Mechanism of action of relaxant effect of Agastache mexicana ssp.mexicana essential oil in guinea-pig trachea smooth muscle

Context: Agastache mexicana ssp. mexicana (Kunth) Lint &; Epling (Lamiaceae), popularly known as ‘toronjil morado’, is used in Mexican traditional medicine for the treatment of several diseases such as hypertension, anxiety and respiratory disorders.

Objective: This study investigates the relaxant action mechanism of A. mexicana ssp. mexicana essential oil (AMEO) in guinea-pig isolated trachea model.

Materials and method: AMEO was analyzed by GC/MS. The relaxant effect of AMEO (5–50?μg/mL) was tested in guinea-pig trachea pre-contracted with carbachol (3?×?10?^??⁶?M) or histamine (3?×?10?^??⁵?M) in the presence or absence of glibenclamide (10?^??⁵?M), propranolol (3?×?10?^??⁶?M) or 2′,5′-dideoxyadenosine (10?^??⁵?M). The antagonist effect of AMEO (10–300?μg/mL) against contractions elicited by carbachol (10?^??¹⁵–10?^??³?M), histamine (10?^??¹⁵–10?^??³?M) or calcium (10–300?μg/mL) was evaluated.

Results: Essential oil composition was estragole, d-limonene and linalyl anthranilate. AMEO relaxed the carbachol (EC_50?=_?18.25?±?1.03?μg/mL) and histamine (EC_50?=_?13.3?±?1.02?μg/mL)-induced contractions. The relaxant effect of AMEO was not modified by the presence of propranolol, glibenclamide or 2′,5′-dideoxyadenosine, suggesting that effect of AMEO is not related to β₂-adrenergic receptors, ATP-sensitive potassium channels or adenylate cyclase activation. AMEO was more potent to antagonize histamine (pA₂′?=??1.507?±?0.122) than carbachol (pA₂′?=??2.180?±?0.357). Also, AMEO antagonized the calcium chloride-induced contractions.

Conclusion: The results suggest that relaxant effect of AMEO might be due to blockade of calcium influx in guinea-pig trachea smooth muscle. It is possible that estragole and d-limonene could contribute majority in the relaxant effect of AMEO.     

Action of a novel potassium channel opener,SR 47063, on human bronchi and on guinea-pig trachea in vitro: comparison with cromakalim

Potassium channels are present on airway smooth muscle cells and their activation results in hyperpolarization and relaxation. Because these effects may have therapeutic relevance to asthma, the aim of our study was to examine the activity of SR 47063, a potassium channel opener (KCO), against a variety of spasmogens or against electrical field stimulation in guinea-pig isolated trachea and in human isolated bronchi in vitro; the effects of SR 47063 were compared with those of cromakalim, isoprenaline, and theophylline. Like cromakalim, SR 47063 reduced the contractility of guinea-pig isolated trachea and the human isolated bronchus in basal tone with pD₂ of 7.79 ± 0.01 and 7.83 ± 0.09, respectively, or during precontractions induced by acetylcholine 10^?4 M, histamine 10^?5 M, or low concentrations of KCl (<30 mM), but not by high KCl concentrations (≥30 mM); these effects were antagonized by glibenclamide 10^?5 M. This spectrum of action is typical of the compounds known as potassium channel openers. Electrical field stimulation (EFS: 16 Hz, 1 ms, 320 mA for 10 sec in the presence of indomethacin 10^?6 M and propranolol 10^?6 M) of guinea-pig isolated main bronchi induced 2 successive contractile responses. Both contractions were reduced significantly by SR 47063 and cromakalim. Although we have not studied the effects of KCOs on exogenous neurokinin A- or substance P-induced contractions, it might be suggested as a hypothesis that this inhibition seems to take place presynaptically and to affect the release of neuromediators produced by electrical field stimulation. In conclusion, SR 47063 exerts in vitro on the bronchial smooth muscle an inhibitory effect which seems to be due to the opening of glibenclamide-sensitive potassium channels. SR 47063 is 3- to 10-fold more potent than cromakalim. © 1993 Wiley-Liss, Inc.     

Discrimination by dipyridamole of two types of responses to adenosine and ATP of the carbachol-induced contraction of guinea-pig trachea

Two types of effect of purines on the carbachol-induced contraction of the guinea-pig trachea in the presence or absence of glucose were evaluated using dipyridamole, an adenosine uptake inhibitor. ATP exerted a greater relaxant effect on the carbachol (10^?6 M)-induced contraction than did adenosine in concentrations ranging from 10^?4 to 10^?3 M. These effects of purines were enhanced by pretreatment with dipyridamole (10^?5 M) but were virtually unaffected by the purine receptor antagonists theophylline (10^?5 M) and quinidine (10^?5 M). The contraction evoked by carbachol was gradually reduced and was almost abolished 4–5 h after exposure to the glucose-free solution. This reduction was almost eliminated by readmitting glucose, and was restored to a certain degree by introducing ATP or adenosine. ATP was less effective than adenosine. This effect of purines but not that of glucose, was markedly diminished by pretreatment with dipyridamole (3 × 10^?6 M to 10^?5 M). The restoration of the carbachol-induced contraction following introduction of purines or glucose was completely antagonized by atropine (10^?6 M). These results suggest that the extracellular effects of adenosine and ATP on the carbachol-induced contraction in normal solution are potentiated by dipyridamole, whereas the possible intracellular effects of these purines in the glucose-free solution are inhibited by this adenosine uptake inhibitor.     

Effect of Dopexamine Hydrochloride on Contractions of Rabbit Isolated Aorta Evoked by Various Agonists

The inhibitory affinity of dopexamine hydrochloride to postsynaptic adrenoceptors, cholinoceptors, 5-hydroxytryptamine and histamine receptors was studied in rabbit isolated aorta. Dopexamine (10^?7–10^?5M) antagonized competitively the contractions of rabbit aorta evoked by noradrenaline (pA₂: 6.60). Neither cocaine plus corticosterone nor cocaine, corticosterone plus propranolol altered the inhibition (pA₂: 6.77 and 6.63, respectively). The antagonism of dopexamine against noradrenaline-evoked contractions was the same after 1 and 4 hr of pretreatment with dopexamine. In the presence of cocaine plus corticosterone, dopexamine antagonized the contractions evoked by phenylephrine (pA₂: 6.94). Removal of endothelium did not influence this antagonism (pA₂: 7.06). Dopexamine (10^?7–10^?5M) did not antagonize the contractions of aorta evoked by histamine (3×10^?7–6 × 10^?5M) and by 5-hydroxytryptamine (3 × 10^?7 –3 × 10^?4M). Dopexamine (10^?8 and 10^?7M) did not alter the contractions of endothelium-free aorta evoked by carbachol. Dopexamine (10^?7–10^?5M) slightly enhanced the contractions of aorta evoked by potassium (10^?2–5.5 × 10^?2M). These results suggest that dopexamine is an α₁-adrenoceptor antagonist. Furthermore, dopexamine has no affinity to cholinoceptors, histamine and 5-hydroxytryptamine (5-HT₂) receptors and is apparently not a calcium antagonist.     

Pharmacology of B-HT 920 in some Isolated Smooth Muscles of the Guinea-pig

Abstract: The effects of B-HT 920 were investigated on four isolated preparations from the guinea-pig, namely the aorta, trachea, ileum and vas deferens. The latter three preparations were studied during electrical field stimulation, which induced contractions by activating cholinergic neurones (trachea and ileum) or adrenergic neurones (vas deferens), respectively. Comparative studies were also made with clonidine and noradrenaline. In ileum and trachea B-HT 920 was almost equipotent with noradrenaline to inhibit the electrically induced contractions. In these tissues, B-HT 920 also displayed almost the same maximal effect as noradrenaline. Clonidine also inhibited the contractions in ileum and trachea; the drug was slightly more potent than noradrenaline. However, in contrast to the intrinsic activity of B-HT 920 that of clonidine was only submaximal. In vas deferens both B-HT 920 and clonidine induced inhibition of contractions on electrical field stimulation at low concentrations. In this organ, both drugs were capable of inducing complete inhibition of the contractile response. In aorta B-HT 920 as well as clonidine were only weak agonists in comparison to noradrenaline. The α₂-blocker, yohimbine, completely blocked the effect of B-HT 920 in ileum at low concentrations (1 × 10^?7 M). Remarkably, however, the inhibitory action of B-HT 920 in trachea was only marginally affected even by high concentrations of yohimbine (1 × 10^?6 M). It is suggested from the present results that B-HT 920 can induce inhibition of both cholinergic and adrenergic neurotransmission presumably by inducing selective stimulation of prejunctional α₂-receptors. In fact, the selectivity of B-HT 920 seems to be comparable to that of clonidine for the α₂-receptor. However, the mode of action of B-HT 920 in trachea may be somewhat uncertain since its effect was not inhibited by yohimbine.     

The role of calcium and alpha-adrenoceptors in contractile response of chick expansor secundariorum muscle to field stimulation

1. The effects of some alpha-adrenergic agonists and antagonists on electrically-evoked contractions and tension of chick expansor secundariorum muscle (ESM), and dependence of these events on extracellular calcium was investigated.2. Both train and continuous electrical stimulation can produce regular contractions in preparations obtained from 40–60 day old chicks.3. Clonidine had a biphasic action on the contractions produced by train electrical stimulation. In concentrations ranging from 10^-8 to 3 × 10^-7 M, clonidine decreased the contraction amplitude, but in higher concentrations, it caused an increase in both the muscle tension and the contraction amplitude. These effects were reversed by application of yohimbine although yohimbine by itself had no effect on the contractions.4. Introduction of calcium free isotonic high potassium medium decreased muscle tone which was followed by further dose-dependent increase in tension, along with the addition of cumulative doses of CaCl₂ (ED₅₀ = 2.8 × 10^-3 M).5. Nifedipine reduced the amplitude of ESM contractions produced by continuous electrical stimulation in a dose dependent manner (IC₅₀ = 6.7 × 10^-7 M).6. Methoxamine induced a completely dose dependent increase in muscle tension which was dependent on extracellular calcium and was inhibited by nifedipine. In the presence of 10^-8 M nifedipine, ED₅₀ of methoxamine stimulatory effect increased from the control value of 2.2 × 10^-7 to 8.4 × 10^-7 M.7. Although BAY-K8644, a calcium channel activator, had no effect on the contraction amplitude produced by continuous electrical stimulation, the muscle tension was increased by this drug in a dose dependent manner (ED₅₀ = 2.2 × 10^-8 M).     

Separate receptors mediating the positive inotropic and chronotropic effect of histamine in guinea-pig atria

The direct positive inotropic effect of histamine was studied on paced left atrial preparations from guinea pigs. Histamine (10^?8 to 10^?4 M) increased the maximum tension developed in left atria incubated at 35°C and driven at 2 Hz. The maximum increase in tension was 60% of that observed with norepinephrine. Metiamide (3 × 10^?5 M; a specific H₂-receptor antagonist) did not alter the inotropic response of left atria to histamine. However, tripelennamine (a typical H₁-receptor antagonist) competitively shifted the histamine inotropic dose—response curve to the right at concentrations from 10^?8 to 10^?7 M. Higher concentrations (3 × 10^?7 and 10^?6 M) caused little further additional shift to the right. The positive chronotropic effect of histamine on spontaneously beating atria was competitively antagonized by metiamide (10^?6 and 3 × 10^?6 M). These results demonstrate that in guinea-pig atria histamine increases myocardial contractility by an interaction with receptors closely related to classical H₁-receptors while its chronotropic effects is mediated by interaction with H₂-receptors.     

An analysis of the B-adrenergic action of oxyfedrine

1-3-methoxy-ω-(1-hydroxy-1-phenylisopropylamino)-propiophenone hydrochloride (oxyfedrine) (10^?8–10^?6 g/ml) produces a positive inotropic effect on electrically driven guinea-pig left atria which is prevented by propranolol; higher concentrations depress contractile force. Oxyfedrine (10^?8–10^?6 g/ml) effectively antagonizes the action of isoprenaline but not that of theophylline ethylenediamine. Oxyfedrine (10^?5 g/ml)-induced relaxation of the guinea-pig tracheal chain is not reversed by repeated washing but is antagonized by propranolol (10^?7 g/ml). The relaxed tracheal chain contracts when an additional dose of oxyfedrine (10^?5 g/ml) or quinidine (10^?5 g/ml) was administered. The oxyfedrine-induced contraction is relaxed by papaverine (5 × 10^?6 g/ml), theophylline ethylene-diamine (10^?5 g/ml) or adenosine (5 × 10^?5 g/ml) but not by isoprenaline (2 × 10^?8 g/ml) or adrenaline (10^?7 g/ml) nor is it prevented by dibenamine (10^?5 g/ml), methysergide (10^?6 g/ml), atropine (10^?5 g/ml) or tripelennamine (10^?7 g/ml). These observations suggest that oxyfedrine interacts with the ß-adrenergic receptor, inducing at adequate concentrations, stimulation and blockade to catecholamines simultaneously; in this interaction, higher concentrations of oxyfedrine produces a direct depression (quinidine-like) of cardiac muscle and a contraction of tracheal muscle.     

Properties of contractions induced by ouabain and K+-free solution in guinea pig taenia coli

The properties of contractions induced by ouabain and by K depletion were studied in comparison with those induced by other stimulants in guinea pig taenia coli. Ouabain 7.5 × 1o^?6 M and K depletion produced biphasic contractions with similar time courses. Both contractions were slightly inhibited by low (0.25 mM) and high (7.5 mM) Ca concentrations, while the high K contraction was strongly inhibited by low Ca and potentiated by high Ca. Contractions induced by ouabain and K depletion were highly sensitive to lowering of the temperature and abolished at 15°C, although contractions induced by carbachol 1.1 × 10^?7 M and histamine 5 × 10^?7 M were still observed below 15°C. In Cl deficient solution substituted by SO₄ or propionate, contractions induced by ouabain and K depletion were potentiated, while contractions induced by high K, carbachol and histamine were suppressed. These results indicate a striking similarity between contractions induced by ouabain and K depletion suggesting a common mechanism for both contractions.     

Interaction between clonidine and histamine on the guinea-pig isolated trachea

In experiments on guinea-pig isolated tracheal spirals, clonidine, in concentrations of 10^?6 to 3 times 10^?4 M. had a contracting effect which was strongly inhibited by prazosin but not significantly modified by yohimbine. Moreover, clonidine (3 times 10^?5 to 3 times 10^?4 M) potentiated histamine-induced contractions; this latter effect was inhibited specifically by α₁-adrenoceptor antagonists (e.g. prazosin, AR-C 239) but unmodified by yohimbine, nicardipine or agents acting on the arachidonic acid cascade. It would therefore appear that clonidine in high concentrations contracts the guinea-pig trachea by stimulating α₁-adrenoceptors and that, contrary to what has been reported with other animal species, notably the dog, the guinea-pig trachea is devoid of α₂-adrenoceptors that mediate contractions.     

Effects of vanadate on mechanical responses and Na-K pump in vascular smooth muscle

The effects of vanadate on tension and on the Na-K pump in isolated guinea-pig aorta were investigated. Vanadates (NH₄VO₃ or Na₃VO₄ · nH₂O) (10^?3 M) produced a sustained contraction (about 0.5 g) which was not influenced by phentolamine (10^?6 M). In the absence of external Ca, vanadate and norepinephrine (2 × 10^?6 M) induced a small contraction, although high K (45.4 mM) did not. In a Ca-depleted, high K (142.2 mM) solution, vanadate and norepinephrine still caused muscle contraction. D600 (10^?6 M) slightly inhibited the contractions induced by vanadate and norepinephrine, while this agent completely inhibited the contraction induced by high K. Sodium nitroprusside (10^?5 M) strongly inhibited the contractions induced by vanadate and norepinephrine but not the contraction induced by high K. Vanadate produced a contraction in K-free solution with ouabain (10^?4 M). The tissue K content did not change during a 2 h treatment of the muscle with vanadate. Reaccumulation of K following a 3 h treatment of the muscle with K-free solution was inhibited by ouabain but not by vanadate. These results indicate a similarity between the contractions induced by vanadate and by norepinephrine and suggest that the vanadate-induced contraction is not due to an inhibition of the Na-K pump.     

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.     

Inhibition by (−)-Deprenyl of Agonist-Evoked Contractions in Rabbit Aorta

Abstract: The effect of (?)-deprenyl, a relatively selective MAO-B inhibitor, was examined for its ability to inhibit the contractions of rabbit isolated aorta evoked by various agonists and potassium. (?)-Deprenyl (10^?5?3 × 10^?4 M) antagonized the contractions evoked by noradrenaline (10^?8?3 × 10^?4 M); pA₂: 5.10. The antagonism was reversible. It was attenuated by cocaine (3x M); pA₂: 4.38, unchanged by corticosterone (4 × 10^?5 M); pA₂ 4.79 and enhanced by cocaine (3 × 10^?5 M) plus corticosterone (4 × 10^?5 M); pA₂: 5.48. (+)-Deprenyl (10^?6?10^?4 M) did not alter the contractions evoked by noradrenaline (3 × 10^?9?10^?4 M). Clorgyline (10^?5 and 10^?4 M) antagonized the noradrenaline-evoked contractions. Pargyline (10^?4 and 3 × 10^?4 M) had no effect. (?)-Deprenyl (10^?5?3 × 10^?4 M) antagonized the contractions evoked by phenylephrine (10^?8?10^?4 M); pA₂: 5.10. Removal of the endothelium did not alter the antagonism; pA₂: 5.35. (?)-Deprenyl (10^?5?3 × 10^?4 M) antagonized the contractions evoked by either 5-hydroxytryptamine (3 × 10^?8?3 × 10^?4 M); pA₂: 4.61 or by histamine (10^?6?3 × 10^?2 M); pA₂: 4.84. (?)-Deprenyl (3 × 10^?4 M) caused a non-competitive antagonism of the contractions evoked by potassium (1.5-5.5 × 10^?2 M). It is concluded that (?)-deprenyl is a weak inhibitor of postjunctional α-adrenoceptors, 5-hydroxytryptamine (5-HT₂) receptors, and histamine (H₁) receptors.     

Mechanism of action of histamine in the estrogen-primed rat uterus

Histamine produced a dose-dependent relaxation of uterine strips obtained from the estrogen-primed rat uterus. The responses to histamine were blocked competitively by metiamide (10^?8 ?10^?8M), a specific H₂-receptor antagonist. Propranolol, a selective β-receptor blocker also produced competitive antagonism of the responses to histamine in the same dose range (10^?8?10^?6 M). The pA₂ value obtained for metiamide (8.9) was not significantly different from that obtained for propranolol (8.6). Nialamide (2.2 × 10^?6 M), the monoamine oxidase inhibitor, and cocaine (4.3 × 10^?6 M), the selective noradrenaline uptake blocker, potentiated the responses to histamine. However bretylium (2.4 × 10^?5 M), an adrenergic neuron blocker inhibited the responses to histamine. The combined effect of tyramine and histamine was found to be additive. Our data suggest that the histamine-induced relaxation of rat uterus may be produced through the stimulation of presynaptic H₂-receptors which causes the release of noradrenaline. The released noradrenaline acts on the postsynaptic β-receptors and produces relaxation of the rat uterus.     

A comparison of histamine effects on the sympathetic neurotransmission of testicular capsule and rat vas deferens

Histamine is an important modulatory agent of the sympathetic neurotransmission, but its exact action on the testicular capsule or rat vas deferens is not fully understood. The present study sought to further investigate the functional effects of histamine on the neuronal and exogenous noradrenaline-induced contraction of the testicular capsule and rat vas deferens as well as to evaluate the contractile properties of this drug. The testicular capsule or vas deferens from Wistar rats, 3–4 months old, weighing 300–400 g, was isolated and mounted in organ baths for functional experiments. The results indicated that the neuronally evoked contraction of the testicular capsule was affected by histamine (10^?10 to 10^?8 M) with participation of inhibitory (H₃ receptors) and excitatory (H₁ receptors) receptors. Histamine (10^?7 to 10^?4 M) modulated the field-stimulated vas deferens by excitatory (H₂ receptors) and inhibitory (H₁ receptors) receptors. Histamine was able to decrease the tonic response for noradrenaline-induced contractions with participation of H₁ receptors (testicular capsule) and H₃ receptors (vas deferens) followed by nitric oxide generation. At high concentration, histamine exerts contractile effects in both tissues. In the testicular capsule, the histamine-induced contractions were related to H₁ receptor activation followed by release of prostaglandins. In contrast, the contractile effects of histamine in the vas deferens were related to H₂ receptor activation followed by release of catecholamines from sympathetic nerve endings. Therefore, our results indicate that histamine induced several effects on the sympathetic neurotransmission of rat testicular capsule and vas deferens. These effects are dependent on the concentration used and with participation of multiple histamine receptors.     

Dual Effect of the Muscarinic Agonist McN-A-343 on Vascular Neuroeffector Transmission

Abstract: The site and mechanism of action of McN-A-343 (4-m-chlorophenylcarbamoyloxy)-2-butynyltrime-thylammonium chloride) on sympathetic neuroeffector transmission in the rabbit isolated pulmonary artery was studied. Low concentrations (10^?6 — 3 × 10^?5 M) of McN-A-343 and cocaine enhanced (up to 210 and 236%, respectively) the contractions evoked by electrical-field stimulation, while higher concentrations (10^?4 — 3 × 10^?4 M) inhibited them. McN-A-343 (10^?4 M) caused an initial transitory potentiation (222% of control) of the stimulation-evoked contractions followed by an inhibition. In the presence of cocaine (3 × 10^?5 M), the potentiation caused by McN-A-343 was prolonged and the secondary inhibitory phase was thus abolished. Physostigmine (10^?5 — 10^?4 M), hexamethonium (10^?5 M), atropine (3 × 10^?7 M), suprofen (10^?5 M), and 4-aminopyridine did not alter the effect of McN-A-343 (10^?4 M). Cocaine (3 × 10^?5 M)and(+)-amphetamine (10^?5 M) reversed the McN-A-343-evoked block, while they did not alter the inhibition caused by tetracaine (3.2 × 10^?5 M). Atropine (3 × 10^?7 M) had no effect on the McN-A-343-induced block, while 4-aminopyridine (10^?4 M) caused a partial and transitory reversal. On the aorta McN-A-343 (10^?4 M) did not alter the contractile concentration-response curve of (—)-noradrenaline (10^?9 — 3 × 10^?4 M), while that of serotonin (10^?8 — 3 × 10^?5 M) was moved to the right in a competitive manner. McN-A-343 (10^?4 M) did not alter the contractions evoked by noradrenaline (10^?7 M) during the period corresponding to the stimulation-evoked enhancement and subsequent inhibition. McN-A-343 (10^?4 M) slightly antagonized the contractions caused by tyramine (10^?6 — 10^?3 M) and carbachol (10^?6 — 10^?3 M). It is concluded that McN-A-343 enhances stimulation-evoked transmitter release by a presynaptic facilitatory action mediated via receptors localized on the outer surface of adrenergic neurones and to a lesser extent by inhibition of noradrenaline re-uptake. The enhancement does not involve presynaptic nicotine or muscarine receptors. Furthermore, McN-A-343 inhibits transmitter release by acting as an adrenergic neurone blocking agent at an intraneuronal site. The inhibition does not involve presynaptic muscarine inhibitory receptors and is prostaglandin-independent.     

Effects of S 9977-2 on the guinea pig isolated trachea and the human isolated bronchus

The effects of S 9977-2, a new compound which belongs to the trimethylxanthine family and has shown in vivo promnesic activity and in vitro acetylcholinesterase activities inhibition, were studied on the guinea pig isolated trachea and on human isolated bronchi. On the guinea pig isolated trachea, S 9977-2 in concentrations of 10^?7–10^?4 M potentiated the contractile effect of acetylcholine. The potency of acetylcholine was increased 3.39, 4.26, 9.54, and 13.18 fold with concentrations of 10^?7, 10^?6, 10^?5, and 10^?4M, respectively. The maximum effect of acetylcholine was not modified. S 9977-2 did not potentiate the effects of carbachol or pilocarpine. Under similar conditions, eserine (10^?8 and 10^?6M) and tacrine (10^?8–10^?6M) also potentiated the effects of acetylcholine. The potentiating effect of these two substances was stronger than that of S 9977-2, with a 44.7 fold increase for eserine (10^?7M) and a 64.6 fold increase for tacrine (10^?6M). However, both eserine and tacrine had a contractile effect of their own on the guinea pig isolated trachea, whereas S 9977-2 had no such effect. On the human isolated bronchus, S 9977-2 at a concentration of 10^?5M produced a 19.1 fold increase of acetylcholine effects. On the guinea pig isolated trachea, the effects of S 9977-2 vs. acetylcholine were not modified by epithelium removal. They were increased by pretreatment with indomethacin 10^?6M. In very high concentrations (10^?4 and/or 10^?3M), S 9977-2 reduced the effects of histamine and those of serotonin on the guinea pig isolated trachea. S 9977-2 had no effect on the contractile action of potassium chloride or on the relaxant action of adenosine. The results suggest that in the airway smooth muscle S 9977-2 partially inhibits acetylcholinesterase and/or pseudocholinesterase activity. © 1992 Wiley-Liss, Inc.     

Effects of suramin on electrical and mechanical activities in antrum smooth muscle of the guinea-pig stomach

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Effect of the Hydroalcoholic Extract of Rauwolfia ligustrina on Smooth and Cardiac Muscles In-vitro

The actions of the hydroalcoholic extract (HE) of Rauwolfia ligustrina (the whole plant) on agonist-induced contractions were analysed in the rat uterus and guinea-pig ileum and trachea, and also in rat atrium contracting spontaneously in-vitro. The HE (100–400 μg mL^?1) caused concentration-dependent rightward shifts of the concentration-response curves and reduced the maximal contraction induced by oxytocin, bradykinin, angiotensin II, prostaglandin F_2α and acetylcholine in the rat uterus. The calculated mean IC50 values were: 300, 147, 158, 197 and 105 μg mL^?1, respectively. In the guinea-pig ileum the HE also caused graded displacement to the right of the concentration—response curves for bradykinin, histamine and carbachol, associated with pronounced inhibition of the agonist-induced maximal contractions. The calculated mean IC50 values were 165, 134 and 241 μg mL^?1, respectively. The HE (100–3000 μg mL^?1) caused graded relaxation (IC50 of 271 μg mL^?1) of strips of guinea-pig trachea precontracted with carbachol (0.2 μM). This effect was not infuenced by propranolol (1 μM), 3-isobutyl-1-methylxanthine (1 μM) or methylene blue (10 μM), but was significantly potentiated (1.5-to 3-fold) by indomethacin (3 μM) and forskolin (1 nM). In addition, N^G-monomethyl-L-arginine (L-NMMA, 100 nM) significantly reduced the HE-induced maximal relaxation, while indomethacin (3 μM) potentiated the HE response. Finally, the HE caused a concentration-dependent and long-lasting inotropic effect in the rat right atrium, contracting spontaneously with a mean EC50 value of 409 μg mL^?1. It is suggested that the effects of the HE of R. ligustrina on smooth and cardiac muscles ‘in-vitro’ may result from its ability to interact, at least partially, with the cAMP pathway.     

Inhibition of ATP-Induced Contraction in the Guinea-pig Urinary Bladder in Vitro and in Vivo

Abstract Contractions were elicited by adenosine 5′-triphosphate (ATP) in the guinea-pig urinary bladder in vitro and in vivo. In isolated detrusor strips, tetrodotoxin (3.1 × 10^-6-4.4 × 10^-5M) did not affect contractions induced by a submaximum concentration (10^-3M) of ATP, nor did atropine (1.7 × 10^-6 - 2.1 × 10^-4M), or the anticholinergic agent PR 197 within the concentration range 2.6 × 10^-8 - 2.6 × 10^-5M. In higher concentrations (5.2 × 10^-5-2.6 × 10^-4M), PR 197 inhibited the ATP-response by 60-70% in a way that was not clearly concentration-related. Isoprenaline (10^-7-2.0 × 10^-5M) and noradrenaline (2.5 × 10^-6-10^-4M) reduced the ATP-induced contractions by up to 79%. The effects of the amines were abolished by propranolol (5.2 × 10^-6-3.8 × 10^-5M). Adenosine, 1.0-2.0 × 10^-2M, reduced the ATP-response by about 50%; in lower concentrations, it had no effect. Nifedipine, 7.8 × 10^-7-1.2 × 10^-5M, reduced the responses by 15-795%. Indomethacin (≤2.0 × 10^-4M), and theophylline (2.0 × 10^-4M) had no consistent effects on ATP-induced contractions. Exposure of the preparations to a calcium-free medium reduced and abolished the ATP-response within 60 min. Intravenous injection of ATP (1 -20 mg/kg) caused a rapid and transient increase in intravesical pressure in the anaesthetized guinea-pig. The effect of ATP (3mg/kg) was reduced by atropine(5-10 mg/kg) by approximately 35%. PR 197 (2.5-5 mg/kg) abolished the ATP-response. Isoprenaline (5-100 pg/kg) caused a 53-95% inhibition that could be blocked by propranolol (1 mg/kg). The inhibiting effect of noradrenaline (10-100,μg/kg) could not be blocked by propranolol (1 mg/kg). Adenosine (1.5-3.0 mg/kg) given immediately before ATP completely inhibited the ATP-response. Nifedipine, 0.1-0.2 mg/kg, reduced the ATP-induced contraction by 34 to 100%. It is concluded that the ATP-induced contraction is elicited by a direct effect on the smooth muscle cell. It can be inhibited non-specifically by drugs with different modes of action.