外周NK-1受体对甲醛致痛大鼠行为学的影响

目的探讨外周NK-1受体在甲醛致痛模型中的作用及可能的作用机制。方法24只雄性Wistar大鼠随机分为4组(n=6)。包括一个对照组:DMSO组和3个不同剂量的RP67580实验组:5 nmol组;20nmol组;100 nmol组。观察注射甲醛后各组大鼠行为学的改变。结果在甲醛致痛的第一、二时相,各实验组累积舔咬爪时间均短于对照组(P<0.05)。且在第二时相,各实验组之间差异有统计学意义(P<0.05),随着给药剂量增加,大鼠累积舔咬爪时间下降明显(P<0.05)。结论外周注射NK-1受体拮抗剂RP67580,对甲醛致痛模型的2个时相均有抗伤害作用,此作用可能与阻断P物质参与的伤害性信息传导有关。     

Prejunctional modulation by angiotensins of noradrenaline release from sympathetic neurons in isolated rabbit aorta

The aims of the present work were to compare the modulating effect of angiotensins I, II, III, IV and (1–7) [AI, AII, AIII, AIV and A(1–7) respectively] on stimulation-evoked noradrenaline release from post-ganglionic sympathetic nerves in rabbit isolated aorta; to examine the influence of inhibiting the neuronal and extraneuronal uptake of noradrenaline on the modulating effect of AII and thirdly, to determine the role of angiotensin converting enzyme (ACE) in the modulating effects of AI and AII and the role of aminopeptidases A and M in the effects of AII and AIII. Rings of aorta were preloaded with (–)-³H-noradrenaline and then subjected to electrical field stimulation. Cumulative addition of AI (10^–8–10^–6M), AII (3×10^–11–10^–8M) and AIII (3×10^–10–10^–6M) enhanced the stimulation-evoked ³H-overflow up to 142, 165 and 188% respectively. The order of potency was AII > AIII > AI. AIV (10^–10–10^–7M) and A(1–7) (10^–10–10^–7M) caused no change. Single concentrations (10^–9–10^–7M) of AI, AII and AIII caused initial enhancement which subsequently decreased, i.e. development of tachyphylaxis. The effect of AII was independent of stimulation frequency at 1–10Hz, but absent at 30Hz. Cocaine (3×10^–5M) plus corticosterone (4×10^–5M) did not alter the enhancing effect of AII. CaNa₂EDTA (3×10^–5M) did not alter the enhancing effect of AI. Captopril (10^–6 and 10^–5M) and lisinopril (10^–6M) attenuated the enhancing effect of AI. Captopril and lisinopril (both 10^–6 and 10^–5M) did not alter the enhancing effect of AII. Captopril (10^–7– 10^–4M) and lisinopril (10^–7–10^–4M) themselves did not alter the stimulation-evoked ³H-overflow. Amastatin (10^–5M) increased the enhancement seen with AIII (3×10^–11–10^–9M) but did not alter the enhancing effect of AII (10^–9–10^–8M). Amastatin (10^–9–10^–5M) had no effect on the stimulation-evoked ³H-overflow. It is concluded that AI, AII and AIII facilitate the stimulation-evoked ³H-noradrenaline release to various degrees (relative order of potency: AII > AIII > AI and of efficacy: AIII > AII > AI). The estimates may be compromised by the development of tachyphylaxis. The facilitation by AII was independent of the neuronal and extraneuronal uptake mechanisms. The action of AI is in part due to its conversion to AII. The effect of AIII was probably underestimated due to its degradation to AIV. AII is apparently not a substrate for aminopeptidase M. Received: 10 September 1996 / Accepted: 18 August 1997     

Inhibition of tachykinin-induced hypotension in dogs by CP-96,345, a selective blocker of NK-1 receptors

Summary The effects of substance P, neurokinin A, neurokinin B, [Sar⁹, Met(O₂)¹¹]-substance P, [Nle¹⁰]neurokinin A (4–10) and senktide {succinyl-[Asp⁶, McPhe⁸]-substance P (6–11)} on blood pressure and heart rate were studied in anesthetized dogs. Dose-dependent decreases in blood pressure and increases in heart rate were caused by each peptide except senktide. The latter elicited weak hypotensive or hypertensive responses at high doses. The order or potency was as follows: [Sar⁹, Met(O₂)¹¹]-substance P substance P > neurokinin ß₁ > neurokinin B > [Nle¹⁰]-neurokinin A (4–10) » senktide.CP-96,345, [(2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1-azabicyclo[2.2.2]octan-3-amine] a selective NK-1 tachykinin receptor blocker, inhibited substance P-induced hypotension in a dose-related manner. R responses to each of the other peptides were inhibited by CP-96,345, 1.0 mg/kg (excluding senktide against which CP-96,345 was not tested). CP-96,344 (1.0 mg/kg i.v.) the 2R-3R enantiomer of CP-96,345 which does not block NK-1 receptors, had no effect on substance P-induced hypotension. We conclude that tachykinin-induced hypotension in dogs is mediated by NK-1 tachykinin receptors. Send offprint requests to J. W. Constantine at the above address     

Synergistic role of muscarinic acetylcholine and tachykinin NK-2 receptors in intestinal peristalsis

It is known that tachykinins (substance P, neurokinin A) participate in the excitatory neural pathways subserving peristaltic motor activity in the intestine. The aim of the present study was to elucidate the types of tachykinin receptor (NK-1 or NK-2) involved in peristalsis by the use of receptor subtype-selective antagonists. Peristaltic motility in isolated segments of the guinea-pig ileum was induced by pumping fluid into the oral end of the intestinal segment. By way of the intraluminal pressure the compliance of the intestinal wall during the preparatory phase and the pressure threshold to trigger the emptying phase of peristalsis were recorded. The tachykinin antagonists were used at concentrations that were at least 30 times in excess of the equilibrium dissociation constants which had previously been evaluated with receptor subtype-selective agonists on the guineapig ileum circular muscle. The NK-1 selective antagonist CP-96,345 (0.3 M) had a slight stimulant influence on peristalsis, whereas the NK-2 selective antagonists MEN-10,376 (10 M), GR-94,800 (0.3 M) and SR-48,968 (0.1 M) led to a small inhibition of motor activity. However, when given after exposure of the ileum to a threshold concentration of atropine (5–20 nM) causing little depression of peristalsis, the tachykinin NK-2 receptor antagonists invariably abolished peristalsis. This synergistic interaction was not seen when SR-48,968 was administered after the ileal segments had been exposed to concentrations of hexamethonium, isoproterenol or calcitonin gene-related peptide that by themselves caused a slight inhibition of peristalsis only. CP-96,345 was without effect on peristalsis when it was applied in the presence of a threshold concentration of atropine. These findings indicate that transmission via tachykinin NK-2, but not NK-1, receptors synergizes with cholinergic transmission via muscarinic receptors in the relay of excitatory enteric pathways subserving intestinal peristalsis. Correspondence to: P. Holzer at the above address     

Effects of viscotoxin on rabbit heart and aorta, and on frog skeletal muscle

The effects of the mistletoe toxins, Viscotoxins A₃ and B, on excitation and contraction processes in isolated preparations of cardiac, smooth, and skeletal muscle were investigated. In low concentrations (1–10 μg/ml), Viscotoxin B reduced the isometric twitch and produced contracture and progressive depolarization of rabbit papillary muscle. These changes were almost completely reversed by increasing the extracellular calcium concentration from 2.0 to 4.0 mM. In single frog muscle fibres, Viscotoxins A₃ and B, 1 μg/ml, caused a progressive depolarization of the cell membrane; associated with this change, a transient contracture developed. The depolarization could be prevented by an increase in extracellular calcium concentration from 1.8 to 12 mM. Rabbit aortic strips were less sensitive to the Viscotoxins than heart and skeletal muscle, but in a concentration of 200 μg/ml, Viscotoxin A₃ produced a slowly developing contracture that could not be reversed by calcium.It is suggested that the Viscotoxins, by binding to the cell membrane, displace bound calcium from a membrane site.     

Vasoconstrictor responses via P2X-receptors are selectively antagonized by NF023 in rabbit isolated aorta and saphenous artery

1. The effects of NF023, the symmetrical 3′-urea of 8-(benzamido)naphthalene-1,3,5-trisulphonic acid), and its parent compound suramin were investigated on vasoconstrictor responses to α,β-methylene ATP in rabbit isolated saphenous artery and vasodilator responses to ATP in noradrenaline-precontracted rabbit isolated thoracic aorta.
2. In rabbit isolated saphenous artery, α,β-methylene ATP-induced vasoconstrictor responses via P2X-receptors were concentration-dependently and competitively antagonised by NF023 (30–300 μM; pA₂=5.69±0.04). Suramin (100–1000 μM) also competitively blocked vasoconstrictor responses to α,β-methylene ATP, albeit with lower potency (pA₂=4.79±0.05). In contrast, NF023 (100 μM) did not significantly affect contractile responses to noradrenaline or histamine in the saphenous artery.
3. In noradrenaline-precontracted rabbit isolated thoracic aorta preparations, ATP (3–3000 μM) concentration-dependently induced relaxations via endothelium-dependent or smooth muscle P2Y-receptor subtypes. NF023 (30–300 μM) failed to block relaxant responses to ATP at endothelium-dependent P2Y-receptors, whereas suramin (100–1000 μM) did antagonise endothelium-dependent vasodilator responses to ATP. Neither NF023 (100 μM) nor suramin (300 μM) influenced vasorelaxant responses to ATP via endothelium-independent P2Y-receptors.
4. In conclusion, this study outlines the selectivity of NF023 as an effective P2X-receptor antagonist in rabbit isolated blood vessels without affecting endothelium-dependent or endothelium-independent P2Y-receptor subtypes, adrenoceptors or histamine receptors.

     

The fate of isoprenaline in the isolated rabbit aorta

Summary The fate of isoprenaline (ISO) was studied in the intact rabbit aorta, as well as in the isolated adventitia and isolated media, by means of liquid scintillation counting of ³H-ISO and ³H-O-methylisoprenaline (OMI) as well as by autoradiography of tissues incubated with 2M ISO. The 3 preparations accumulated and O-methylated ISO; O-methylation was proportionally higher in the intact vessel than in its constituents. The isolated adventitia differed from the other preparations in reaching a steady-state of cortexone-resistant accumulation after 8 min of incubation and in exhibiting an O-methylating capacity which was partly resistant to the COMT inhibitor, U-0521. The effect of cocaine gave evidence for a participation of neuronal uptake in the accumulation of the amine in the intact aorta. In the media, most of the accumulation occurred in smooth muscle cells and was reduced by cortexone and increased by U-0521; elastin and collagen, present both in the media and the adventitia, showed accumulation which was not affected by the inhibitory drugs studied.The results show that in the rabbit aorta there is a corticosteroid-resistant uptake mechanism (which predominates in the adventitia) which involves structures devoid of COMT activity. Furthermore, smooth muscle cells represent, in the media, the extraneuronal metabolizing site of loss. The adventitia is a complex layer, with different types of cells which may intervene in accumulation and metabolism of ISO. Therefore, it is concluded that the isolated media represents an acceptable model for the study of both corticosteroidsensitive and-resistant extraneuronal mechanisms, whereas the isolated adventitia is characterized by the presence of neuronal and extraneuronal mechanisms.Some of the results were presented to the 3rd Meeting on Adrenergic Mechanisms, Porto, July 12–13, 1978 (Proceedings, p. 93) and to the 1st Joint Meeting of the Spanish and Portuguese Pharmacological Societies (Santiago de Compostela, 21–23.5.79). Supported by Instituto Nacional de Investigação Científica (Centro de Farmacologia e Biopatologia Quimica-FmPl)     

Inhibitory presynaptic imidazoline receptors on sympathetic nerves in the rabbit aorta differ from I1- and I2-imidazoline binding sites

The involvement of imidazoline receptors in modulation of noradrenaline release was investigated in the rabbit aorta preincubated with [³H]noradrenaline and superfused with physiological salt solution containing cocaine, corticosterone and propranolol.After blockade of ₂-autoreceptors by rauwolscine, the electrically evoked tritium overflow was inhibited by various imidazolines and guanidines. The rank order of potency was BDF 7579 (4-chloro-2-isoindolinyl) guanidine) BDF 6143 (4-chloro-2-(2-imidazolin-2-ylamino)-isoindoline] > BDF 6100 [2-(2-imidazolin2-y-lamino)-isoindoline] > clonidine > ST587 (2-(2-chloro-5-trifluoromethylphenylimino) imidazolidine nitrate) cirazoline > tolazoline > idazoxan > phentolamine. Comparison of the potencies of these drugs with those previously found for the presynaptic imidazoline receptors in the rabbit pulmonary artery revealed a very good correlation. In contrast, no positive correlation was found with their affinities for the I₁-and I₂-imidazoline binding sites in bovine adrenal medullary membranes and with their lipophilicity (log P values). The electrically evoked tritium overflow was also inhibited by the recently identified endogenous imidazoline receptor ligand agmatine, but was not affected by amiloride. In further series of experiments, the ability of putative antagonist at presynaptic imidazoline receptors to counteract the inhibitory effect of imidazoline derivatives was determined. Amiloride, imidazole-4-acetic acid and 1-benzylimidazole did not attenuate the inhibitory effect of BDF 6143 on the electrically evoked tritium overflow. In contrast, rauwolscine antagonized the inhibitory effect of various imidazolines; rauwolscine was clearly less potent in antagonizing the effect of clonidine, BDF 6143 and cirazoline (apparent pA₂ 6.48–7.32) than in antagonizing that of oxymetazoline and moxonidine (apparent pA₂ 8.33 and 8.12, respectively). In a final series of experiments, BDF 6143 (under the conditions applied a selective agonist at presynaptic imidazoline receptors) proved to be considerably less potent in inhibiting tritium overflow evoked by high K⁺ than by electrical stimulation, whereas moxonidine (in rabbit aorta a selective agonist at presynaptic ₂-adrenoceptors) exhibited similar potency in inhibiting the overflow evoked by both methods of stimulation.It is concluded that noradrenaline release in the rabbit aorta is inhibited via both ₂-autoceptors and presynaptic imidazoline receptors which can be activated by the endogenous imidazoline receptor ligand agmatine. The occurrence of such an ₂-adrenoceptor-independent mechanism is compatible with the ability of K⁺ ions to attenuate the inhibitory effect of an imidazoline receptor agonist but not of an ₂-adrenoceptor agonist, since susceptibility to K⁺ ions has been suggested to be a typical feature of imidazoline recognition sites. The presynaptic imidazoline receptor in rabbit aorta appears to be identical with the previously characterized presynaptic imidazoline receptor in rabbit pulmonary artery, but differs clearly from the I₁ and I₂ binding sites in the bovine adrenal medulla.     

功能性P2X1样受体在离体兔动脉的分布

目的:研究功能性P2X_1-like受体在兔6种动脉平滑肌的分布.方法:观察兔离体肾动脉(Re)、股动脉(Fe)、隐动脉(Sa)、肠系膜动脉(Me)、脾动脉(Sp)和耳动脉(Ea)环的收缩反应.结果:NA的最大收缩反应(E_(max·NA))值为Re>Fe>Sa>Me=SP>Ea;经氯化钾最大收缩反应(E_(max·KCl))标准化后,NA的标准化最大收缩反应(E_(max·NA)/E_(max·KCl))值,在 6种血管基本一致.α,β-Methylene ATP最大收缩反应(E_(max·α,β-meATP))值为 Re>Sa=Fe>Ea=Sp=Me;经E_(max·KCL)标准化后,α,β-methylene ATP的标准化最大收缩反应(E_(max·α,β-meATP)/E_(max·KCl))数值各血管仍不同,Fe相似文献   

Synthesis and purification of two SP (6–11) analogues with enhanced selectivity for the NK-1 receptor

Two hexapeptide analogues of Substance P (6–11) have been synthesized. Replacement of Gly₉ by proline provides a peptide with tenfold enhanced selectivity for the NK-1 receptor. The corresponding proline-containing glycopeptide incorporating a β-d -glucopyranosyl residue linked to the side-chain of Glus was 100 times more selective than Substance P for the same receptor.     

Inhibition of 3H-noradrenaline accumulation by dopexamine hydrochloride in the isolated aorta of the rabbit

Summary The aim of the present work was to study the ability of dopexamine hydrochloride to interfere with the neuronal and extraneuronal uptake mechanisms by investigating the effect of dopexamine hydrochloride on ³H-noradrenaline accumulation by rabbit isolated aorta. Dopexamine hydrochloride (3 × 10^–9 – 10^–5 mol/l) reduced the accumulation of tritium by aorta incubated with ³H-noradrenaline (10^–8 mol/l). The effect of dopexamine was compared to cocaine, dopamine, dobutamine, ADTN [(+-)-2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene], ouabain and isoprenaline. Dopexamine hydrochloride (3 × 10^–9 – 10^–7 mol/l) caused the same degree of inhibition irrespective of whether corticosterone (4 × 10^–5 mol/l) was present or not. The order of inhibitory potency was: desipramine > dopexamine hydrochloride > dopamine > ADTN cocaine > dobutamine > ouabain > isoprenaline. In the presence of desipramine (10^–6 mol/l), corticosterone (10^–6 – 10^–4 mol/l), but not dopexamine hydrochloride (10^–6 – 10^–4 mol/l), reduced the ³H-accumulation. It is concluded that dopexamine hydrochloride is a potent inhibitor of uptake-1 in rabbit isolated aorta. Dopexamine hydrochloride has no affinity for the uptake-2 mechanism in this tissue. Send offprint requests to O. A. Nedergaard at the above address     

Stereoselectivity of extraneuronal uptake of catecholamines in rabbit aorta

Summary In incubated rabbit aorta, stereoselective preference of (-)isoprenaline and (-)adrenaline, but not of (-)noradrenaline, was observed with respect to extraneuronal (corticosterone-sensitive) catecholamine accumulation at relatively low amine concentrations. The ranking order (isoprenaline > adrenaline > noradrenaline) and the degree of stereoselectivity were similar to those described for the perfused rat heart. Thus, stereoselectivity of the carriermediated extrancuronal uptake process is demonstrable for different species and under conditions of incubation as well as of perfusion. On the other hand, amine distribution into the tissue that is linked neither to uptake₂ nor to uptake₁ (but which might be rather important under incubation conditions) showed no stereoselectivity in rabbit aorta.This study was supported by the Deutsche Forschungsgemeinschaft (He 813); the results were presented in a preliminary form to the German Pharmacological Society (Grohmann et al. 1983)     

Effects of tachykinin receptor agonists and antagonists on the guinea-pig isolated oesophagus

1. Vagal nerve stimulation of the guinea-pig isolated oesophagus produced a triphasic tetrodotoxin (TTX)-sensitive contractile response. The third phase, which was resistant to ganglion blocking drugs, was selectively abolished by capsaicin, suggesting the involvement of one or more neuropeptides released from afferent neurons. Receptors on cholinergic neurons were subsequently activated because the response was atropine sensitive. Contractile responses resulting from exogenous substance P were abolished by atropine and TTX and enhanced by physostigmine. These findings suggest that the third phase may be mediated by the action of a substance P-like neuropeptide released from sensory nerve endings that subsequently activated cholinergic neurons. 2. The tachykinin receptors in the body of the guinea-pig oesophagus were characterized by determining the relative agonist potencies of natural tachykinins as well as tachykinin receptor-selective analogues. Antagonist affinities were also determined. The results indicated the presence of both NK2 and NK3 receptors. In addition, the effects of a cocktail of peptidase inhibitors (captopril, thiorphan and amastatin) on responses to various tachykinins and synthetic analogues were determined. The results indicate that one or more peptidases are present in this preparation. 3. Experiments using various tachykinin receptor antagonists were performed to determine whether the activation of tachykinin receptors played a role in the mediation of the third phase of the response to vagal nerve stimulation. While this response was unaffected by NK1 and NK2 receptor-selective antagonists, it was only partially inhibited (23%) by the NK3 receptor antagonist SR 142801. Thus, in the guinea-pig oesophagus, it appears that NK3 receptors play only a minor role in mediating a contractile response when afferent neurons are excited by vagal nerve stimulation.     

The influence of oestrogen and oestrogen metabolites on the sensitivity of the isolated rabbit aorta to catecholamines

Summary 1. In the present study the influence of oestradiol, catechol oestrogens, and O-methylated oestrogens was determined on the contractile responses of the isolated rabbit aorta to (–)-adrenaline. 2. Oestradiol (40 mol/l), 2-hydroxyoestradiol (2OHE₂) (20 mol/l), and 2-methoxyoestradiol (2MeOE₂) (20 mol/l) all sensitized the rabbit aorta to contractile responses to (–)-adrenaline. Similarly, the 2-hydroxy and 2-methoxy derivatives of oestrone and oestriol also sensitized the aorta to (–)-adrenaline-induced contractions. The largest degree of sensitization was seen in the presence of the 2-methoxysteroids. 3. Oestradiol and 2OHE₂ did not increase responses of the aorta to (–)noradrenaline, while slight potentiation of contraction was seen in the presence of 2MeOE₃. 4. The potentiating effect of 2OHE₂ on contractile responses to (–)-adrenaline was abolished by prior treatment of the tissue with a COMT inhibitor (U-0521, 55 mol/l). Conversely, pretreatment of the tissue with 2OHE₂ prevented the augmented aortic contraction to (–)-adrenaline usually seen after inhibition of COMT. The non-additive nature of the sensitization seen after combined treatment with 2OHE₂ and U-0521 was qualitatively similar to that seen following combined exposure to maximally effective concentrations of U-0521 and an inhibitor of extraneuronal uptake (hydrocortisone 100 mol/l). 5. Oestradiol and 2MeOE₂ reduced the formation of both the ³H-O-methylated, ³H-deaminated and the ³H-O-methylated deaminated metabolites of ³H-(–)-adrenaline (0.15 mol/l) during exposure of the aorta to the tritiated catecholamine. Treatment of the aorta with the extraneuronal uptake inhibitor phenoxybenzamine (33 mol/l) produced a similar inhibition of formation of all ³H-metabolites of ³H-(–)-adrenaline. 6. While preincubation with 2OHE₂ markedly reduced the formation of ³H-O-methylated and ³H-O-methylated deaminated metabolites from ³H-(–)-adrenaline (0.15 ol/l), the formation of ³H-deaminated adrenaline metabolites was considerably enhanced by exposure to 2OHE₂. Pretreatment of the aorta with the COMT inhibitor U-0521 produced a similar effect on ³H-adrenaline metabolism.7. Oestradiol, 2OHE₂, and 2MeOE₂ did not alter the tritium contents retained in segments of aorta incubated with ³H (±)-isoprenaline (0.15 ol/l). In contrast, the three steroids reversed the enhanced retention of tritium in the aorta induced by prior inhibition of COMT (U-0521 55 mol/l).8. It is concluded that the biotransformation of oestradiol to its 2-hydroxy and 2-methoxy metabolites does not diminish the potentiating actions of the steroids on adrenaline-induced aortic contractions. Oestradiol and 2MeOE₂ appear to produce their effects through inhibition of the extraneuronal amine uptake process, while 2OHE₂, a substrate for COMT, probably exerts is sensitizing through a combination of inhibition of the extraneuronal uptake process and competitive inhibition of COMT.Abbreviations 2OHE₁ 2-hydroxyoestrone - 2OHE₂ 2-hydroxyoestradiol - 2OHE₃ 2-hydroxyoestriol - 2MeOE₁ 2-methoxyoestrone - 2MeOE₂ 2-methoxyoestradiol - 2MeOE₃ 2-methoxyoestriol - U-0521 34-dihydroxy-2-methylpropiophenone Supported by the part in West Virginia University Biomedical Fund; American Heart Association, West Virginia Affiliate; and NIH grants HL30351 and K04-HL01228Selected aspects of this study were presented to the American Society for Pharmacology and Experimental Therapeutics (Barone et al. 1985; Panek et al. 1986) Send offprint requests to R. E. Stitzel at the above address     

Calcium antagonistic effects of terodiline in rabbit aorta and human uterus

Abstract The possible calcium antagonistic action of the anti-anginal drug terodiline was investigated by two experimental techniques. In isolated preparations of rabbit aorta and pregnant human uterus exposed to a calcium-free medium and then depolarized by potassium, terodiline in concentrations of 4.5–36 μM inhibited contractions produced by cumulative addition of calcium to the extracellular medium. This effect of terodiline could be reversed by high concentrations of calcium. Within the same concentration range, terodiline also reduced potassium-induced ⁴⁵Ca influx in isolated aorta without affecting calcium efflux. It is suggested that terodiline, which structurally has similarities to prenylamine and fendiline, like these drugs can be classified as a calcium antagonist.     

Effects of perhexiline on contractile response of rabbit aorta to norepinephrine and potassium

Perhexiline (3.2 × 10^?7 -6.4 × 10^?6 M) and verapamil (2 × 10^?8 -2 × 10^?7 M) inhibited the contraction of rabbit aorta induced with 40 mM K⁺ and with low concentrations (5.9 × 10^?9 -5.9 × 10^?8 M) of norepinephrine more effectively than the contraction induced by higher concentrations of norepinephrine. The tension induced by 1.2 × 10^? M norepinephrine was augmented with the above concentrations of perhexiline and verapamil. Higher concentrations (3.2 × 10^?5 -6.4 × 10^?5 M) of perhexiline significantly reduced the peak tension induced by norepinephrine. The results suggest that perhexiline is a Ca²⁺ antagonist and also has an unspecific spasmolytic action.     

Mechanisms of action of 7-O-ethyl tetrandrine in isolated vascular smooth muscle of the rabbit aorta

Summary Tetrandrine is an alkaloid from a Chinese herb which has been used to treat hypertension in humans. The mechanism(s) of its antihypertensive action is not clear. The goal of this study was to examine the direct effects of a derivative of tetrandrine, 7-O-ethyl tetrandrine (TD), on vascular smooth muscle. In particular, the goals were to study (1) the involvement of the endothelium in the responses of isolated aortic rings to TD, and (2) the effects of TD at intracellular sites involved in muscle contraction in skinned aortic strips treated with saponin. TD (1–100 µmol/l) decreased noradrenaline (NA) and K⁺-evoked contraction of isolated aortic rings with or without endothelium in a concentration-dependent manner although to a lesser degree with the K⁺-evoked contraction. In NA-contracted rings, the IC₅₀ for TD was approximately 28–30 µ mol/l, at which a 20% decrease in K⁺-force development of aortic rings was observed. The slope of the concentration-relaxation curve was steeper in aortic rings with endothelium than without endothelium (1.09 vs. 0.88) in NA-contracted rings. TD increased tone in acetylcholine (ACh)-relaxed rings but did not change the force in aortic rings relaxed by sodium nitroprusside (NaNP) or ATP. In TD pretreated rings, TD blocked ACh-induced relaxation, but not NaNP or ATP-induced relaxation. In skinned aortic strips, TD decreased Ca²⁺ uptake by the SR (IC₅₀ 77.4 µmol/l slope = 0.88), did not affect Ca²⁺ release from the SR, and decreased Ca²⁺-activation of the contractile proteins at 300 µmol/l TD. The conclusions are that TD prevented endothelium-dependent ACh relaxation by blocking muscarinic receptors, and that the endothelium-independent relaxation is caused by blocking Ca²⁺ entry through the sarcolemma and by the decreased Ca²⁺ uptake by the SR.Correspondence to Judy Y. Su at the above address     

NK-1 receptor antagonists as antitumor drugs: a survey of the literature from 2000 to 2011

Introduction: After binding to the neurokinin (NK-1) receptor, substance P (SP) induces tumor cell proliferation, the migration of tumor cells (invasion and metastasis) and angiogenesis. By contrast, NK-1 receptor antagonists inhibit tumor cell proliferation (tumor cells die by apoptosis), block the migratory activity of tumor cells and exert antiangiogenic properties.

Areas covered: This review offers a 12-year overview of the underlying mechanism of the action of the SP/NK-1 receptor system and NK-1 receptor antagonists in cancer, providing a new approach to the treatment of tumors.

Expert opinion: Chemically diverse NK-1 receptor antagonists have been identified. The antitumor action of these compounds is independent of their chemical structures and such action is associated with their affinity for the NK-1 receptor and with the dose of the antagonist administered. The NK-1 receptor can be considered as a target in cancer treatment and NK-1 receptor antagonists could be considered as new antitumor drugs. The NK-1 receptor antagonist aprepitant is used in clinical practice and exerts an antitumor action against tumor cells in vitro. In the future, such antitumor action should be tested in human clinical trials.     

Presynaptic action of adrenaline on adrenoceptors modulating stimulation-evoked 3H-noradrenaline release from rabbit isolated aorta

Summary The purpose of this investigation was to study the effect of adrenaline on presynaptic adrenoceptors by recording the release of ³H-noradrenaline evoked by electrical-field stimulation. Adrenaline (10^–10–³ × 10^–9 mol/l) had no effect on the ³H-overflow evoked by stimulation of aorta preloaded with ³H-noradrenaline. At 10^–8 and 3 × 10^–8 mol/l, the ³H-overflow was decreased by up to 47%. The maximum decrease was more marked in the presence of either cocaine (3 × 10^–5 mol/l) plus corticosterone (4 × 10^–5 mol/l), cocaine (3.3 × 10^–6 mol/l) plus normetanephrine (4 × 10^–5 mol/l), or desipramine (10^–6 mol/l) plus normetanephrine (10^–5 mol/l). The relationship between adrenaline-induced decrease and stimulation-frequency was dependent on the experimental design: either the decrease was the same at all frequencies (1–16 Hz) or it was more marked, the lower the frequency (1 > 3 > 8 Hz). Phentolamine and rauwolscine (both 10^–6 mol/l) antagonized the inhibitory effect of adrenaline (10 ^{– 8}–10^–6 mol/l). Phenoxybenzamine (10^–6 mol/l), prevented the inhibitory effect. No enhancing effect of adrenaline (10^–9–10^–6 mol/l) was observed in the presence of these three -adrenoceptor antagonists. Our results suggest that adrenaline activates inhibitory ₂-adrenoceptors, but not facilitatory -adrenoceptors on postganglionic sympathetic nerve terminals in rabbit aorta. Send offprint requests to J. Abrahamsen at the above address