Effects of oxamniquine on chick isolated esophagus

The effects of oxamniquine, a potent schistosomicide, on chick isolated esophagus have been examined. Oxamniquine (2.5 X 10(-8)-5 X 10(-5) M) caused rhythmic and tonic contractions of the chick isolated esophagus. The concentration of oxamniquine required to produce 50% of the maximal contractile response (EC50) was 4.2 X 10(-5) M. Pre-incubation of the muscle preparation with procaine (40-120, microM), scopolamine (0.40 microM) or indomethacin (10 microM) attenuated oxamniquine-induced myogenic contractions of the muscle preparation. It is suggested that inhibition of oxamniquine-induced contractions by indomethacin, scopolamine or procaine probably indicates that oxamniquine-induced contractions of the muscle preparation is due to the release of a prostaglandin-like substance and/or a yet unknown contractile compound from the muscle.     

Neurogenic contractile responses of the circular smooth muscle of the guinea-pig vas deferens

Contractile responses of the circular smooth muscle of the guinea-pig vas deferens to electrical stimulation were recorded isometrically using ring preparations of about 2 mm in breadth. Stimulation of low frequency (2.5 to 10 Hz, 0.05 msec duration) for 20 sec produced twitch contractions which occurred once or repetitively during the application of stimulation. Higher frequency stimulation (20 to 80 Hz) produced biphasic contractions, an initial phasic and a secondary tonic contraction. These contractions were abolished by 3 X 10(-6) M tetrodotoxin or 3 X 10(-5) M guanethidine; however, 3 X 10(-6) M atropine or hexamethonium did not affect the contractions. Prazosin at 10(-6) M, like 3 X 10(-7) M yohimbine, increased the amplitudes of twitch contractions to the low frequency stimulation and caused the twitch contractions to occur repetitively. On the other hand, prazosin suppressed the tonic contractions to the high frequency stimulation without substantially inhibiting the phasic contractions. Cocaine at 3 X 10(-6) M potentiated the twitch contractions in the presence of yohimbine. After in vivo reserpine treatments, the low and high frequency stimulation produced twitch and phasic contractions, respectively; however, tonic contractions were not induced. Prazosin at 10(-6) M did not qualitatively affect the contractions in preparations from the reserpine-treated animals. These results suggest that the neurogenic contractions of the circular muscle of the guinea-pig vas deferens are sympathetic in nature, but that they are not mediated solely by norepinephrine. Co-release of other transmitters was indicated to occur upon the electrical stimulation of wide frequency range.     

Analysis of the responses of rainbow lizard (Agama agama Linn.). Isolated portal vein to electrical stimulation and to drugs

The responses of the rainbow lizard (Agama agama Linn.) isolated portal vein to transmural electrical stimulation and to drugs have been examined. The isolated venous muscle preparation strongly contracted in response to exogenously administered adrenaline and noradrenaline (10(-8)-2.5 x 10(-6) M) and also weakly contracted to acetylcholine and 5-hydroxytryptamine (10(-7) - 10(-5) M). The vein relaxed in response to exogenous administrations of isoprenaline (10(-8) - 2.5 x 10(-6) M) and adenosine triphosphate (ATP, 10(-7) - 10(-5) M). Transmural electrical stimulation of the isolated vein at 1-40 Hz induced frequency-dependent contractions of the venous smooth muscle which were inhibited or abolished by tetrodotoxin, alpha-adrenoceptor blockers, adrenergic neurone blocking agents, local anaesthetics, and by pretreatment of rainbow lizards with reserpine. Analysis of these findings shows that the electrical stimulation-evoked contractions of the venous blood vessel resulted from the excitation of post-ganglionic sympathetic neurones. A comparison of the relative potentiation of the venous preparation contractions induced by electrical stimulation, adrenaline and noradrenaline suggested that noradrenaline is the sympathetic transmitter mediating the contractile effects due to electrical excitation. The advantages of this preparation for studying sympathetic nerve-smooth muscle mechanisms and as a pharmacological model for investigating venous blood vessel activity are discussed.     

An amplifying effect of exogenous and neurally stored 5-hydroxytryptamine on the neurogenic contraction in rat tail artery.

1. The interactions between sympathetic neuroeffector transmission and 5-hydroxytryptamine (5-HT) were investigated in segments of rat isolated tail artery. 2. Contractile responses to field stimulation of the artery segments were abolished by tetrodotoxin (3 x 10(-7) M). A subthreshold concentration of acutely applied exogenous 5-HT (10(-8) M) markedly enhanced the contractions induced by sympathetic nerve stimulation, through an action on postjunctional 5-HT2-receptors. 3. The amplifying effect of 5-HT involved an enhanced influx of extracellular calcium into the smooth muscle cells. In contrast, the neurogenic contractions in vessels not exposed to 5-HT were not dependent on extracellular calcium. 4. The adrenergic component of the amplified response involved postjunctional alpha 1- but not alpha 2- adrenoceptor activation. 5. Exposure of the vessels to 5-HT (5 x 10(-7) M) for 30 min resulted in uptake of the amine into the perivascular sympathetic nerves, as demonstrated by immunohistochemistry. After chemical sympathectomy with 6-hydroxydopamine in vitro or in vivo, or surgical sympathectomy, there was little or no uptake. 6. Exposure to 5-HT followed by repeated washing resulted in an enhancement of the neurogenic contraction, which was still fully tetrodotoxin-sensitive. The enhanced response was blocked by ketanserin (10(-8) M) and prevented by the presence of the 5-HT uptake blocker, paroxetine (3 x 10(-8) M), during the period of exposure to 5-HT.     

[Met5]enkephalin acts via delta-opioid receptors to inhibit pelvic nerve-evoked contractions of cat distal colon.

1 The effects of opioids on the sacral parasympathetic outflow to cat distal colon were studied in vitro using muscle strips orientated in the axis of the longitudinal muscle layer, with pelvic nerves attached. Electrical stimulation of the pelvic nerves evoked contractions that were blocked by atropine (1 X 10(-6) M) and tetrodotoxin (3 X 10(-7) M). 2 [D-Pen2, D-Pen5]enkephalin and [Met5]- and [Leu5]enkephalin caused concentration-dependent, reversible inhibition of pelvic nerve-evoked contractions, with IC50 values of 8.3 X 10(-10) M, 2.2 X 10(-9) and 2.1 X 10(-9) M respectively. 3 Morphine (1 X 10(-7)-1 X 10(-5) M) and [D-Ala2, MePhe4, Gly-ol5]enkephalin (1 X 10(-8)-1 X 10(-6) M) and U-50,488H (1 X 10(-8)-10(-6) M) were much less potent as inhibitors than [Met5]- or [Leu5]enkephalin. 4 Naloxone (1 X 10(-7) M), an antagonist at each of the three opioid receptor types, antagonized the effects of both [Met5]enkephalin and morphine. However, ICI 174,864, a specific delta-opioid receptor antagonist, antagonised the effects of [Met5]enkephalin only. 5 The inhibitory actions of [Met5]enkephalin were inversely related to frequency of pelvic nerve stimulation. Also, [Met5]enkephalin at a concentration (3 X 10(-9) M) which produced a large inhibition of neurogenic contractions, had no effect on contractions to exogenous acetylcholine. These results suggest a prejunctional site for inhibitory opioid receptors. 6 In summary, prejunctional inhibitory delta-opioid receptors are present on the sacral parasympathetic outflow to cat distal colon; kappa- and/or mu-opioid receptors may also be present, but appear to be of lesser importance.     

Inhibitory action of propranolol on the contractions induced by nerve stimulations or calcium in the smooth muscle of rat vas deferens

Inhibitory effects of propranolol on the contractions to various treatments were investigated in the epididymal half of the rat vas deferens. Reportedly, 10(-5)-3 X 10(-4) M propranolol inhibited 150 mM K-induced contractions dose-dependently; 3 X 10(-4) M propranolol abolished the contractions. The present results showed that propranolol at concentrations up to 10(-4) M did not inhibit the maximal contractions to 10(-3) M norepinephrine (NE) or 10(-2) M methacholine (MCh). Propranolol at 3 X 10(-4) M slightly inhibited contractions to NE and MCh by 11% and 12%, respectively. In contrast, propranolol inhibited twitch components of the contractions induced by nerve stimulations at similar doses to those reported for high K contractions. Propranolol also inhibited contractions to Ca in high K-containing solution and shifted the dose-response curve to the right. Propranolol did not affect the depolarizations by high K measured by microelectrodes. Propranolol at concentrations of 10(-5)-3 X 10(-5) M diminished the magnitude of spikes dose-dependently. Spikes were rarely observed in the presence of 10(-4) M propranolol in spite of generation of e.j.p.s with amplitudes that would be sufficient to induce spikes in the absence of propranolol. These results suggest that propranolol inhibits contractions by decreasing Ca-influx through the potential-operated Ca-channels in the smooth muscle cells of rat vas deferens.     

In vitro evidence for dopaminergic receptors in human renal artery

Effects of dopamine on human renal arteries were pharmacologically investigated in vitro. Norepinephrine (5 X 10(-10)-5 X 10(-5) M) produced concentration-dependent contractions of isolated renal arterial strips, which were significantly depressed by prior administration of phentolamine or phenoxybenzamine. Isoproterenol (4 X 10(-10)-4 X 10(-6) M) concentration dependently relaxed the strips under potassium contracture, but a high dose (4 X 10(-5) M) constricted them. Biphasic responses to isoproterenol were changed to concentration-dependent contractions by prior administration of propranolol, and abolished by propranolol together with phentolamine. Dopamine (5 X 10(-8)-5 X 10(-4) M) produced concentration-dependent contractions of human renal arteries, which were not significantly influenced by propranolol but which were reversed to relaxations by phentolamine. Dopamine-induced relaxations, which were obtained after administration of phentolamine, were not significantly affected by propranolol, but were significantly depressed by combined application of propranolol and haloperidol, or of propranolol and droperidol. Results suggest that isolated human renal arteries have dopaminergic receptors in their smooth muscles which show relaxations of renal arteries after alpha-adrenoceptor blockade.     

Adrenoceptors and regulation of intestinal tone in the isolated colon of the mouse.

Adrenaline, noradrenaline, phenylephrine, dopamine, clonidine and apomorphine at low concentrations (from 10(-9) M to 10(-6) M) contracted the longitudinal muscle of the isolated distal colon of the mouse. Phentolamine, tetrodotoxin and indomethacin antagonized these contractile responses. Yohimbine antagonized them at lower concentrations than prazosin. Dopamine and clonidine had the same contractile activity on preparations from mice pretreated with 6-hydroxydopamine (6-OHDA). Isoprenaline (10(-9) to 3 X 10(-7) M) induced relaxations of the colon which were antagonized by propranolol. At higher concentrations, adrenaline and noradrenaline (from 3 X 10(-7) M), dopamine (from 3 X 10(-5) M), phenylephrine (from 3 X 10(-6) M) and apomorphine (from 10(-4) M) relaxed the colon. Clonidine (10(-6) to 3 X 10(-5) M) inhibited the spontaneous activity of the colon but never induced relaxations. At 10(-4) and 10(-3) M clonidine elicited contractions. Prazosin antagonized the inhibitory effect of phenylephrine and clonidine, a mixture of propranolol and prazosin antagonized the relaxations to adrenaline, noradrenaline and dopamine and unmasked contractions that were sensitive to yohimbine and tetrodotoxin. The relaxations induced by apomorphine and the contractions induced by clonidine (greater than 10(-6) M) were resistant to all these antagonists. Electrical field stimulation (1 ms, 2 Hz, 2-20 V) of the mouse colon induced contractile responses which increased with the frequency of the stimulus. After cessation of stimulation at 4 Hz a rebound contraction was generally observed, followed by a progressive decline in tone. In the presence of atropine, the contractile response to field stimulation was abolished and transformed into a rapid and sustained relaxation. A rebound contraction was always observed after cessation of stimulation. The responses to electrical stimulation (in the presence or absence of atropine) were abolished by tetrodotoxin. The rebound contractions were abolished by indomethacin. The relaxations induced in the presence of atropine were not modified by phentolamine, propranolol, guanethidine, methysergide, mepyramine, cimetidine or naloxone. Tetrodotoxin (from 3 X 10(-8) M) caused a sustained contraction of the colon with increased spontaneous activity. This contraction was not modified by atropine, phentolamine, propranolol, guanethidine, methysergide, mepyramine, cimetidine, naloxone, but was abolished by preincubation of the preparation with indomethacin. These results indicate that, at low concentrations, various sympathomimetics contracted the mouse distal colon by stimulating alpha 2 presynaptic adrenoceptors.(ABSTRACT TRUNCATED AT 400 WORDS)     

The effects of cyanide and its interactions with norepinephrine on isolated aorta strips from the rabbit, dog, and ferret

Effects of sodium cyanide on isolated strips of rabbit, dog, and ferret aorta were determined. In the rabbit aorta strip, cumulatively added cyanide caused small contractions beginning at approximately 10(-11) M cyanide and reaching a maximum response at 10(-5) M. A concentration of cyanide between 10(-5) M and 10(-3) M produced relaxation. When cyanide was cumulatively added to norepinephrine (NE)-contracted rabbit aorta strips, no contractions were observed. Cyanide concentrations above 10(-5) M produced relaxation in the NE-contracted vessels. Sensitivity of the aorta strips to NE differed among the species examined. The ED50 for contractions in the dog and ferret aorta was 4 X 10(-4) M and in the rabbit was 5 X 10(-6) M. Pretreatment with cyanide in concentrations up to 10(-2) M did not reduce contractions of dog aorta to NE, although 10(-2) M cyanide abolished contractions of rabbit aorta to NE and reversed NE-contractions of ferret aorta to relaxation. The antagonism of cyanide for NE-induced contractions was completely reversible with cyanide concentrations up to 10(-3) M. Cyanide pretreatment of strips of aorta increased the rate of contraction to NE. A concentration of 10(-2) M cyanide caused small contractions of aorta strips from each species. Thus, cyanide exerts dose and species dependent responses on vascular smooth muscle.     

Flunarizine inhibits endothelium-dependent hypoxic facilitation in canine coronary arteries through an action on vascular smooth muscle.

1. Hypoxia augments contractile responses to several vasoactive agents in canine isolated coronary arteries with intact endothelium. Calcium antagonists inhibit the further increases in tension caused by hypoxia. The present experiments were designed to determine whether the calcium-antagonist flunarizine would inhibit hypoxic contractions in isolated blood vessels through an action on the endothelium or on the vascular smooth muscle. 2. Rings of canine coronary arteries, with or without endothelium, were suspended at optimal length for isometric tension recording in organ chambers filled with modified Krebs-Ringer bicarbonate solution. 3. Hypoxia (95% N2 and 5% CO2) augmented contractile responses to prostaglandin F2 alpha (2 x 10(-6) M); removal of the endothelium abolished this hypoxic facilitation. 4. Flunarizine (5 x 10(-5)-5 x 10(-7) M) exerted a long-lasting inhibition of the hypoxic facilitation in a concentration-dependent manner. Flunarizine did not inhibit the response to prostaglandin F2 alpha. 5. To differentiate between the response of smooth muscle and the endothelium, strips of coronary arteries without endothelium were layered with strips with or without endothelium. Hypoxia augmented contractions only in layered preparations with endothelium. Flunarizine prevented the hypoxic contractions in layered preparations in which only the smooth muscle was treated with flunarizine. In contrast, when only the endothelium was treated, no or minimal inhibition of the hypoxic contraction occurred with flunarizine (10(-5) and 5 x 10(-5) M, respectively). 6. These experiments indicate that the calcium antagonist flunarizine inhibits endothelium-dependent hypoxic facilitation in canine coronary arteries primarily through its action on vascular smooth muscle.     

Blockade of adrenergic and cholinergic transmissions by tetramethylpyrazine.

The pharmacological actions of an amide alkaloid, tetramethylpyrazine (TMPZ), isolated from the stem of JATROPHA PODAGRICA H OOK (Euphorbiaceae) have been investigated on the electrically-evoked contractions, relaxations and twitches of some cholinergically- and adrenergically-innervated muscle preparations IN VITRO and IN VIVO. The amide alkaloid depressed or abolished the electrically-evoked contractions of the chick oesophagus, rabbit duodenum and guinea-pig vas deferens IN VITRO. Tetramethylpyrazine also inhibited or abolished the indirect electrically-induced twitches of the rat isolated hemidiaphragm, or the contractions of the cat nictitating membrane evoked by pre-ganglionic cervial sympathetic nerve electrical stimulation IN VIVO. Moreover, TMPZ prevented or reversed the high frequency electrical stimulation-induced relaxations of the rabbit isolated duodenum. These results were taken to imply blocking actions of the amide alkaloid at the cholinergic and adrenergic neuro-effector junctions, the neuro-muscular junction, and at the ganglia (presumably indicating blockade of peripheral cholinergic and adrenergic transmissions). The inhibitory effects of TMPZ on the electrically-provoked contractions (or relaxations) of the cholinergically-innervated and adrenergically-innervated muscle preparations set up are thought to be possibly linked with the non-specific spasmolytic action of the amide alkaloid, or, probably mediated through its local anaesthetic (membrane-stabilizing) activity; since its inhibitory effects were not modified by any specific antagonist. The pharmacological implications of the above findings are discussed.     

alpha-Sympathomimetic amines and calcium-mediated action potentials in guinea-pig ventricular muscle.

1 The ability of amines, having alpha- or alpha- and beta-adrenoceptor stimulating activity, to restore excitability and contractility in heart preparations partially depolarized by potassium, was investigated in guinea-pig ventricular muscle in order to elucidate the mechanism of the positive inotropic effect mediated via alpha-adrenoceptors. 2 In preparations in which fast sodium channels were inactivated by K+-rich medium (22 mM) slow electrical responses as well as contractions were consistently induced by high concentrations of phenylephrine (10(-4) to 3 X 10(-4) M) and synephrine (3 X 10(-4) M). 3 The restorative effective effects of both phenylephrine and synephrine were unaffected by phentolamine (10(-5) M) but were readily abolished by practolol (10(-5) M) or sotalol (10(-5) M). 4 Methoxamine induced a dose-dependent positive inotropic effect in ventricular strips paced at 0.5 Hz in normal Tyrode solution; the maximum increase in contractile tension was obtained with methoxamine 10(-4) M. However, at the same concentration, the amine did not induce slow electrical responses in potassium-depolarized preparations. 5 It is concluded that the induction of slow responses by phenylephrine and synephrine is due to beta-adrenoceptor stimulation, and that the increase in cardiac contractility caused by alpha-adrenoceptor stimulation does not involve an increase in slow inward calcium current.     

Comparison of pinaverium bromide, manganese chloride and D600 effects on electrical and mechanical activities in rat uterine smooth muscle

The effects of pinaverium bromide, were compared with those of D600 and manganese chloride (Mn), on membrane potentials, ionic currents and isometric contractions in uterine smooth muscle strips from pregnant rats. Pinaverium bromide (10(-7) - 10(-6) M) depressed twitch contractions and K-contractures within 15-20 min while D600 (2 X 10(-6) M) and Mn (10(-3) M) abolished both contractions. D600 and pinaverium bromide were more potent inhibitors in K-depolarized preparations than in polarized tissues. At a supramaximal dose (10(-5) M), pinaverium bromide decreased the rate of rise, amplitude, and rate of repolarization of the action potential, and prolonged the potential duration. The inward Ca current was depressed and the reduction in Cai was responsible for the decrease in K current. Pinaverium bromide (10(-5) M) depressed the myometrial contractions induced in Ca-free solution by acetylcholine (10(-4) M) and by prolonged membrane depolarizations. Mn (2.5 X 10(-3) M) only reduced the Ach-induced contraction and D600 (10(-5) M) had no effect on intracellular Ca stores. The results indicate that pinaverium bromide has Ca channel blocking properties similar to those of currently used Ca antagonists; it may also exert an effect to depress contractions supported by intracellular Ca release.     

Stimulation of Autonomic Cholinoceptors in the Rat Uterus by a Crude Extract from Eleophorbia drupifera Leaves

The crude extract from E. drupifera was tested for its effects on isolated rat uterine preparations. The extract (2.0-300 µg/ml) produced graded increases in uterine contractions. The contractions were potentiated by neostigmine (1.64 × 10 -6 M) and abolished by atropine (4.4 × 10 -4 M). The extract-induced contractions were not prevented by previous addition to the bath of hexamethonium or 5-hydroxytryptamine and bradykinin antagonist. However, extract-induced increase in uterine contraction was abolished by either lidocaine (4.2 × 10 -5 M) or tetrodotoxin (5 × 10 -8 M). These data seem to indicate that the crude extract-induced increase in myometrial contractility is due to actions on post-ganlionic autonomic nerve endings, with acetylcholine release and stimulation of muscarinic receptors.     

Effects of prostaglandin F2 alpha and indomethacin on the contractile activity of different compartments of the complex stomach

In vitro experiments have shown that PGF2 alpha or indomethacin produces different effects on muscle strips isolated from different compartments of sheep complex stomach. PGF2 alpha (10(-6) - 10(-5) M) increases the tone of the ruminal preparations and exerts a negligible effect on the reticulum and omasum strips. Indomethacin (5 X 10(-6) M) inhibits the mechanical activity of the rumen and omasum and has no effect on that of the reticulum. More pronounced are the effects on the different parts of the abomasum: PGF2 alpha (10(-9) - 10(-6) M) markedly increases the tone of the proximal abomasum and decreased the amplitude and the phasic contractions of the antral abomasum; indomethacin (5 X 10(-6) M) inhibits the tone and the phasic contractions of the middle abomasum. PGF2 alpha (10(-9) - 10(-6) M) inhibits while indomethacin (5 X 10(-6) M) stimulates the contractile activity of the antral abomasum.     

Effects induced by Tityus serrulatus scorpion venom and its toxins TsTX-I and TsTX-V on the rat isolated retractor penis muscle

The aims of the present study were to investigate the pharmacological effects induced by Tityus serrulatus venom (TsV) and its fractions and to compare with the effects induced by pure alpha (TsTX-V) and beta (TsTX-I) toxins isolated from TsV on rat retractor penis muscle (RPM). TsV, fractions X, XI, XIIa, XIIb (0.01-100 microg/ml) and TsTX-V (1 nmol/l-10 micromol/l) induced concentration-dependent contractions. Prazosin and guanethidine or tetrodotoxin (TTX, 5 micromol/l, 30 min) completely abolished these contractions, suggesting complete dependence on sympathetic nerves. TsV or fractions X, XI, XIIa, XIIb (0.01- 100 microg/ml), TsTX-I and TsTX-V (1 nmol/l-10 micromol/l) induced concentration-dependent relaxations in the precontracted RPM. TTX or N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 micromol/l, 30 min) completely abolished the relaxations. Our results suggest that most of TsV-derivated toxins induce contraction and relaxation on RPM by sympathetic and NANC nitrergic nerve stimulation. Noteworthy, TsTX-I only induces relaxation on RPM suggesting that this protein selectively acts on inhibitory nerves.     

Endothelin-1-induced contractions of isolated pig detrusor and vesical arterial smooth muscle: calcium dependence and phosphoinositide hydrolysis.

1. In isolated pig detrusor and vesical arterial smooth muscle preparations, endothelin-1 (ET-1) caused concentration-dependent contractions. Nifedipine (10(-6) M) did not significantly affect the action of ET-1 in the vessels, but almost abolished its effect in the detrusor. Incubation for 30 min in Ca(2+)-free solution markedly reduced the ET-1-induced contractions in both detrusor and vesical arteries. 2. The protein kinase C inhibitor H-7 (3 x 10(-5) M), reduced the response to ET-1 in detrusor muscle as well as in vessels, and abolished the contractions evoked by ET-1 in Ca(2+)-free solution. 3. ET-1 caused an increase in the accumulation of inositol phosphates (IPs) in preparations prelabelled with myo-[3H]inositol. After exposure to ET-1 (10(-7) M) for 60 min, an approx. 4-fold increase in IPs levels were demonstrated, compared to untreated controls, in both detrusor and vessel preparations. Pretreatment with nifedipine (10(-6) M) did not reduce IPs formation. In contrast, no increase in IPs formation was demonstrated in Ca(2+)-free medium. 4. The increase in accumulation of IPs was slow in onset in both detrusor and vesical arteries, with no significant accumulation demonstrable during the first 30 min. Time-course studies of tension development for ET-1 revealed that maximum tension was reached before significant levels of IPs could be detected.     

The effect of thymoxamine on guinea-pig ileum contractions

The effects of thymoxamine on the contractions induced in guinea-pig isolated ileum were examined. The drug was tested in a large range of concentrations (10(-8)-10(-4) M). The twitch response induced by acetylcholine was potentiated by low concentrations and inhibited by high concentrations of the alpha 1-blocking drug thymoxamine. The contractions in response to carbachol were always inhibited. Thymoxamine also affected the responses of the ileum to other stimulants: angiotensin, pentagastrin, cholecystokinin. The drug (8 X 10(-5), 5 X 10(-4) M) inhibited the calcium contraction of high K+ depolarized preparations.     

Inhibition of ATP-induced contraction in the guinea-pig urinary bladder in vitro and in vivo.

Contractions were elicted by adenosine 5'-triphosphate (ATP) in the guinea-pig urinary bladder in vitro and in vivo. In isolated detrusor strips, tetrodotoxin (3.1 x 10(-6)--4.4 x 10(-5) M) did not affect contractions induced by a submaximum concentration (10(-3) M) of ATP, nor did atropine (1.7 X 10(-6)--2.1 x 10(-4) M), or the anticholinergic agent PR 197 within the concentration range 2.6 x 10(-8)--2.6 x (0(-5) M. In higher concentractions (5.2 x 10(-5)--2.6 x 10(-4) M), PR 197 inhibited the ATP-response by 60-70% in a way that was not clearly concentration-related. Isoprenaline (10(-7)--2.0 x 10(-5) M) and noradrenaline (2.5 x 10(-6)--10(-4) M) reduced the ATP-induced contractions by up to 79%. The effects of the amines were abolished by propranolol (5.2 x 10(-6)--3.8 x 10(-5) M). Adenosine, 1.0--2.0 x 10(-2) M, reduced the ATP-response by about 50%; in lower concentrations, it had no effect. Nifedipine, 7.8 x 10(-7)--1.2 x 10(-5) M, reduced the responses by 15-79%. Indomethacin (less than 2.0 x 10(-4) M), and theophylline (2.0 x 10(-4) M) had no consistent effects on ATP-induced concentrations. 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 (3 mg/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 microgram/kg) caused a 53-95% inhibition that could be blocked by propranolol (1 mg/kg). The inhibiting effect of noradrenaline (10-100 microgram/kg) could not be blocked by propranolol (1 mg/kg). Adenosine (1.5-3.0 mg/kg) given immedicately 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 elicted by a direct effect on the smooth muscle cell. It can be inhibited non-specifically by drugs with different modes of action.     

Effects of local anesthetics, tetrodotoxin, aconitine and verapamil on the mechanoreceptors of isolated frog heart

Effects of local anesthetics, tetrodotoxin (TTX), aconitine and verapamil on the rate of afferent discharges from the mechanoreceptors of isolated hearts of the bullfrog were studied. When procaine (1 X 10(-4) M), tetracaine (1 X 10(-6) M) and dibucaine (1 X 10(-5) M) decreased the contractile force and beating rate of the heart, high frequency discharges that were synchronized with the contraction of the heart appeared. When concentrations of these local anesthetics were increased, the afferent discharges were abolished. When TTX (1 X 10(-8) M - 1 X 10(-7) M) caused a cardiac arrest, high frequency discharges, consisting of maintained discharges and the discharges synchronized with small contractions of the ventricle, appeared. Occasionally, in the presence of TTX (1 X 10(-7) M) the cardiac arrest occurred, and then very irregular contractions appeared. At that time, high frequency discharges synchronized with contractions appeared. On the other hand, aconitine (1 X 10(-7) M - 1 X 10(-6) M) initially increased the rate of afferent discharges from mechanoreceptors in the atrium and ventricle and then abolished the discharges without significantly affecting beating rhythms and contractile force. When verapamil (1 X 10(-6) M - 1 X 10(-5) M) was applied, the beating rate and contractile force were significantly decreased, but high frequency discharges synchronized with contractions were observed. These results indicate that local anesthetics, TTX and verapamil at those concentrations which depressed the cardiac functions did not inhibit the heart mechanoreceptor excitability and the concentration of aconitine that markedly affected the cardiac functions stimulated the heart mechanoreceptor.