Effects of selective dopamine receptor compounds on single,spontaneously-active neostriatal neurons

• 1.1. The effects of selective dopamine receptor compounds on the spontaneous activity of single neostriatal neurons were examined extracellularly.
• 2.2. Intravenous administration of quinpirole, the D₂ agonist, elicited a dose-dependent depression in discharge rate.
• 3.3. Quinpirole-evoked depression was reversed by the D₂ antagonist eticlopride, but not the D₁ antagonist SCH 23390.
• 4.4. The partial D₁ agonist, SKF 38393 induced depression and excitation in equal proportion.
• 5.5. A dose of 0.25 mg/kg SCH 23390 blocked SKF 38393-induced depression but not excitation.
• 6.6. SKF 38393-induced excitation was antagonized by eticlopride and in some cases by a higher dose of SCH 23390.

     

Central and peripheral dopamine D1/DA1 receptor modulation of gastric secretion and experimental gastric mucosal injury

• 1.1. Dopamine D₁ (central)/DA₁ (peripheral) receptors are believed to influence gastrointestinal function and pathology.
• 2.2. When given i.c.v. or i.p., an agonist (SKF38393) and an antagonist (SCH23390) of this DA receptor subtype inhibit and enhance, respectively, gastric secretion and gastric mucosal injury.
• 3.3. When given both i.c.v. and i.p., their respective effects in the gut were amplified.
• 4.4. Antagonist or agonist given i.p., blocked the corresponding protective and worsening effect of the agonist or antagonist given i.c.v.
• 5.5. Both central and peripheral D₁/DA₁ receptors modulate gastric function and response to injury.

     

Post-junctional excitatory adenosine A1 receptors in the rat vas deferens

• 1.1. At concentrations between 1 nM and 1 μM, the A₁-selective agonists N⁶-cyclopentyladenosine (CPA) and (R)-N⁶-phenylisopropyladenosine (R-PIA) each enhanced contractions of the rat vas deferens induced by ATP (10 μM), and this enhancement was blocked by an A₁-selective concentration (1 nM) of the antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX).
• 2.2. No such enhancement was observed with the non-selective agonists adenosine and 5′-N-ethylcarboxamidoadenosine (NECA) at concentrations between 1 nM and 100 μM, which instead inhibited the contractions.
• 3.3. These results show that in addition to the previously demonstrated inhibitory A₁ and A₂ adenosine receptors, the rat vas deferens also possesses post-junctional excitatory A₁ adenosine receptors.

     

The Role of Dopamine in the Expression of Morphine Withdrawal

• 1.Both L-dopa and low doses of apomorphine potentiated withdrawal symptoms such as jumping,“wet dog” shakes and burrows. L-dopa reduced hypothermia and potentiated body weight loss, whereas apomorphine produced opposite effects.
• 2.Higher doses of apomorphine attenuated jumping and burrows but had no effect on “wet dog” shakes. On the other hand, and with the exception of sulpiride, all other dopamine (DA) antagonists produced effects opposite those of the agonists with regard to jumping, “wet dog” shakes and burrows.
• 3.In addition, DA antagonists reduced hypothermia and body weight loss. The effects of DA agonists and antagonists were investigated in mice injected with 6-hydroxydopamine (6-OHDA) intracerebrally to examine whether DA-mediated effects are somehow linked to noradrenergic pathways.
• 4.Mice pretreated with 6-OHDA developed a higher degree of naloxone-induced withdrawal jumping than did untreated mice. 6-OHDA reversed the effects of apomorphine on “wet dog” shakes and burrows while abolishing those of L-dopa on all withdrawal symptoms, the only exception being jumping, which remained unchanged.
• 5.6-OHDA also reversed the effects of sulpiride on all withdrawal symptoms while reversing the effects of pimozide on jumping, and it abolished its effect on hypothermia.
• 6.These findings provide evidence suggesting that the effects of DA agonists and antagonists are dependent at least partly on intact noradrenergic pathways.

     

Effects of tandospirone on second messenger systems and neurotransmitter release in the rat brain

• 1.1. We studied the effects of tandospirone, a novel serotonin (5-HT)_1A receptor-related anxiolytic, on the intracellular second messenger systems and neurotransmitter release.
• 2.2. Tandospirone inhibited forskolin-stimulated adenylate cyclase activity in rat hippocampal membranes by activation of 5-HT_1A receptors and had high efficacy comparable to 5-HT_1A receptor agonists such as 5-HT and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT).
• 3.3. Tandospirone suppressed carbachol-stimulated phosphatidyl-inositol metabolism (PI response), which was shown to be a 5-HT_1A receptor-mediated event.
• 4.4. Tandospirone did not affect the release of 5-HT, norepinephrine (NE), dopamine (DA) and acetylcholine (ACh) from rat brain slice preparations.
• 5.5. These findings suggested that tandospirone shows high agonistic efficacy on the postsynaptic 5-HT_1A receptors but does not affect the presynaptic autoreceptors located on nerve endings. The modulation of the second messenger system via postsynaptic 5-HT_1A receptors might be involved in the anxiolytic efficacy of tandospirone.

     

Central effects of opioid agonists and naloxone on blood pressure and heart rate in normotensive and hypertensive rats

• 1.1. The central cardiovascular effects of several opioid receptor selective agonists and the nonselective opioid antagonist, naloxone, were studied in anesthetized normotensive control rats, in spontaneously hypertensive rats (SHR), and in foot-shock-stressed rats.
• 2.2. Receptor-selective agonists injected into the rostral ventrolateral medulla (RVLM), paraventricular nucleus (PVN), and dorsal hippocampus (dHip) were DAGO (μ), DADLE (δ), and U50, 488H (κ).
• 3.3. DAGO and DADLE (3 nM) decreased arterial pressure and heart rate in RVLM and PVN of all rat strains, while U-50,488H (9 nM) had only minimal effects in these areas.
• 4.4. In dHip, only DADLE (3 nM) had depressor and bradycardic effects, and then, only in SHR, with DAGO and U50,488H being ineffective in any strain, even at 9 nM.
• 5.5. Prior injection of naloxone (10 nM) into the RVLM, PVN and dHip blocked and postinjection reversed the cardiovascular effects of the agonists. Naloxone alone increased blood pressure and heart rate in all three areas, in all rat strains except SHR, suggesting a tonic depressor effect of endogenous opioids.
• 6.6. Lack of significant quantitative differences in opioid agonist and antagonist effects between normotensive and hypertensive or stressed rats argues against a role for endogenous brain opioids in experimental hypertension.

     

Effects of chronic lithium pretreatment on apomorphine-induced penile erection

• 1.1. The effects of chronic lithium pretreatment (600 mg/l in drinking rats, 30 days) on penile erection (PE) induced by apomorphine were investigated in rats. This treatment resulted in a serum Li concentration after 30 days of 0.31 ± 0.01 mmol/l.
• 2.2. Subcutaneous (s.c.) administration of mixed Dl/D2 dopamine receptor agonist apomorphine (0.05–0.5 mg/kg) induced PE in a biphasic manner. The maximum effect was obtained with 0.1 mg/kg of the drug while the response decreased with increasing doses of apomorphine from 0.1 to 0.5 mg/kg.
• 3.3. Pretreatment of animals with 0.0125-0.1 mg/kg of D1 dopamine receptor antagonist SCH 23390 or D2 dopamine receptor antagonist sulpiride (12.5–100 mg/kg) decreased apomorphine-induced PE. Combination of SCH 23390 (0.025 mg/kg) with sulpiride (12.5 mg/kg) caused a stronger inhibitory effect on apomorphine response. This indicates that both D1 and D2 dopamine receptors may be involved in PE induced by apomorphine.
• 4.4. The response induced by apomorphine (0.05-0.5 mg/kg) was decreased in animals pretreated with chronic lithium. The inhibitory effect of sulpiride on apomorphine response, increased in animals pretreated with lithium, in contrast the inhibitory effect of SCH 23390 did not change in this condition. However, a combination of SCH 23390 with sulpiride increased inhibitory effect on apomorphine response in lithium pretreated rats.
• 5.5. It is concluded that chronic lithium inhibits PE induced by dopaminergic mechanism(s).

     

The Effect of Fenoldopam on the Blood Pressure of the Rat

• 1.Fenoldopam mesylate, a benzazepine derivative, is a D₁ receptor agonist that lowers blood pressure through vasodilation of renal, mesenteric, coronary and cerebral vascular beds.
• 2.Experiments were performed in rats, and mean carotid blood pressure and heart rate were registered. Two series of experiments were performed: (1) fenoldopam as control group and (2) fenoldopam after pretreatment with one of the following drugs: the D₁ antagonist SCH 23390, the D₂ antagonist sulpiride, the selective β₁-adrenergic antagonist atenolol, the selective β₂-adrenergic antagonist ICI 118.551, the nonselective β-adrenergic antagonist propranolol and the neurotoxin that destroys catecholaminergic nerve terminals 6-hydroxydopamine (6-OH-DA).
• 3.Fenoldopam produced a dose-dependent hypotensive effect that was not modified by pretreatment of the rat with atenolol or propranolol; however, ICI 118.551 produced a significant reduction of the hypotensive response induced by fenoldopam.
• 4.Pretreatment of the animals with SCH 23390 produced a significant dose-related reversal of the rat blood pressure reduction induced by low doses of fenoldopam. Sulpiride produced a result similar to that induced by pretreatment with SCH 23390.
• 5.The pretreatment of the animals with 6-OH-DA surprisingly attenuated the response induced by fenoldopam and produced only a significant reversal of the reduction of mean blood pressure induced with the lower dose of fenoldopam.
• 6.The findings obtained in the present work do not provide further evidence of direct participation of β₂-adrenergic receptors on the mechanism of action of fenoldopam. Its action seems to be mainly due to activation of D₁ cardiovascular receptors.

     

Are imidazoline receptors involved in sympathetic neurotransmission in rat vas deferens

• 1.1. An involvement of imidazoline receptors in the modulation of neurotransmitter release was investigated in the prostatic portion of the rat vas deferens stimulated transmurally at 0.2 Hz or by single pulses.
• 2.2. Idaxozan and yohimbine induced a concentration-dependent potentiation of the contractile response to 0.2-Hz transmural stimulation in the epididymal and prostatic portion of the vas.
• 3.3. After reserpine treatment, idazoxan, but not yohimbine, still potentiated the contractile response, suggesting a possible involvement of imidazoline receptors.
• 4.4. Clonidine and rilmenidine, agonists with different affinities to α₂-adrenoceptors and imidazoline receptors, inhibited with the same potency the contractile responses to a single pulse transmural stimulation.
• 5.5. Yohimbine (a selective α₂-adrenoceptor antagonist) antagonized the inhibitory concentration effect curve to rilmenidine in a competitive manner. pA₂ values for idaxozan (an antagonist to α₂-adrenoceptors and imidazoline receptors) were not different when noradrenaline or rilmenidine were used as agonists. Phenoxybenzamine blocked the effect of both agonists.
• 6.6. Thus, the potency relationship of agonists, as well as the effect of the antagonists, did not favor the hypothesis that imidazoline receptors are involved in the idazoxan-potentiating effect in the rat vas deferens.

     

Smooth Muscle Layer-Specific Variations in the Autonomic Innervation of Bovine Myometrium

• 1.To clarify the autonomic innervation regulating longitudinal muscle (LM) and circular muscle (CM) motility in the bovine uterus, functional (nerve stimulation, adrenergic drug responsiveness) and biochemical studies (catecholamine content, radioligand binding) were conducted on parous luteal-phase myometrium.
• 2.Electrical field stimulation (EFS; 60 V, 0.5-msec duration) caused tetrodotoxin (1 μM)-sensitive contractions in a frequency-dependent manner (0.5–20 Hz) in both LM and CM layers.
• 3.The EFS-induced LM contractions were potentiated by propranolol and conspicuously decreased by phentolamine, yohimbine, idazoxan or guanethidine, but were unaffected by prazosin or atropine.
• 4.On the other hand, CM contractions were only slightly decreased by phentolamine, idazoxan, yohimbine and guanethidine, but were insensitive to propranolol, prazosin or atropine.
• 5.The noradrenaline content in LM was about five times higher than that in CM.
• 6.Noradrenaline, adrenaline, clonidine, xylazine, UK14,304 and phenylephrine caused concentration-dependent contractions of both smooth muscle layers.
• 7.Clonidine, UK14,304 and xylazine were more potent contractile agents than noradrenaline and phenylephrine.
• 8.The contractile response to noradrenaline was competitively antagonized by yohimbine, but not by prazosin.
• 9.Binding studies using [³H]-prazosin and [³H]-rauwolscine revealed that the bovine myometrium contained both α₁- and α₂-adrenoceptors, but the α₂-type receptor was dominant in both LM (94% of α-adrenoceptors) and CM (88%) layers.
• 10.The distribution of α-adrenoceptors was muscle layer-specific; that is, the concentration of α₁-receptors in LM was the same as in CM, but the concentration of α₂-receptors in LM was 2.6 times higher than that in CM.
• 11.The results of the present study indicate that there are layer-specific variations in the functional innervation of the parous bovine myometrium (exclusive adrenergic innervation in LM and adrenergic [minor] plus nonadrenergic, noncholinergic innervation [major] in CM), and that α₂-adrenoceptors, which were responsive to the excitatory response of endogenous and exogenous noradrenaline, were dominant in both muscle layers of the bovine myometrium.

     

Interplay between milrinone and adenosine in the inhibition of human platelet response

• 1.1. In this study, we investigated the influence of the isotropic agent and coronary vasodilator milrinone on platelet aggregation and intracellular levels of 3′,5′ cyclic adenosine monophosphate (cAMP) in human platelet-rich plasma (PRP) and whole blood (WB). Furthermore, we evaluated the influence of milrinone on the effects of adenosine, which reduces the platelet aggregation through an elevation of intraplatelet cAMP levels.
• 2.2. Milrinone decreased the platelet aggregation in response to agonists in both PRP and WB. A dose-dependent increase of intraplatelet cAMP levels was demonstrated: this result is in accordance with an effect on platelet phosphodiesterases.
• 3.3. Milrinone at low concentration and adenosine exerted additive effects on platelet aggregation and intraplatelet cAMP levels.
• 4.4. An interplay between milrinone and adenosine was shown in WB. Furthermore, dipyridamole, which prevents the uptake of endogenous adenosine, markedly enhanced the milrinone antiaggregating effect, whereas the adenosine receptor blocker, theophylline, decreased it.
• 5.5. The present data provide evidence that milrinone modulates the platelet function through an influence on intraplatelet levels of cAMP and it is able to interplay with substances stimulating adenylyl cyclase.
• 6.6. The interplay between milrinone and adenosine in the inhibition of the human platelet function could be effective during milrinone administration in the treatment of heart failure, when blood adenosine levels are significantly increased. These milrinone effects could be advantageous from a therapeutic point of view, since patients with heart failure are at risk of thrombosis and ischemic heart disease.

     

Pre- and postjunctional muscarinic receptor subtypes in the vas deferens of rat

• 1.1. A pharmacological study of the pre- and postjunctional muscarinic receptors of the isolated rat vas deferens was carried out using more selective agonists and antagonists.
• 2.2. The prejunctional receptor was characterized on electrically stimulated preparations, while the postjunctional receptor was studied on vasa deferentia without stimulation.
• 3.3. The results indicate that atropine exhibited a similar affinity for the two populations of muscarinic receptor subtypes of this tissue.
• 4.4. 4-DAMP was able to differentiate with high affinity a subtype located at postjunctional level which had pharmacological similarities with the M₃-ACh subtype and with low affinity a subtype located at prejunctional level.
• 5.5. The selective M₁-ACh agonist McN-A-343 was not able to activate the postjunctional receptor, but showed a similar affinity to ACh for the prejunctional one.
• 6.6. At present, the prejunctional receptor can be considered as an atypical M₁-ACh subtype based on the results obtained with the selective drugs available.

     

IP3 Production in A10 cells,an Established Aortic Smooth Muscle Cultured Cell Line: Effects of Agonist Administration Procedure and Culture Conditions

• 1.After normal culture (10% FBS), medium exchange itself evoked marked increases in IP₃ levels in A10 cells that masked the net change in IP₃ in response to vasopressin (100 nM).
• 2.Low-serum (0.3% FBS) culture for 10 days abolished the increase in IP₃ by medium exchange, and increased expression of cGMP kinase.
• 3.Stimulation of cells with vasopressin (100 nM) by a pipetting procedure, increased IP₃ levels irrespective of culture conditions.
• 4.This cell line therefore could be used in a contractile form (after low-serum culture) with pipetting procedure to observe IP₃ response, especially with regard to interactions with the cGMP signaling system.

     

Some pharmacodynamic aspects on long-acting β-adrenoceptor agonists

• 1.1. Formoterol and salmeterol are the first members of a new generation of long-acting β₂-adrenoceptor agonists for inhalation. The discovery of the long effect duration of formoterol was made by chance, while the development of salmeterol appeared to follow a purposeful research strategy.
• 2.2. Preclinical evaluation predictive of the clinical duration of effect of long-acting bronchodilators is not straightforward. Experiments in vitro may give false positive results, while experiments in vivo may show false negative results.
• 3.3. Once the principle of a long duration of effect was established, a number of novel long-acting β₂-adrenoceptor agonists of various chemical structure have emerged.
• 4.4. There are two alternative models for the explanation of the long duration of effect: the exosite binding explaining the mode of action of salmeterol, and the more general diffusion microkinetic model applicable for both formoterol and salmeterol.
• 5.5. Long-acting β-adrenoceptor agonists with a relatively low efficacy like salmeterol may, under certain circumstances, inhibit competitively the relaxing effect of agonists with higher efficacy like formoterol and salbutamol.
• 6.6. Like all other β₂-adrenoceptor agonists in current clinical use, formoterol and salmeterol comprise racemic mixtures. Only the RR- and R-enantiomers are pharmacologically active. The experimental compounds TA-2005 and picumeterol have been developed as pure RR- and R-enantiomers, respectively.

     

Endothelin-1 inhibition of the ATP-sensitive K+ channel in guinea-pig ventricular cardiomyocytes

• 1.1. Effects of endothelin-1 on the ATP-sensitive K⁺ channel were examined in guinea-pig ventricular cardiomyocytes.
• 2.2. The ATP-sensitive K⁺ channel was activated outwardly with amplitude of about 2.2 pA at 0 mV. The conductance was 31 pS at 5.4 mM external K⁺ solution. The open probability was inhibited, and was completely blocked at 1 nM of endothelin-1.
• 3.3. In contrast, endothelin-3 (1 nM) did not cause any effects on the channels.
• 4.4. Endothelin-1 (10 nM) significantly prolonged the action potential duration. These responses were reversible.
• 5.5. These results suggest that endothelin-1 may reverse the physiological responses to the stimulation of ATP-sensitive K⁺ channels, indicating its regulatory mechanisms under the disease conditions.

     

A lack of supersensitivity to opioid receptor agonists following chronic spinal opioid receptor antagonist administration in the rat

• 1.1. Male Sprague-Dawley rats were chronically tested with intrathecal (i.t.) receptor selective opioid antagonists to determine if antinociceptive supersensitivity developed to selective i.t. opioid receptor agonists.
• 2.2. A subcutaneously implanted osmotic minipump was used to deliver the μ-opioid receptor antagonist CTOP (0.3 nmol) or the b-opioid receptor antagonist naltrindole (5.5 nmol) for 7 days.
• 3.3. Following a 24 hr washout period, rats received a single i.t. dose (ED₅₀) of either DAMPGO (for CTOP-treated animals) or DPDPE (for naltrindole-treated animals) and the antinociceptive effects of the agents were tested on the tail-flick test.
• 4.4. Our findings revealed that chronic spinal treatment with selective opioid receptor antagonists did not induce an antinociceptive supersensitivity to selective opioid receptor agonists.
• 5.5. Perhaps this lack of supersensitivity is reflective of difficulties inherent to opioid receptor antagonists that do not possess negative intrinsic activity

.     

Pharmacologic characterization of [3H]dopamine and [3H]spiperone binding in mouse cerebellum

• 1.1. [³H]Dopamine and [³H]spiperone binding to cerebellar homogenates was characterized utilizing dopaminergic agonists, antagonists and non-dopaminergic drugs.
• 2.2. The [³H]DA binding to low affinity binding sites reveals a heterogenous population consisting of dopaminergic as well as serotonergic and noradrenergic sites. However, the high affinity binding of [³H]DA reflects dopaminergic sites, although a small contribution of serotonergic and noradrenergic binding sites cannot be excluded.
• 3.3. [³H]Spiperone also labels a heterogenous population of binding sites which, however, are mainly dopaminergic.

     

5-HT receptors on identified Lymnaea neurones in culture: Pharmacological characterization of 5-HT3 receptors

• 1.1. The selective agonist, 1-(m-chlorophenyl)-biguanide (m-CPBG) and antagonist, 3-tropanyl-3,5-dichlorobenzoate (MDL 72222) were used to characterize the 5-HT₃ receptors in cultured identified neurones; the serotonin-containing cerebral giant cells (CGCs) and some follower neurones in the buccal ganglia of Lymnaea stagnalis.
• 2.2. 5-HT and its agonists were pressure ejected, while the 5-HT antagonists were bath applied.
• 3.3. Although m-CPBG evoked mostly depolarizing responses, hyperpolarizing responses were sometimes evoked.
• 4.4. At 10⁻⁴ M, m-CPBG failed to mimic the responses of 5-HT, but at a concentration higher. 10⁻³ M, pressure-ejected m-CPBG mimicked most 5-HT responses.
• 5.5. The 5-HT₂ antagonist ketanserin failed to block the m-CPBG-evoked responses, whilst partially blocking the 5-HT responses.
• 6.6. These results suggest the presence of 5-HT₃ receptors similar to those found in mammalian neurones, and that multiple subtypes of these receptors may be present in Lymnaea neurones.

     

Influence of diethylcarbamazine and mefloquine on PGI2 synthesis by the rat thoracic aorta and myometrial tissues

• 1.1. The influence of the antifilarial drug diethylcarbamazine citrate (D) and dl-erythro mefloquine hydrochloride (Mf) on PGI₂ synthesis by the male rat thoracic aorta and day-20 pregnant rat myometrium was investigated in vitro using a rat platelet antiaggregatory bioassay method.
• 2.2. Pretreatment of the tissues with D (25.5–204 μM) or Mf (24–192 μM) for 30 min at 37°C significantly inhibited PGI₂ synthesis in a concentration-dependent manner.
• 3.3. D exhibited its inhibitory effect even in presence of exogenous arachidonic acid (AA) (16.6 μM) whereas Mf lost its inhibitory effect in presence of AA.
• 4.4. Pretreatment of urethane-anaesthetized rats with D (32 μmol kg⁻¹) but not Mf (7.5 μmol kg⁻¹) for 30 min significantly antagonized AA (4 nmol kg⁻¹)-induced hypotension
• 5.5. Furthermore, D (0.25–0.5 μM) antagonized AA-induced aggregation in rabbit platelet-rich plasma without affecting that of ADP.
• 6.6. D seemed to interfere with the action of the PG endoperoxide synthase (PG cyclooxygenase) whereas Mf seemed to interfere with the action of phospholipase A₂ (PLA₂) enzyme.
• 7.7. D may have exerted its effect via release of toxic O₂ radicals whereas Mf effect may have been due to an interaction with PLA₂ substrate phospholipids.
• 8.8. The demonstrated inherent property of these two drugs to inhibit the synthesis of the potent vasodilator, platelet antiaggregatory, anticonvulsant and antiinflammatory mediator PGI₂ may partly contribute towards better understanding of the biochemical mechanisms that underly some of the previously known but poorly understood actions of these drugs.

     

Neuromodulation in molluscan smooth muscle: the action of 5-HT,FMRFamide and purine compounds

• 1.1. The RR, OR, RS and RP muscles of Buccinum did not respond directly to 5-HT, but this monoamine converted their normally tonic ACh responses to fast twitch contractions with lowered tonic force. This action was not accompanied by significant membrane potential changes.
• 2.2. Pre-treatment with dibutyryl cAMP potentiated ACh responses and enhanced 5-HT modification of the responses.
• 3.3. All muscles responded strongly to FMRFamide with twitch contractions but this was not accompanied by significant membrane potential changes.
• 4.4. FMRFamide enhanced ACh contracture force and converted the responses into fast twitch activity. FMRFamide responses were dramatically inhibited by 5-HT with loss of all tonic force and fast twitch activity.
• 5.5. While dibutyryl cAMP did not affect FMRFamide responses, the IP₃ inhibitor lithium, at very high concentrations, caused a significant diminution of FMRFamide responses.
• 6.6. All four muscles were unresponsive to adenosine and ATP but all except the RP responded in a dose-dependent manner to GTP and GTP-γ-S over the 10⁻⁷-10⁻⁴ mol 1⁻¹ range. The responses showed moderate fast twich activity which was unaccompanied by action potential discharges. Guanosine was without effect, except at very high concentrations where it inhibited FMRFamide responses.
• 7.7. ACh and GTP acted additively to increase muscle force and to enhance ACh-induced depolarization. Similarly both GTP and GTP-γ-S acted additively, considerably enhancing FMRFamide responses.
• 8.8. It is proposed that 5-HT, FMRFamide and GTP may, via their separate receptors or by possible interaction with ion channels, activate secondary messenger systems to modify the calcium released by ACh-induced depolarization to modulate excitation-contraction coupling and force generation in these muscles.