The denervated cremaster muscle of the guinea-pig as a pharmacological preparation.

The pharmacological responses of both denervated and innervated cremaster muscle preparations from the guinea-pig have been investigated and compared. Acetylcholine (ACh) dose-response curves were obtained in both preparations. The affinity constants for (+)-tubocurarine and for atropine were calculated and indicated that the ACh receptors in both preparations were nicotinic. Histamine dose-response curves could be obtained only in the denervated preparation. The response was unaltered by metiamide, and the affinity constant for mepyramine fitted in with those previously obtained by others on ileum and trachea, indicating that the histamine receptors are H1 in type. Sustained contractions were obtained to adrenaline and noradrenaline but not isoprenaline, with the denervated preparations. Schultz-Dale responses were obtained with denervated muscle in sensitized guinea-pigs. This preparation did not respond to 5-hydroxytryptamine, bradykinin, or the slow-reacting substance of anaphylaxis.     

Pre- and postjunctional muscarinic receptor subtypes in dog airways.

To examine muscarinic receptor subtypes involved in cholinergically mediated contractions of the airway, we studied the effects of the M1-selective antagonist, pirenzepine, the M2-selective antagonist, AF-DX 116, the M3-selective antagonist, 4-diphenyl-acetoxy-N-methylpiperidine (4-DAMP) methiodide, and the non-selective antagonist, atropine, on acetylcholine (ACh)- and electrically induced contractions in dog bronchi and bronchioles. The relative potencies of the antagonists based on IC50 values of each antagonist for contractions induced by the two concentrations of ACh that produced 50% of the maximum (ED50) and the maximum (EDmax) contractions and the pA2 values were atropine greater than or equal to 4-DAMP methiodide greater than pirenzepine = AF-DX 116 in both the bronchi and bronchioles. The IC50 and pA2 values of each antagonist did not differ significantly between the bronchi and bronchioles. 4-DAMP methiodide significantly inhibited the contractile response to electrical field stimulation (EFS) at 5 Hz at concentrations that did not alter the contractile responses to exogenous ACh in both the bronchi and bronchioles, whereas pirenzepine, AF-DX 116 and atropine inhibited the EFS-induced contraction only at the concentrations that reduced the contraction induced by exogenous ACh. The present results suggest that the cholinergic contraction is mediated via the postsynaptic receptor M3, based on functional potencies of muscarinic antagonists and presynaptic receptor auto-facilitatory M3, based on the suppression of the contractile response to EFS by 4-DAMP methiodide in central and peripheral airways.     

Irreversible inhibitory effect of atropine on contractile responses to drugs in isolated rabbit ileum.

Effect of atropine sulfate (atropine) on the contractile responses to acetylcholine chloride (ACh), potassium chloride (K) and barium chloride (Ba) was investigated in isolated rabbit ileum. Tension of the strips suspended in the bath medium (Locke solution, 30 degrees C) was isotonically recorded. The K(ED50)- and Ba(ED50)-induced contractions were not affected by atropine at 3.0 X 10(-4) mM, which reversibly abolished the ACh(ED100)-contraction. After washout of 6.0 X 10(-4) mM atropine, the phasic, but not the tonic, component of ACh(ED50)-, K(ED50)- and Ba(ED50)- contractions was to some extent inhibited irreversibly. On the contrary, such irreversible inhibition of the phasic component was not produced by atropine methylbromide even in the high concentration of 3.0 X 10(-3) mM. The irreversible inhibitions by atropine of 6.0 X 10(-4) mM on the phasic component of ACh- and K-contractions were protected by pretreatment with a high concentration of ACh or K. Further, these irreversible inhibitions by atropine were potentiated by the absence of Ca and were abolished by the increase of Ca content in bath media. These results suggest that the irreversible inhibition of the contractile responses to drugs by atropine in high concentration may be due to the interference with the mobilization of Ca in the deep layer of the membrane, rather than by a blockade of muscarinic receptor sites.     

Action of tacrine on muscarinic receptors in rat intestinal smooth muscle

1 The reversible cholinesterase inhibitor, tacrine (THA) was examined against the contractions of rat duodenum to acetylcholine and carbachol (cholinesterase resistant). 2 Tacrine (10^–6 M ) showed a similar behaviour to physostigmine (10^–6 M ), changing the characters of the concentration–response curve to Ach. The contractual responses were shifted to the left at low concentrations of ACh to reveal a bell‐shaped curve with declaring contradictions at high concentrations of ACh. 3 Antagonism by atropine (10^–8 M ) was reduced in the presence of tacrine (10.54, dose‐ratio) compared with the shift of the curve in the absence of tacrine (73.9, dose‐ratio). The declining phase of the concentration–response curve to ACh was also antagonized by atropine. 4 Further evidence for muscarininc receptor antagonism by tacrine was a small rightward shift of the concentration‐response curve for carbachol, an agonist immune to cholinesterase. 5 This study has shown that tacrine acts both as a cholinesterase inhibitor and muscarinic antagonist on rat intestinal smooth muscle.     

The effects of Bay K 8644 and nifedipine on the responses of rat urinary bladder to electrical field stimulation, beta,gamma-methylene ATP and acetylcholine.

1. Bay K 8644 (0.33 nM to 1 microM) greatly increased the contractions of rat urinary bladder detrusor muscle induced by beta, gamma-methylene ATP (beta, gamma-MeATP, 10 microM) and by electrical field stimulation of the purinergic component (the cholinergic response was blocked by atropine). 2. The contractions induced by acetylcholine (ACh, 10 microM) and by electrical field stimulation of the cholinergic component (the purinergic response was blocked following desensitization by alpha, beta-MeATP) were also potentiated by Bay K 8644, although to a lesser extent than the purinergic responses. 3. Nifedipine (1 nM to 3.3 microM) inhibited all the contractions induced by beta, gamma-MeATP, ACh and electrical field stimulation. However, while the responses to beta, gamma-MeATP and electrical field stimulation of the purinergic component were almost abolished, a substantial proportion of the responses to ACh and electrical field stimulation of the cholinergic component were nifedipine resistant. 4. The concentration-effect curves for the potentiation by Bay K 8644 of the responses to beta, gamma-MeATP, ACh and electrical field stimulation were shifted to the right by nifedipine (10 nM). At concentrations greater than 1 microM, Bay K 8644 inhibited contraction. 5. It is concluded that voltage-sensitive calcium channels play an important role in the excitatory mechanical action of P2X-purinoceptor-mediated purinergic responses in the rat urinary bladder, while cholinergic-mediated responses are less dependent on such channels.     

Differential effects of omega-conotoxin GVIA and tetrodotoxin on vasoconstrictions evoked by electrical stimulation and nicotinic receptor stimulation in canine isolated, perfused splenic arteries.

1. The effects of omega-conotoxin GVIA (omega-CgTX) and tetrodotoxin (TTX) on vasoconstrictions induced by acetylcholine (ACh) and nicotine were investigated and compared with those induced by periarterial electrical stimulation in the isolated and perfused canine splenic arteries. 2. ACh and nicotine at doses of 0.01 to 1 mumol constricted the splenic artery, dose-dependently. ACh induced consistent responses, but the vasoconstrictor responses to nicotine became significantly smaller with repeated administration of nicotine. 3. Periarterial electrical stimulation produced a vasoconstriction that was abolished by either TTX (30 nmol) or omega-CgTX (3 nmol), but the vasoconstrictor response to nicotine was not significantly affected by the same doses of TTX and omega-CgTX. Inhibitions by TTX and omega-CgTX of ACh-induced vasoconstrictions were small but statistically significant, showing that the percentage inhibition was less than 15%. TTX and omega-CgTX did not affect the vasoconstrictor responses to exogenous noradrenaline (NA). 4. ACh did not produce any vasoconstriction in the preparations treated either with alpha-adrenoceptor antagonists (10 microM bunazosin and 10 microM midaglizole) or with 30 microM guanethidine. NA-induced responses were abolished by alpha-adrenoceptor antagonists, but not affected by guanethidine treatment. 5. Vascular responses to ACh were completely inhibited by 1 mumol hexamethonium. In the preparations treated with 100 nmol nicotine, ACh did not produce any vasoconstriction. However, the NA-induced vasoconstriction was affected by neither hexamethonium nor nicotine treatment. 6. Atropine (1 microM) significantly inhibited but did not abolish the vasoconstrictor responses to ACh. The vascular responses to nicotine and NA were also significantly inhibited by atropine treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

5-Hydroxytryptamine receptors,especially the 5-HT4 receptor,in guinea pig urinary bladder

The function of 5-hydroxytryptamine (5-HT) receptors, especially the 5-HT4 receptor, in the urinary bladder were examined in preparations isolated from the guinea pig by in vitro receptor autoradiography and determinations of mechanical activity and acetylcholine (ACh) release. Specific [125I]SB207710 binding sites were detected evenly throughout the urinary bladder. 5-HT (3 x 10(-8)-10(-4) M) caused contractions of strips of the urinary bladder, in a concentration dependent manner. Ketanserin antagonized the 5-HT-induced contractions, while granisetron and SB204070 antagonized the contractions induced by high concentrations of 5-HT. Atropine inhibited the contractions induced by high concentrations of 5-HT. Ketanserin prevented the 5-HT-induced contractions in the presence of atropine, but granisetron and SB204070 did not affect the contractions under such a condition. 5-HT enhanced the electrically-stimulated (5 Hz, 0.5 ms) outflow of [3H]acetylcholine from strips preloaded with [3H]choline, and the enhancement was antagonized by granisetron and SB204070. Thus, the contractile response to 5-HT was mediated by activations of 5-HT2, 5-HT3 and 5-HT4 receptors. The 5-HT2 receptor may be a property of high affinity to 5-HT and located on the smooth muscle cells. The 5-HT4 as well as 5-HT3 receptor may be a property of low affinity to 5-HT and located on the cholinergic neurons.     

Cyclo-oxygenase inhibitors antagonize indirectly evoked contractions of the guinea-pig isolated ileum by inhibiting acetylcholine release

The effects of indomethacin, sodium meclofenamate and ketoprofen on the contractile responses of the guinea-pig isolated ileum to directly and indirectly evoked stimuli were investigated. The effects of the cyclo-oxygenase inhibitors on acetylcholine (ACh) release from plexus containing longitudinal muscle strips were also studied. The cyclo-oxygenase inhibitors reduced contractile responses to transmural stimulation (TMS) and nicotine at concentrations which had no effect on ACh-induced contractions. In whole ileum preparations (WIP) indomethacin and ketoprofen (40 micrograms ml-1) reduced TMS responses by 17 +/- 1.8% and 12 +/- 1.8% (n = 6), respectively (30 min incubation). In longitudinal muscle strips (LMS) in which Auerbach's plexus is exposed, indomethacin and ketoprofen (1 microgram ml-1) reduced TMS responses by 28 +/- 2.3% and 34 +/- 2.7% (n = 6), respectively (10 min incubation). Thus the cyclo-oxygenase inhibitors were up to 80 times more effective in LMS than in WIP. The drugs were similarly more effective in blocking nicotine contractions in LMS than in WIP. The cyclo-oxygenase inhibitors reduced basal and stimulated ACh release from LMS. For example, indomethacin (1 microgram ml-1) reduced stimulated ACh release by 35% after 10 min incubation. The percentage inhibition increased to 79% after 40 min incubation (n = 6). Prostaglandin E2 (PGE2) (0.1-2.5 ng ml-1) restored the contractile responses and ACh release depressed by the cyclo-oxygenase inhibitors but not the contractile responses depressed by atropine. PGF2 alpha had no effect on mechanical responses or ACh release depressed by the cyclo-oxygenase inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacological Characterization of the Autonomous Innervation of the Guinea Pig Tracheobronchial Smooth Muscle

Abstract: From the trachea, main bronchi and hilus bronchi of guinea pigs, preparations were isolated for registration of mechanical tension on electrical field stimulation and drugs. The trachea contracted on short trains of electrical stimulation. Usually these contractions were followed by a relaxant response. The contractions were abolished while the relaxations were potentiated by atropine. In the main bronchi field stimulation induced a contractile response which was abolished by atropine. In the latter preparation relaxant responses were never observed, even not after atropine. In the trachea and main bronchi neither the α₁ blocker prazosin nor the α₂ blocker yohimbine affected the contractile or relaxant responses when used in α-blocking concentrations. The relaxant response in trachea was neither affected by the “P1 blocker” theophylline nor by the “P2 blocker” quinidine but it was partially inhibited by guanethidine or β-blocking agents. The hilus bronchi contracted on field stimulation as well as by histamine. The contractile response on electrical stimulation was only slightly inhibited by atropine or guanethidine. In all three preparations responses on field stimulation were abolished by tetrodotoxin. It is suggested that in both trachea and main bronchi excitatory cholinergic innervation is present. Further, the trachea but not the main bronchi is innervated by both adrenergic and nonadrenergic inhibitory nerves. The hilus bronchi contains a non-adrenergic non-cholinergic excitatory nervous system.     

Regionally selective cholinergic stimulation by BRL 24924 in the human isolated gut.

1. The effects of BRL 24924 on cholinergic activity was studied in longitudinal muscle strips obtained from human stomach and colon (taenia). Contractions were evoked by exogenous acetylcholine (ACh) or by electrical field stimulation (EFS) of cholinergic neurones. Inhibitory nerve activity (predominantly non-adrenergic, non-cholinergic; NANC) was detected by measuring the relaxations evoked by EFS in the presence of atropine 1.4 microM. 2. In the stomach, BRL 24924 0.28-28 microM consistently increased the EFS-evoked contractions; lower concentrations (0.0028 and 0.028 microM) increased the contractions in most, but not all of the specimens studied. Since BRL 24924 28 microM did not affect NANC-mediated, EFS-evoked relaxations, and since high concentrations of BRL 24924 (28 and 282 microM) were required to increase ACh-evoked contractions, the increase in EFS-evoked contractions caused by BRL 24924 may be due to a facilitation of ACh release. 3. In the colon, BRL 24924 0.0028-282 microM did not affect EFS-evoked contractions. 4. BRL 24924 may therefore be regionally selective in its ability to stimulate human gastrointestinal cholinergic activity.     

Contractile Effects of Some Polypeptides on the Isolated Urinary Bladder of Guinea-pig,Rabbit, and Rat

Abstract: In isolated detrusor from guinea-pigs and rats substance P (SP) induced concentration-dependent phasic contractions. Rabbit detrusor strips responded to SP with an initial phasic and an ensuing tonic contraction. The concentration-response curve to SP in this preparation had a biphasic appearance. Eledoisin (E) caused contractile responses similar to those of SP when tested on the guinea-pig detrusor. Somatostatin was tested on the rabbit urinary bladder; it caused a concentration-dependent rise in basal tone, but no phasic contraction. The responses to SP and E were not affected by tetrodotoxin or physostigmine. They were only partly inhibited by high concentrations of atropine and the anticholinergic drug PR 197. Noradrenaline and isoprenaline caused a concentration-dependent inhibition of the peptide induced responses in guinea-pig bladder; at high concentrations of the amines this inhibition was almost complete. Indomethacin did not affect the SP induced contractions in the guinea-pig bladder, reduced the responses in the rabbit detrusor, but increased them in the rat bladder. Contractions elicited by SP and E were rapidly diminished or abolished after 30 min. treatment in a calcium-free medium. The responses were also inhibited by the calcium antagonist nifedipine. In guinea-pig preparations depolarized by potassium (127 mM) both SP and E caused a contractile response approximately 20% of that obtained in normal Tyrode solution. It is concluded that SP and E cause contraction of detrusor by a direct effect on the smooth muscle cells, and that this response is dependent on the extracellular calcium concentration. Prostaglandins may be involved in the SP-induced response of the rabbit detrusor.     

Regional and functional differences of 5-hydroxytryptamine-receptor subtypes in guinea pig stomach

Functions and the presence of 5-hydroxytryptamine (5-HT) receptors in the fundus, corpus and antrum of the guinea pig stomach were examined by measuring contractile force and acetylcholine (ACh) release. Stimulation of the 5-HT1 receptor caused tetrodotoxin (TTX)-insensitive relaxations in the preparations from 3 regions. Stimulation of the 5-HT2 receptor caused TTX-insensitive contractions in the preparations of fundus and antrum. Stimulation of 5-HT3 receptors caused contractions that were sensitive to TTX and atropine and enhanced the outflow of [3H]ACh from preparations of only antrum. Stimulation of 5-HT4 receptors caused contractions of antral strips and decreased relaxations of corporal strips and enhanced the outflow of [3H]ACh from the preparations of both corpus and antrum. In the guinea pig stomach, the fundus possesses relaxant 5-HT1 receptor < contractile 5-HT2 receptors and caused the contractile response to 5-HT. The corpus possesses relaxant 5-HT1 receptors and relaxant receptors other than 5-HT1, 5-HT2, 5-HT3 and 5-HT4 receptors > contractile 5-HT4 receptor, and therefore 5-HT caused relaxations. The antrum possesses relaxant 5-HT1 receptor < contractile 5-HT2, 5-HT3 and 5-HT4 receptors, and thus 5-HT caused contractions.     

The role of prostacyclin in modulating cholinergic neurotransmission in guinea-pig ileum.

The mechanism of action of prostacyclin (PGI2) on isolated segments of guinea-pig terminal ileum was studied by recording the changes in isometric tension. In these preparations PGI2 (1 nM-1 microM) caused a concentration-dependent increase in muscle tension. This effect was rapid and short-lasting. PGI2-induced contractions were inhibited by atropine and potentiated by physostigmine. Hemicholinium-3 reduced the response to PGI2 and the inhibition was quantitatively comparable at any PGI2 concentration tested. Tetrodotoxin as well as low temperature (20 degrees C) abolished and beta-bungarotoxin reduced the effect of PGI2. Hexamethonium decreased the response to submaximal, but not to maximal PGI2 concentrations. PGI2 potentiated the twitch response of the ileum to electrical stimulation. In the presence of tetrodotoxin, PGI2 did not alter the effect of a sub-maximal concentration of acetylcholine (ACh). The present results give indirect evidence for the ability of PGI2 to facilitate ACh release from intramural nerves possibly by increasing the excitability of cholinergic cell bodies.     

An ubiquitous modulating function of rabbit tracheal epithelium: degradation of tachykinins.

1. To examine the role of epithelium in the responsiveness of tracheal smooth muscle in rabbit, we measured the contractile responses to acetylcholine (ACh), KCl, 5-hydroxytryptamine (5-HT), histamine, substance P (SP), neurokinin A (NKA), and electrical field stimulation EFS) in intact and epithelium-denuded preparations. 2. Removal of epithelium did not alter the contractile response to any agonist examined, except SP. 3. Removal of epithelium enhances the contractile response to SP. In the presence of phosphoramidon, the contractile response to SP was not significantly different in either group. The results suggest that the effect of epithelium is largely due to degradation of SP by enzymes in the epithelium. 4. Arachidonic acid metabolites did not seem to be related to the responses induced by contractile agonists or EFS. 5. In the presence of SP, the contractile responses and [3H]-choline outflow evoked by EFS were dose-dependently enhanced. Contractile responses to EFS and [3H]-choline outflow evoked by EFS were enhanced by SP significantly more than by NKA. Both were abolished by atropine or tetrodotoxin. 6. These results suggest that rabbit tracheal epithelium may modulate SP-induced contractions, both direct and indirect, by inactivation of SP. This phenomenon is widespread in mammals. The rabbit may be a useful model to examine airway cholinergic functions.     

Anaphylactic bronchoconstriction in BP2 mice: interactions between serotonin and acetylcholine

1. Immunized BP2 mice developed an acute bronchoconstriction in vivo and airway muscle contraction in vitro in response to ovalbumin (OA) and these contractions were dose dependent. 2. Methysergide or atropine inhibited OA-induced bronchoconstriction in vivo and airway muscle contraction in vitro. 3. Neostigmine potentiated the OA-induced bronchoconstriction in vivo and airway muscle contraction in vitro of BP2 mice. This potentiation was markedly reduced by the administration of methysergide or atropine and when the two antagonists were administered together, the responses were completely inhibited. 4. Neostigmine also potentiated the serotonin (5-HT)- and acetylcholine (ACh)-induced bronchoconstriction and this potentiation was significantly reversed by atropine. 5. These results indicate that OA provokes a bronchoconstriction in immunized BP2 mice by stimulating the release of 5-HT, which in turn acts via the cholinergic mediator, ACh.     

Acetylcholine-induced contractions in the perforating branch of the human internal mammary artery: protective role of the vascular endothelium

The effect of acetylcholine (ACh) on the isolated, nonprecontracted perforating branch of the human internal mammary artery (HIMA) was investigated. ACh induced concentration-dependent contractions of nonprecontracted rings with denuded endothelium (pEC(50) = 6.72 +/- 0.02, E(max) = 88.8% of contractions induced by phenylephrine, 10(-5) mol/l) and was without effect on arterial segments with intact endothelium. An inhibitor of nitric oxide synthase, N(G)-monomethyl-L-arginine (L-NMMA), or indometacin, a cyclooxygenase inhibitor, had no effect on acetylcholine-induced contractions of rings of the perforating branch of HIMA with denuded endothelium (pEC(50) = 6.76 +/- 0.03 and 6.62 +/- 0.05, respectively). In the presence of indometacin, ACh did not evoke contractions of arterial segments with intact endothelium. In contrast, in the same type of preparations ACh induced contractions in the presence of L-NMMA (E(max) = 34%). The muscarinic receptor antagonists atropine (no selectivity), pirenzepine (M(1)), methoctramine (M(2)), and p-fluoro-hexahydro-sila-difenidol (M(1)/M(3)) competitively antagonized the response to ACh. The pA(2) values were 9.60 +/- 0.10, 6.99 +/- 0.02, 6.37 +/- 0.17, and 8.02 +/- 0.06, respectively. In conclusion, the results obtained indicate that secretion of nitric oxide from vascular endothelium may protect the perforating branch of HIMA against the contractile effects of ACh. On the basis of differential antagonist affinity, it can be suggested that the muscarinic receptors involved in the ACh-induced contractions of the isolated perforating branch of the HIMA are predominantly of the M(3) subtype.     

In vivo microdialysis assessment of nerve-stimulated contractions associated with increased acetylcholine release in the dog intestine

Intestinal contractility and release of endogenous acetylcholine (ACh) were measured simultaneously in vivo in the small intestine of the anesthetized dog. Electrical stimulation of nerves in the intestinal seromuscular layers caused contractions and increased concentrations of ACh in the dialysate, which were abolished by infusion of tetrodotoxin into the intestinal marginal artery at 75 nmol/ml. Intraarterial administration of atropine at 150 nmol/ml abolished the stimulated contractions, without significant effects on increases in concentrations of dialysate ACh. Thus, the nerve-stimulated contractions were found in vivo to be associated with a local increase in ACh release from the intestinal cholinergic neurons.     

Muscle layer and regional differences in autonomic innervation and responsiveness to transmitter agents in swine myometrium

1 To clarify possible regional and muscle layer differences in adrenergic innervation of swine myometrium, functional, biochemical and histochemical experiments were performed on longitudinal (LM) and circular (CM) muscle isolated from nonpregnant uteri of 84 gilts. 2 Transmural stimulation (TMS) in the presence of propranolol evoked tetrodotoxin-sensitive contractions in a frequency-dependent manner (2–20 Hz) in LM and CM. The cornual LM contractions were attenuated by phentolamine (1 μm ) and by guanethidine (10 μm ) though unaffected by atropine (1 μm ). Contractions in cervical LM were diminished by atropine but not by phentolamine, and the corpus LM contractions were reduced incrementally by atropine and phentolamine when added sequentially. In CM, the TMS-induced contractions were abolished by tetrodotoxin and atropine in all three regions. 3 In response to noradrenaline (NA) and acetylcholine (ACh), LM contractile intensity was the most potent in cornua, slightly weaker in the corpus and weakest in the cervix. CM was insensitive to NA, and contractile responses elicited by ACh indicated no regional variation. 4 NA content, significantly greater in LM than in CM, was most highly concentrated in cornual LM. Nerves exhibiting glyoxylic acid-induced histofluorescence occurred in both LM and CM, though more abundantly in LM and with notable density in the cornual LM. Cholinesterase activity, distributed evenly throughout the three myometrial regions studied, was more intense in LM than in CM. 5 These results show that, in swine myometrium, innervation in cornual LM is predominantly noradrenergic, cervical LM is mostly cholinergic, and throughout the myometrium the CM layers are principally cholinergic.     

Anticholinergic and calcium antagonistic effects of terodiline in rabbit urinary bladder

Abstract The effects of terodiline on contractions induced in isolated rabbit detrusor by carbachol and potassium, and by electrical field stimulation were investigated. Terodiline relaxed preparations contracted by carbachol and potassium and, when added 15 min before stimulation, decreased the contractile responses to these agents in a concentration-dependent way. Terodiline more effectively inhibited carbachol than potassium induced contractions. The “pure” calcium antagonist nifedipine had the opposite effect. Both atropine and terodiline caused a parallell shift to the right of the concentration-response curve to carbachol. The maximum contractile tension and slope were not affected, suggesting a competitive antimuscarinic effect within the concentration range used. Atropine was approximately 750 times more potent than terodiline. The maximum inhibitory effect of atropine and the calcium antagonist nimodipine on the electrically induced response were 40 % and 69 %, respectively. Terodiline caused complete inhibition of the response, as also did a combination of nimodipine and atropine. — The results suggest that terodiline in low concentrations has mainly an antimuscarinic action. To this, a calcium antagonistic effect is added at higher concentrations. The two-fold action of the drug makes it an effective inhibitor of bladder contraction, and an interesting tool for investigations of bladder contractility.     

The effect of substance P on the mechanical and electrical responses of frog, chick and rat skeletal muscle

The effect of substance P (SP) on the electrical and contractile responses of skeletal muscles of frog, chick and rat were studied using electrophysiological techniques. In low concentrations, SP increased the amplitude of twitch and tetanic contractions in response to motor nerve stimulation of frog, chick and rat preparations, increased the amplitude and duration of frog sciatic nerve compound action potential and reduced the contracture responses produced by acetylcholine (ACh) or tetraethylammonium (TEA) in the chick skeletal muscle. In all these actions, the effect of SP was calcium-dependent. The results provide evidence that SP had a dual action; a prejunctional facilitatory effect by causing a further release of ACh and/or Ca2+ entry or release, and postjunctional effect by reducing the sensitivity of the postjunctional membrane to depolarizing drugs.