppression of mechanical activity had no causal relation to the membrane activity. In contrast, in the guinea-pig portal vein, suppression of mechanical activity was slightly modified by changes in the membrane activity, i.e. hyperpolarization additively contributes to the relaxation and depolarization slightly suppresses the relaxation.
相似文献 下载免费PDF全文 2 No difference was detected between either 6-oxo-PGF1α or PGI2 concentration when rings were incubated with U-PPP or C-PPP for 4, 8 and 30 min for 6-oxo-PGF1α (P > 0.05, n = 8); and 30 min for PGI2 (P > 0.05, n = 8).
3 Consistently more 6-oxo-PGF1α was produced in PPP that had been heated at 100°C for 5 min (H-PPP) than in C-PPP: mean 6-oxo-PGF1α was increased by factors of 1.45, 1.61, 1.57 and 1.57 at 4, 8, 30 and 60 min respectively (P < 0.005 at each time, n = 8).
4 Similar amounts of 6-oxo-PGF1α were produced by aortic rings incubated in H-PPP and in Tris buffer (50 mM, pH 7.5), P > 0.05 at all times (n = 8).
5 The half-life of PGI2 in U-PPP was similar to that in C-PPP; 7.8 ± 0.6 min and 10.2 ± 1.9 min (mean ± s.e. mean) respectively (P > 0.05).
6 In separate experiments a comparison was made of 6-oxo-PGF1α production by aortic rings incubated in C-PPP, H-PPP and H-PPP to which albumin had been added to restore its original concentration. It was confirmed that more 6-oxo-PGF1α was produced in H-PPP than in C-PPP (P < 0.05, n = 4). This increment was abolished in the H-PPP to which albumin had been added.
7 It was concluded that the heat-labile inhibitor of vascular PGI2 synthesis in human plasma is albumin.
8 The failure to demonstrate a stimulator of PGI2 synthesis in fresh aortic rings by U-PPP does not support the hypothesis that the bleeding diathesis of renal failure is due to an excess of a PGI2 stimulating factor in plasma.
相似文献 下载免费PDF全文 2 Changes in muscle tone were observed in colon and rectum and to a lesser extent in jejunum and ileum of both species. Rat colon and rectum contracted to the peptides. Guinea-pig colon and rectum relaxed after an initial short-lasting contraction.
3 On the rat rectum (D-ala2)met-enkephalin, leu-enkephalin, γ-endorphin, α-endorphin and β-LPH 80-91 caused dose-dependent contractions, their ED50 values being 0.96 × 10-12 mol, 1.05 × 10-11 mol, 1.22 × 10-11 mol, 1.08 × 10-10 mol, 2.65 × 10-10 mol and 6.5 × 10-9 mol, respectively.
4 Naloxone dose-dependently shifted the dose-response curve of met-enkephalin to the right. Atropine, hexamethonium, burimamide, mepyramine, propranolol and indomethacin did not influence the response to met-enkephalin.
5 In the presence of tetrodotoxin, the ED50 for met-enkephalin and the maximal contractor response induced by met-enkephalin, appeared to be increased.
6 The 5-hydroxytryptamine (5-HT) antagonists, methysergide and cyproheptadine, reduced the contractor response in a non-competitive manner. The α-adrenoceptor antagonist phentolamine, in contrast, caused an increase of the maximal response to met-enkephalin of up to 200%. Noradrenergic and tryptaminergic systems, therefore, might be involved in the changes in muscle tone induced by met-enkephalin.
7 These results demonstrate that rectum and colon of guinea-pig and rat are very sensitive to opioid-like peptides.
相似文献 下载免费PDF全文 2 The responses evoked by stimulation of postsynaptic adrenoceptors in all the tissues and presynaptic α-adrenoceptors in the mouse vas deferens were diminished by the perfusion of noradrenaline through the organ bath for 30 min.
3 The concentration of noradrenaline required to produce desensitization was higher in the mouse vas deferens than in the other tissues and more was required to desensitize the chronotropic responses than the inotropic responses in rat isolated atria.
4 The inclusion of cocaine (10-5 M) in the bathing solution to block uptake1 increased the sensitivity of most tissues to noradrenaline. With the possible exception of the response to stimulation of presynaptic receptors in the mouse vas deferens, desensitization was somewhat increased in its presence.
5 When uptake2 was blocked by oestradiol (10-5 M), it was not possible to desensitize the contractor responses of the aortic strip and vas deferens to exogenous noradrenaline, nor the inotropic response of the atria to the drug. However, oestradiol failed to block the desensitization of chronotropic responses and responses to stimulation of presynaptic receptors in the vas deferens.
6 Blockade of monoamine oxidase (MAO) with iproniazid (7.2 × 10-4 M) or with pargyline (5 × 10-4 M) did not affect the desensitization process in the aortic strip.
7 Blockade of catechol-O-methyltransferase (COMT) with U-0521 (5.3 × 10-5 M) greatly increased desensitization in the aortic strip and desensitization of inotropic responses in the atria. It had no effect on desensitization of chronotropic responses. Its effect on responses in the mouse vas deferens was not determined.
8 The perfusion of methoxamine at concentrations about 1000 times higher than those of noradrenaline also produced desensitization in the aortic strip.
9 The desensitization of presynaptic receptors in the mouse vas deferens was shown to be specific and that of the responses to postsynaptic receptor stimulation to be non-specific.
10 It is concluded that responses to adrenoceptor stimulation may be desensitized by accumulation of noradrenaline inside the cells bearing the receptors and that the desensitization is caused by noradrenaline itself not by a metabolite. Desensitization may also be caused without accumulation of noradrenaline in uptake2 and for some receptors these may not be alternative mechanisms.
相似文献 下载免费PDF全文 2 Intrapulmonary arteries produced no measurable contractile responses to prostaglandin A1 (PGA1), PGA2, PGB1, PGD2, PGE1, PGE2 or to PGF1α. However, high concentrations of both PGB2 (> 10-7 M) and PGF2α (> 10-6 M) elicited concentrated-related, but weak, contractile responses, measuring only 5-25% of KCl-induced maximum contractions.
3 Intrapulmonary arteries, partially contracted by 5-hydroxytryptamine (5-HT), exhibited concentration-related relaxations in response to PGE1; PGE2, PGA1 or PGA2 produced only weak superimposed contractions.
4 In contrast to intrapulmonary arteries, intrapulmonary veins contracted in a concentration-related fashion to all prostaglandins tested, where the contractile sensitivity was (based on EC50 s and threshold concentrations): PGB2 > PGB1 > PGD2 > PGF2α > PGA2 >> PGA1 > PGF1α > PGE2 > PGE1.
5 In terms of the ability to generate maximum contractile responses on intrapulmonary veins, the prostaglandins were also variable, with PGA2 and PGB2 being the most potent and PGD2 the least potent.
6 Intrapulmonary veins, partially contracted by 5-HT, exhibited concentration-related relaxations to PGE1 at low concentrations, followed by secondary contractile responses at higher concentrations.
7 Neither PGA1 nor PGA2 (3.4 × 10-8 to 3.4 × 10-5 M) inhibited or potentiated 5-HT responses of intrapulmonary arteries.
8 These data suggest that there are species, regional and major qualitative and quantitative, differences in the responsiveness of intrapulmonary arteries and veins to prostaglandin.
相似文献2 GABA at doses ranging from 10-7 M to 3 × 10-6 M elicited a relaxation while at higher doses (3 × 10-6 M — 10-4 M), as previously described, it caused a contraction followed by relaxation.
3 GABA-induced relaxation was bicuculline-insensitive, was mimicked by (-)-baclofen but not by homotaurine and muscimol. The effect of baclofen was stereospecific. GABA- and (-)-baclofen-induced relaxations were dose-dependent and their ED50 values were similar. A specific cross-desensitization occurred between GABA and (-)-baclofen.
4 The bicuculline-insensitive relaxation induced by GABA and (-)-baclofen was prevented by tetrodotoxin and hyoscine but not by phentolamine plus propranolol, naloxone or theophylline.
5 In preparations in which the muscle tone was raised by histamine or prostaglandin F2α, GABA and (-)-baclofen induced relaxation to the same extent as before increasing the tone. If the tone was raised by DMPP, a greater bicuculline-insensitive relaxation occurred.
6 Contraction caused by GABA was bicuculline-sensitive and was mimicked by homotaurine and muscimol. Contraction was dose-dependent and muscimol was about three times more potent than GABA or homotaurine. A specific cross-desensitization occurred between the contractile effects of GABA and those of homotaurine or muscimol.
7 Bicuculline competitively antagonized the contractile effects of GABA, homotaurine and muscimol and gave closely similar pA2 values. The slope of the Schild plot for the above drugs was near 1, confirming the competitive nature of the antagonism.
8 The bicuculline-sensitive contraction induced by GABA, homotaurine and muscimol was abolished by tetrodotoxin and was non-competitively antagonized by hyoscine, while it was unaffected by hexamethonium, mepyramine and methysergide.
9 It is concluded that two receptors mediate the GABA effects in guinea-pig ileum: a bicuculline-sensitive GABAA receptor, which elicits contraction through an excitatory action on cholinergic post-ganglionic neurones; and a bicuculline-insensitive GABAB receptor which causes relaxation through an inhibitory presynaptic action on cholinergic post-ganglionic neurones. We confirm that GABA, homotaurine and muscimol are GABAA agonists, while GABA and (-)-baclofen are GABAB agonists.
相似文献2 The influence of propranolol on prazosin binding has been studied. In addition, red blood cell to plasma partitioning of prazosin has been quantified.
3 The dissociation constant for prazosin binding to albumin was 3 × 10-5 M and to α1-acid glycoprotein was 1.9 × 10-6 M.
4 In fourteen normal subjects the free fraction of prazosin was 0.051 ± 0.007.
5 In seven patients with cirrhosis free fraction of prazosin was 0.064 ± 0.017 (P < 0.05 compared to normal). In nine patients with chronic renal failure the free fraction was 0.077 ± 0.033 (P < 0.05) and in eight congestive heart failure patients the value was 0.064 ± 0.027 (P > 0.05).
6 The range of prazosin free fraction was substantially greater in the patients than in normal subjects. In cirrhotic patients free fraction of prazosin correlated significantly (r = -0.92) with albumin concentration.
7 Propranolol did not influence prazosin protein binding. In blood 20% of prazosin is associated with red cells.
8 The considerably greater range of prazosin free fraction in the patients suggests that caution should be used when prescribing the drug for subjects with these conditions. Both albumin and the acute phase reactant α1-acid glycoprotein bind prazosin in vitro.
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