Depolarization of membrane potential and the smooth muscle contraction by isothiocyanatobenzyl imidazoline in guinea-pig stomach circular muscle

Isothiocyanatobenzyl imidazoline (IBI) produces characteristic slowly developing contraction of many smooth muscle preparations including the circular smooth muscle of the guinea-pig stomach. Changes in the membrane potential were recorded intracellularly, and the muscle contraction induced by IBI was investigated. IBI at 100 micromol/l slowly produced a sustained depolarization of the membrane with a maximum change of approximately 15 mV. This depolarization could not be blocked by 1-hyoscyamine, 100 nmol/l. An imidazoline analogue, oxymetazoline at 1 micromol/l, did not change the resting membrane potential as observed after IBI. Significant membrane depolarization after IBI still occurred in Ca2+-free medium. During IBI-induced depolarization, sudden reduction of Na+ to 30 mmol/l in the medium reduced the depolarization slightly. IBI-induced depolarization was additive with that produced by 20 mmol/l K+ in the medium. In the presence of tetraethylammonium chloride or levcromakalim or nifedipine, IBI continued to depolarize the membrane although functional pharmacological experiments showed that the contractile effects of IBI were significantly inhibited by 30 micromol/l levcromakalim and abolished by 100 nmol/l nifedipine. At 100 micromol/l phentolamine (reported by others as an inhibitor of ATP-sensitive potassium channels) completely blocked IBI-induced contraction. Phentolamine (30 micromol/l) blocked the contractile effects of IBI by 50%. On the other hand, S(-)-Bay K 8644, a voltage-dependent calcium channel activator, was additive with the contractile response of IBI. These results indicated that IBI produced membrane depolarization and contraction of the guinea-pig stomach circular muscle, by a mechanism not involving muscarinic receptors or alpha-adrenoceptors. Even though levcromakalim, an ATP-sensitive potassium channel opener, could not inhibit IBI-induced depolarization, the ATP-sensitive potassium channel and the voltage-dependent calcium channel may be intrinsically linked with the action of IBI.     

Effects of cromakalim on acetylcholine release and smooth muscle contraction in guinea-pig small intestine

Summary The effects of the potassium channel opener cromakalim on smooth muscle contraction and ³H-acetylcholine release were studied simultaneously in guinea-pig longitudinal muscle myenteric plexus preparations which had been preincubated with ³H-choline. Cromakalim (10 mol/1) inhibited more markedly the smooth muscle contractions caused by the release of endogenous acetylcholine (via electrical stimulation or via activation of nicotine- and 5-HT₃-receptors) than contractions induced by pilocarpine. Cromakalim (10 ~mol/1) did not affect the release of ³Hacetylcholine evoked by electrical stimulation or by stimulation of nicotine- and 5-HT₃-receptors. In contrast, the release of ³H-acetylcholine caused by stimulation of M₁-receptors was concentration-dependently reduced by cromakalim (1–100 gmol/1). The results suggest that the relaxant effect of cromakalim on smooth muscle contraction is not caused by a reduction of acetylcholine release from myenteric neurones. An opening of cromakalim-sensitive potassium channels may be involved in the inhibition of the M₁-receptor mediated acetylcholine release.This work was supported by the Deutsche Forschungsgemeinschaft (Ki 210/6-3). Send offprint requests to H. Schwörer at the above address     

The sources of calcium for carbachol-induced contraction in the circular smooth muscle of guinea-pig stomach.

1. The action of carbachol on the mechanical activity of circular muscle from guinea-pig upper stomach was studied. High concentrations of carbachol (e.g. 10(-4) M) produced a rapid phasic contraction followed by a smaller, sustained tonic contraction. Low concentrations (e.g. 10(-7) M) caused a contraction which did not generally show marked distinction between phasic and tonic components. 2. The response to 10(-7) M carbachol was very sensitive to 10(-5) M nifedipine as was the phasic response to 10(-4) M carbachol. The tonic contraction to the latter, however, was only slightly reduced by nifedipine. 3. The carbachol-induced contractions remaining in the presence of nifedipine were dose-related and very dependent on the presence of external calcium. 4. Carbachol, 10(-7) M, did not produce a contraction after 4 min exposure to calcium-free solution whereas 10(-4) M carbachol did and this was phasic in nature but much reduced relative to the control in normal Ca. 5. A phasic followed by a small tonic contraction to 10(-4) M carbachol was seen superimposed on the K contracture in tissues depolarized with 100 mM K, whereas only a small tonic response occurred for 10(-7) M carbachol. 6. In the absence of a functional carbachol-sensitive intracellular store, 10(-4) M carbachol was unable to trigger a contraction in calcium-free solution. However, when calcium was simultaneously readmitted with carbachol after exposure to calcium-free solution, a contraction occurred. 7. Carbachol, 10(-7) M, did not significantly increase inositol polyphosphate levels, whereas 10(-4) M carbachol did.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of cromakalim on neurally-mediated responses of guinea-pig tracheal smooth muscle.

1. The ability of cromakalim to modulate several different types of neuroeffector transmission has been assessed in guinea-pig isolated trachea. 2. In trachea treated with propranolol (10(-6) M) and indomethacin (2.8 x 10(-6) M), stimulation of the extrinsic vagal nerves evoked contractions which were blocked by hexamethonium (5 x 10(-4) M) or by tetrodotoxin (TTX; 10(-6) M). Cromakalim (10(-5) M) caused a two fold rightward shift of the frequency-response curve. 3. In carinal trachea treated with propranolol and indomethacin, transmural stimulation evoked an initial, rapid contraction followed by a more sustained secondary contraction. The initial, rapid contractile response was virtually ablated by atropine (10(-6) M) or by TTX but was resistant to hexamethonium. Cromakalim (10(-8)-10(-5) M) caused a concentration-dependent rightward shift of the frequency-response curve for the initial contraction. 4. In carinal trachea treated with atropine, propranolol and indomethacin, transmural stimulation evoked only the secondary (non-adrenergic, non-cholinergic (NANC] contractile responses. These were markedly reduced by TTX but were resistant to hexamethonium. Cromakalim (10(-8)-10(-5) M) suppressed the NANC contractile responses in a concentration-dependent manner. This action could be offset by glibenclamide (10(-6) M). 5. In trachea treated with atropine, histamine (10(-4) M), propranolol and indomethacin, transmural stimulation evoked NANC relaxant responses. Cromakalim (up to 10(-5) M) was without effect on the frequency-response curve for the stimulation of NANC inhibitory nerves. 6. Tested on trachea bathed by drug-free Krebs solution, cromakalim (10(-7)-10(-5) M) caused concentration-dependent suppression of tracheal tone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Carbachol-induced contraction in the circular muscle of guinea-pig stomach in calcium-free solution.

In the circular muscle of the fundic part of the guinea-pig stomach, a small tonic contraction could be repeatedly produced by carbachol in Ca-free solution containing 2 mM EGTA. The carbachol-induced response was gradually increased during prolonged exposure to Ca-free solution for 50 h, whereas a short treatment with 0.1-0.2 mM Ca suppressed the subsequent carbachol response in Ca-free solution. The response was not essentially modified by increasing the external K+ concentration to 40 mM. Calmodulin antagonists, N-(6-aminohexyl)-5-chloro-1-naphthalene sulphonamide (W-7) and trifluoperazine selectively suppressed the carbachol response in the presence of Ca (0.05 mM) and the contraction induced by Ca (0.1 mM), but they had little effect on the response to carbachol in Ca-free solution at a concentration of less than 10 microM. A vasodilator agent, N-(2-guanidinoethyl)-5-isoquinoline sulphonamide (HA-1004), inhibited the carbachol response both in the presence and absence of Ca, as well as the Ca-induced contraction, to a similar extent, provided that the external Ca concentration was less than 0.1 mM. These results led us to propose that the contraction evoked by carbachol in the absence of external Ca is mediated by a process independent of the Ca-calmodulin system.     

Catecholamines act as alpha 2-adrenoceptors to cause contraction of circular smooth muscle of guinea-pig stomach

Circular smooth muscle strips taken from the body region of the guinea-pig stomach responded to dopamine and noradrenaline with contraction at lower concentrations followed by relaxation at higher concentrations. A beta-adrenoceptor-mediated relaxation response was excluded by propranolol treatment and this allowed the remaining alpha-adrenoceptor involvement with relaxation and contraction to be incisively differentiated in terms of two distinct alpha-adrenoceptor mechanisms. Thus, the relaxation responses to the catecholamines were mimicked by phenylephrine and antagonized by prazosin, phentolamine but not by yohimbine or rauwolscine. In contrast, the catecholamine-induced contractions were mimicked by clonidine and antagonized by yohimbine and phentolamine but not by prazosin. It is therefore concluded that the alpha mechanisms via which dopamine and noradrenaline are able to relax and contract the circular smooth muscle from the body region of guinea-pig stomach are of the alpha 1- and alpha 2-type respectively.     

Field stimulation-induced responses of circular smooth muscle from guinea-pig stomach

Summary Field stimulation of circular smooth muscle of guinea-pig stomach from the regions of the cardia and fundus caused contraction responses at low stimulation frequencies (0.25–1 Hz) with relaxation at higher frequencies (1–10 Hz), whilst tissues of the body and antrum responded with contraction throughout the frequency range. Atropine (10^–9–10^–8 M) antagonised the contraction responses of all tissues, with relaxation developing at higher concentrations (except for antral tissue). In contrast, metoclopramide (10^–8–10^–6 M) caused modest (cardia, fundus) or marked (body, antrum) enhancement of contractions to field stimulation, whilst domperidone (10^–8–10^–7 M), haloperidol (10^–8–10^–6 M), prazosin, propranolol and methysergide (10^–8–10^–6 M) failed to modify the contraction responses. However, whilst yohimbine and guanethidine failed to modify the contractions of the cardia, fundus and body tissues, those of the antral preparations were antagonised by nanomolar concentrations of yohimbine and by guanethidine (10^–6–5×10^–5 M). To optimise the relaxation responses for study, atropine was included in the physiological solution. Relaxation to field stimulation of preparations from the body and cardia, but not the fundus, was antagonised by reserpine pretreatment (5 mg/kg i.p., 24h), addition of guanethidine (10^–5–10^–4 M), phentolamine, prazosin or propranolol (10^–7–10^–6 M) (the effects of prazosin and propranolol being additive). Higher concentrations of haloperidol and domperidone antagonised the relaxation responses of the body preparations only. Metoclopramide, yohimbine and methysergide (10^–8–10^–6 M) were ineffective. Thus, it is concluded that the contractile effects of the 4 stomach areas to field stimulation reflects a major cholinergic involvement, with an additional ₂-adrenoceptor contractile component in antral tissue. Relaxation responses of cardia and body tissue involve ₂- and -adrenoceptors plus a further, unidentified, non-adrenergic component; the latter represents the total relaxation response of the fundic preparation.     

Effects of cromakalim on the electrical slow wave in the circular muscle of guinea-pig gastric antrum.

1. In circular muscle strips of the antrum of guinea-pig stomach, the effects of cromakalim were studied on mechanical activity and intracellular membrane potential. 2. Cromakalim inhibited mechanical activity at concentrations higher than 1 microM, accompanied by membrane hyperpolarization and a decrease in membrane resistance. The hyperpolarization was markedly potentiated in K(+)-free solution and was still observed in the absence of Na+. 3. Slow wave electrical activity was relatively resistant to cromakalim. Changes in its amplitude and frequency were not consistent but blockade of slow waves was never observed. In many preparations cromakalim induced spike-like potentials at the top of slow waves, or when spike-like potentials already existed they were potentiated. However, mechanical activity was always inhibited. 4. Inhibition by cromakalim of the phasic contractions associated with the slow waves, could not be reversed by increasing the external K+ concentration (12-30 mM). 5. The results suggest that in guinea-pig stomach muscle mechanical suppression by cromakalim does not simply result from membrane hyperpolarization or from inhibition of slow waves. A clear dissociation was found between the mechanical and electrical activities. Slow waves, particularly their frequency, are relatively insensitive to membrane hyperpolarization.     

The effect of cromakalim on the smooth muscle of the guinea-pig urinary bladder.

1. The actions of cromakalim were studied on the detrusor muscle from guinea-pig urinary bladder. Cromakalim reduced the frequency and amplitude of spontaneous contractile activity of the smooth muscle of the guinea-pig urinary bladder at 5 x 10(-8)M and abolished the activity at concentrations above 5 x 10(-7)M. 2. Electrophysiological experiments demonstrated that cromakalim increased membrane conductance, caused a dose-dependent hyperpolarization of the cell membrane and loss of spike activity. These events are consistent with the opening of K+ channels. 3. The effects of 10(-6)M and 10(-5)M cromakalim on the contractile responses to carbachol, potassium and transmural nerve stimulation were studied. Cromakalim did not prevent the detrusor from responding to these agents, although it significantly reduced the contractile response to K+ at concentrations below 70 mM. 4. Uptake and efflux experiments using 86Rb+ were unable to demonstrate any significant effect on transmembrane movement produced by cromakalim (10(-5)M). 5. 43K+ efflux showed a dose-dependent increase in the rate constant on addition of cromakalim. The difference in the selectivity for K+ over Rb+ was confirmed in dual label uptake experiments. 6. Substitution experiments in which the K+ ions in the tissue were gradually replaced by Rb+ demonstrated that cromakalim had a progressively decreasing effect on spontaneous activity as internal K+ was lowered. When all the K+ was replaced by Rb+, cromakalim no longer inhibited spontaneous activity, confirming that the channel opened by cromakalim appears relatively impermeant to Rb+.     

Effect of cromakalim on smooth muscle cells of guinea-pig taenia caeci

Cromakalim caused hyperpolarization and reduction of the electrotonic potential in a concentration-dependent manner in smooth muscle cells of guinea-pig taenia caeci. There was a relatively constant change in the electrotonic potential under calcium-free, low-sodium and low-chloride conditions in the presence of cromakalim as compared to control conditions with Krebs solutiuon. The effect of cromakalin (10(-5) M) was inhibited by glibenclamide (5 X 10(-5) M). These results indicate that cromakalim specifically promotes potassium efflux in smooth muscle cells of the guinea-pig taenia caeci via glibenclamide-sensitive potassium channels, to cause hyperpolarization, suppression of spike activity and relaxation.     

Investigation into the 5-hydroxytryptamine-induced relaxation of the circular smooth muscle of guinea-pig stomach fundus.

The 5-HT receptor that mediates relaxation of circular muscle strips of the guinea-pig stomach fundus under resting tone was investigated. Concentration-dependent relaxation was obtained in the presence of atropine (0.2 microM) with 5-hydroxytryptamine (5-HT) (apparent mean pEC50 value, 5.27), 5-carboxamidotryptamine (7.35), 5-methoxytryptamine (4.98) and 5-methyltryptamine (4.58). 1-(m-Trifluoromethyl-phenyl)piperazine and 8-hydroxy-2-(di-n- propylamino)tetralin acted as partial agonists while 2-methyl-5-hydroxytryptamine, alpha-methyl-5-hydroxytryptamine, sumatriptan, metoclopramide and cisapride had little or no effect on the guinea-pig stomach fundus. The concentration-response curve for 5-HT was not affected by tetrodotoxin (0.3 microM), guanethidine (5 microM) or indomethacin (2 microM), suggesting that the relaxation is non-neuronal in origin and is independent of the release of catecholamines or prostanoids. The non-selective 5-HT receptor antagonist, metitepine (0.03-0.1 microM), the 5-HT1C/5-HT2 receptor antagonists, mianserin (0.3-1 microM), pizotifen (0.3-1 microM), ketanserin (3-10 microM), and the 5-HT1A/5-HT2 receptor antagonist, spiperone (3 microM), shifted the concentration-response curves for 5-HT to the right. A 5-HT3 receptor antagonist, ICS205-930 (1 microM), propranolol (1 microM) and phentolamine (1 microM) failed to block the 5-HT-induced relaxation. In conclusion, the results found with agonists and antagonists are compatible with the view that a 5-HT1-like receptor is involved in 5-HT-induced direct relaxation of circular muscle of guinea-pig stomach fundus.     

Apomorphine contracts and relaxes circular smooth muscle of guinea-pig stomach via action on adrenoceptor mechanisms

Summary Nanomolar concentrations of apomorphine caused contractions of the circular smooth muscle from the body region of the guinea-pig stomach, the response showing rapid tachyphylaxis. These contractions were antagonised by yohimbine but not by prazosin, haloperidol, propranolol or methysergide. Higher concentrations of apomorphine caused concentration-related relaxations of the stomach body which were not subject to tachyphylaxis. These were antagonised by propranolol but not by prazosin, yohimbine or haloperidol. Dopamine-induced contractions of the circular smooth muscle from the stomach body were antagonised by apomorphine in nanomolar concentration; acetylcholine-induced contractions and isoprenaline-, dopamine- and phenylephrine-induced relaxations were unaffected by apomorphine. Thus, it is concluded that the contraction of circular smooth muscle from the stomach body to apomorphine is mediated via an adrenoceptor with characteristics of the ₂-type, and that a partial agonist-antagonists action prevents subsequent contractile responses to apomorphine and dopamine. Relaxation caused only at higher concentrations of apomorphine is mediated via an adrenoceptor with characteristics of the -type.     

Pardaxin produces postjunctional muscle contraction in guinea-pig intestinal smooth muscle.

The action of pardaxin (PX), a toxin isolated from the secretion of the Red Sea flatfish, Pardachirus marmoratus, was studied on longitudinal muscle of guinea-pig ileum. Pardaxin contracted the ileum and subsequently abolished muscle contraction to 5-hydroxytryptamine (5-HT), but did not affect the responses to acetylcholine (ACh) and substance P(SP). Pardaxin-induced contraction was only partially suppressed by atropine and not affected by tetrodotoxin or morphine. Preparations desensitized to 5-HT or SP responded normally to pardaxin. Pardaxin-induced contractions were normal in K+-depolarizing Krebs Ringer solution and not affected by black widow spider venom. It is concluded that the pardaxin-induced muscle contractions are not mediated through the release of neurotransmitters and do not involve 5-HT, SP or ACh receptors, but are due to a direct action on the muscle contractile mechanism.     

Mechanism of vanadate-induced contraction of airways smooth muscle of the guinea-pig.

The characteristics of vanadate-induced contraction of airways smooth muscle are described in isolated preparations of guinea-pig central and peripheral airways. Vanadate (1-1000 microM) induced sustained contractions of trachea and lung parenchymal strips within 1 min of challenge. It was more potent (P less than 0.001) on the lung strip (EC50 = 63 microM) than on the trachea (EC50 = 123 microM). The lung strip also developed greater maximum isometric tension (P less than 0.001) than the trachea. The efficacy on the lung strip was 2 and the trachea 0.6, relative to the response to acetylcholine (efficacy = 1). Vanadate-induced contractions of the trachea were not inhibited by atropine, mepyramine, phentolamine or indomethacin, nor after mast cell depletion by compound 48/80, showing that contractions were not mediated via specific receptors or by release of endogenous mediators of tone. Inorganic phosphate specifically inhibited vanadate responses in a dose-dependent and reversible manner, suggesting a common site of action. Contractions could be elicited in depolarized muscle and after treatment with ouabain plus propranolol, showing that membrane depolarization and inhibition of the Na, K-ATPase system were not involved in the contractile action of vanadate. Pretreatment of tracheal smooth muscle with verapamil had no influence on contractions elicited by vanadate. After removal of extracellular calcium, vanadate-induced contractions declined slowly with time, indicating that influx of extracellular calcium was not giving rise to contractions elicited by vanadate. Vanadate markedly increased the rate of calcium efflux from trachealis muscle loaded with 45Ca into both Ca2+-free and normal Krebs solutions; this is compatible with vanadate mobilizing an intracellular store of Ca2+. Such a store involving sites with Ca-ATPase activity would be consistent with the action of vanadate in isolated membrane preparations. Membrane-skinned tracheal fibres contracted by micromolar Ca2+ were relaxed by vanadate in a reversible dose-related manner, indicating that the contractile action of vanadate was not related to its interaction with proteins at the cross-bridge level.     

Effects of histamine on the guinea-pig stomach: excitation of smooth muscle and inhibition of transmitter release.

1 The effects of histamine on electrical responses of smooth muscle cells of the guinea-pig stomach were studied. 2 In the fundus, histamine (above 10(-6) M) depolarized the membrane and decreased the membrane resistance. In the antrum, the slow waves were enhanced by histamine, without change in the resting membrane potential or membrane resistance (10(-7)-10(-6) M), or with depolarization of the membrane (above 10(-5) M). 3 When the effects of histamine on neuromuscular transmission were estimated from changes in the amplitude of junction potentials, the amine (above 10(-7) M) inhibited the excitatory junction potential (e.j.p.) recorded in the fundus. Inhibitory junction potentials (i.j.p.) recorded in the antrum and atropine-treated fundus were also inhibited by histamine. 4 Repolarization of the histamine-induced depolarization to the resting potential level did not restore the amplitude of the e.j.p. to the control value. 5 These actions of histamine on the smooth muscle cells and on junction potentials were inhibited by either mepyramine or cimetidine, agents which block the H1- and H2-receptor, respectively. 6 It is concluded that in the guinea-pig stomach, histamine exerts a direct excitatory effect on the smooth muscle cells and has inhibitory actions on cholinergic excitatory and non-adrenergic, non-cholinergic inhibitory transmission.     

骆驼蓬总生物碱对豚鼠离体气管平滑肌收缩功能的影响

目的研究骆驼蓬总生物碱对刺激因素诱发的豚鼠气管平滑肌收缩的影响。方法制备豚鼠离体气管平滑肌螺旋条,于恒温浴槽装置中,用乙酰胆碱、组胺和KCl刺激气管平滑肌,观察药物的作用。结果骆驼蓬总碱和鸭嘴花碱均可使乙酰胆碱、组胺的刺激量-效曲线明显右移,并呈剂量依赖性地抑制乙酰胆碱、组胺和KCl诱发的豚鼠气管平滑肌收缩。结论骆驼蓬总碱、鸭嘴花碱能够明显地抑制刺激因素诱发的豚鼠气管平滑肌收缩。     

Modification by charybdotoxin and apamin of spontaneous electrical and mechanical activity of the circular smooth muscle of the guinea-pig stomach.

1. The effects of charybdotoxin and apamin, putative blockers of Ca(2+)-activated K+ channels, on spontaneous electrical and mechanical activity of circular smooth muscle of the guinea-pig stomach antrum were examined in the presence of 1 microM tetrodotoxin and 1 microM atropine. 2. Both charybdotoxin (> 3 nM) and apamin (> 3 nM) dose-dependently increased the amplitude of spontaneous contractions without altering their frequency. The maximum effect of charybdotoxin was much greater than that of apamin. Both toxins increased the amplitude of intracellular Ca2+ oscillations measured with fura-2. 3. When the extracellular Ca2+ concentration was lowered to 1.5 mM or less, apamin did not significantly potentiate the contractions whereas charybdotoxin still potentiated them but with less potency. 4. Charybdotoxin (30 nM) increased the amplitude of spikes and slow waves, and slightly decreased the resting membrane potential. On the other hand, apamin (100 nM) preferentially increased the slow wave amplitude with no effect on the resting membrane potential. 5. These results suggest that both toxins affect the spontaneous contraction by modifying the electrical activity and that charybdotoxin-sensitive K+ channels and apamin-sensitive ones are differently involved in the spontaneous electrical activity.     

Cooling-induced contraction in ileal longitudinal smooth muscle of guinea-pig

The ileal longitudinal smooth muscle developed a transient contraction on cooling from 37 degrees C to 1 degree C in normal Ca2+ (2.5 mM) medium. The transient contraction was not inhibited by pretreatment with the Ca2+ antagonist, D-600 (1 X 10(-6)M). The contractions were sustained by cooling to 1 degree C in the presence of added Ca2+ greater than 10 mM. After the pretreatment with D-600, when the muscle incubated in normal medium with added 20 mM Ca2+ had been cooled to 1 degree C, a phasic response was only seen. However, D-600 did not inhibit the sustained contraction at 1 degree C after incubation in the presence of added 20 mM Ca2+. It is suggested that the transient and sustained contraction at 1 degree C is maintained by Ca2+ release from a cellular site, probably the cell membrane and it requires more calcium for the sustained tension.     

On the ability of domperidone to selectively inhibit catecholamine-induced relaxation of circular smooth muscle of guinea-pig stomach

The effects of noradrenaline and dopamine, and their interactions with alpha- and beta-adrenoceptor antagonists and with domperidone, were studied on circular smooth muscle strips taken from the cardia, fundus, body and antrum of the guinea-pig stomach. Noradrenaline and dopamine caused relaxations of all tissues which were generally susceptible to antagonism by either propranolol or phentolamine in concentrations shown to antagonize the relaxations caused by isoprenaline or phenylephrine respectively. In addition, dopamine, in concentrations subthreshold for relaxation, caused contraction of the muscle strips which increased in intensity from the cardia to the antral region: these contractions were antagonized by phentolamine and yohimbine but were insensitive to prazosin: prazosin selectively inhibited the phenylephrine relaxations. With the exception of a modest reduction in the responses of the cardia to dopamine, all tissue responses to noradrenaline and dopamine were resistant to reserpine. Domperidone and haloperidol were found to selectively inhibit the phenylephrine- noradrenaline- and dopamine-induced relaxations of the stomach strips and to enhance the contractile component of dopamine's action: this ability of domperidone to facilitate a dopamine induced contraction, which was most marked in the body and antral regions, was prevented by phentolamine. It is thus concluded that domperidone antagonizes noradrenaline- and dopamine-induced relaxations at one adrenoceptor site having characteristics consistent with an alpha 1-adrenoceptor type whilst failing to antagonize at a further dopamine-sensitive adrenoceptor site involved in contraction of circular smooth muscle of the stomach and having characteristics consistent with an alpha 2-adrenoceptor.     

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

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