Showing papers on "Atropine published in 2002"

Muscarinic Receptors Control Postprandial Release of Glucagon-Like Peptide-1: In Vivo and in Vitro Studies in Rats

Abstract: Plasma levels of glucagon-like peptide-1 (GLP-1) rise rapidly after nutrient ingestion through an indirect mechanism triggered from the proximal intestine and involving the vagus nerve that stimulates the L cell in the distal gut. The role of muscarinic receptors in this pathway was thus investigated using the anesthetized rat and fetal rat intestinal cells (FRIC) in culture. GLP-1 secretion from the distal gut increased 5-fold after 3 ml corn oil were placed into the proximal duodenum (P < 0.001). Atropine (a nonspecific muscarinic receptor antagonist) completely inhibited fat-induced GLP-1 secretion in vivo (P < 0.01). Pirenzepine (an M1 muscarinic receptor antagonist) also inhibited fat-induced GLP-1 secretion in vivo, by 91 +/- 6% (P < 0.01). Gallamine (an M2 muscarinic receptor antagonist) and 4-diphenylacetoxy-N-methylpiperidine (an M3 muscarinic receptor antagonist) had no effect. Incubating FRIC cultures with bethanechol (a muscarinic receptor agonist) stimulated GLP-1 secretion to 200 +/- 22% of control (P < 0.01). Pirenzepine and gallamine significantly inhibited bethanechol-stimulated GLP-1 secretion, by 96 +/- 12% and 98 +/- 8%, respectively (P < 0.01). Unexpectedly, 4-diphenylacetoxy-N-methylpiperidine stimulated GLP-1 secretion by FRIC cells, to 324 +/- 52% of the control value (P < 0.01). Double immunofluorescent staining using GLP-1 and M1, M2, and M3 muscarinic receptor antibodies showed expression of the three subtypes of muscarinic receptors by the L cells in rat ileal sections and FRIC cultures. These results demonstrate the role of M1 muscarinic receptors expressed by L cells in the control of postprandial secretion of GLP-1. M2 muscarinic receptors also seem to play a role in controlling GLP-1 secretion by fetal, but not adult, L cells.

Effects of beta(3)-adrenoceptor stimulation on prostaglandin E(2)-induced bladder hyperactivity and on the cardiovascular system in conscious rats.

Abstract: Aims To investigate the effects of selective beta(2)- and selective beta(3)-adrenoceptor (AR) agonists on prostaglandin (PG) E-2-induced bladder hyperactivity in conscious free-moving rats Methods Female Sprague-Dawley rats were anesthetized for implantation of bladder, intravenous, and intra-arterial catheters The effects of a beta(3)-AR agonist (CL316,243) on cystometric and cardiovascular parameters were assessed in conscious rats Intravesical instillation of PGE(2) (20-60 muM, 6 mL/hr) in conscious rats produced a concentration-dependent increase in voiding frequency Results In this model iv CL316,243 (beta(3)-AR agonist) reduced basal bladder pressure, increased micturition volume, and prolonged micturition interval in a dose-dependent manner, without affecting threshold pressure or micturition pressure On the other hand, iv procaterol (beta(2)-AR agonist) did not counteract the bladder hyperactivity Atropine (muscarinic antagonist) reduced micturition pressure and micturition volume, and shortened micturition interval CL316,243 slightly decreased mean blood pressure and increased heart rate only when given at high doses (10 and 100 mug/kg, iv) In contrast, procaterol caused a significant decrease in mean blood pressure and a significant increase in heart rate Atropine significantly increased heart rate Conclusions The present results clearly demonstrated that the beta(3)-AR agonist prolonged the micturition interval without producing significant cardiovascular side effects The human detrusor, like the rat detrusor, relaxes on beta(3)-AR stimulation Provided that these results are valid in humans, selective beta(3)-AR agonists might be clinically useful for controlling a certain type of bladder overactivity (Less)

Zebrafish M2 muscarinic acetylcholine receptor: cloning, pharmacological characterization, expression patterns and roles in embryonic bradycardia.

Abstract: 1. A zebrafish M2 muscarinic acetylcholine receptor (mAChR) gene was cloned. It encodes 495 amino acids in a single exon. The derived amino acid sequence is 73.5% identical to its human homologue. 2. Competitive binding studies of the zebrafish M2 receptor and [(3)H]-NMS gave negative log dissociation constants (pK(i)) for each antagonist as follows: atropine (9.16)>himbacine (8.05)>/=4-DAMP (7.83)>AF-DX 116 (7.26)>/=pirenzepine (7.18)>/=tropicamide (6.97)>/=methoctramine (6.82)>/=p-F-HHSiD (6.67)>carbachol (5.20). The antagonist affinity profile correlated with the profile of the human M2 receptor, except for pirenzepine. 3. Reverse transcription polymerase chain reaction and Southern blotting analysis demonstrated that the M2 mAChR mRNA levels increased during the segmentation period (12 h post-fertilization; h.p.f.) in zebrafish. By whole-mount in situ hybridization, the M2 mAChR was first detectable in the heart, vagus motor ganglion, and vagus sensory ganglion at 30, 48 and 60 h.p.f., respectively. 4. The muscarinic receptor that mediates carbachol (CCh)-induced bradycardia was functionally mature at 72 h.p.f. The effect of CCh-induced bradycardia was antagonized by several muscarinic receptor antagonists with the order of potency (pIC(50) values): atropine (6.76)>methoctramine (6.47)>himbacine (6.10)>4-DAMP (5.72)>AF-DX 116 (4.77), however, not by pirenzepine, p-F-HHSiD, or tropicamide (<10 micro M). 5. The effect of CCh-induced bradycardia was abolished completely before 56 h.p.f. by M2 RNA interference, and the bradycardia effect gradually recovered after 72 h.p.f. The basal heart rate was increased in embryos injected with M2 mAChR morpholino antisense oligonucleotide (M2 MO) and the effect of CCh-induced bradycardia was abolished by M2 MO in a dose-dependent manner. In conclusion, the results suggest that the M2 mAChR inhibit basal heart rate in zebrafish embryo and the M2 mAChR mediates the CCh-induced bradycardia.

Adverse reaction to atropine and the treatment of organophosphate intoxication.

Abstract: Atropine is the drug of choice for treatment of organophosphate nerve agent and insecticide intoxication and has been used for this indication for several decades. Adverse reactions to atropine may occur, and are of two types: toxic and allergic. Toxic reaction, the most common form, results from the anti-muscarinic effects of the drug. Since it is most probably related to interpersonal variation in sensitivity to atropine, toxic effects may appear at the usual therapeutic doses. The second type, allergic reaction, includes local manifestations, usually after the administration of eyedrops, and systemic reaction in the form of anaphylaxis. Since most patients manifest only a mild reaction, allergy testing is not performed and the prevalence of allergy to atropine is therefore not known. Severe allergic reaction to atropine is rare, as evidenced by the small number of case reports in the literature despite the drug's extensive use. Alternative anti-muscarinic drugs recommended for OP poisoning include glycopyrrolate and scopolamine. Glycopyrrolate is a peripheral anti-muscarinic drug that has been studied in comparison to atropine for many clinical indications, while scopolamine is an anti-muscarinic drug with both peripheral and central effects. An acceptable alternative regimen for patients with proven allergy to atropine is a combination of glycopyrrolate with centrally active drugs such as benzodiazepines or scopolamine.

The hepatic vagus nerve in the control of insulin sensitivity in the rat

Abstract: The objective was to determine if the cervical vagus or hepatic branch of the vagus nerve is a suitable site to produce functional parasympathetic denervation of the liver in the rat as assessed from the ability to produce insulin resistance. Anterior plexus denervation in both anesthetized rats and cats results in insulin resistance as assessed by the rapid insulin sensitivity test (RIST). This diagnostic test is a modified euglycemic clamp using the amount of glucose required to be infused to maintain euglycemia following a bolus administration of insulin (50 mU kg−1 over 5 min, 0.1 ml min−1 infusion) as the index of insulin sensitivity. Blood sampling was achieved through an arteriovenous silicone vascular shunt connecting the left carotid artery and the right jugular vein and allowed the close monitoring of blood glycemia throughout the test (every 2 min). The control RIST index (249.2±10.2 mg kg−1) was significantly decreased (P<0.001) following hepatic vagotomy (134.0±13.9). The intraportal infusion of 2.5 μg kg−1 min−1 of acetylcholine partially reversed (202.1±12.3) the insulin resistance. Intravenous atropine (1 mg kg−1) or hepatic anterior plexus denervation did not produce significant further insulin resistance. A similar degree of insulin resistance was produced by bilateral cervical vagotomy which was also partially reversed by acetylcholine. Complete hepatic parasympathetic denervation was achieved by selective hepatic vagal branch section. The data suggest that all of the parasympathetic nerves that regulate hormonal control of insulin resistance pass through the cervical vagus and the hepatic branch, and finally, through the anterior hepatic plexus along the common hepatic artery and that denervation at any of these sites leads to functional elimination of all hepatic parasympathetic input regulating insulin sensitivity. This approach provides an additional research tool to study the hepatic parasympathetic reflex control of peripheral insulin action.

Muscarinic agonist properties involved in the hypotensive and vasorelaxant responses of rotundifolone in rats.

Abstract: The acute cardiovascular effects of rotundifolone (ROT), the major constituent (63.5 %) of the essential oil of Mentha x villosa (OEMV), were tested in rats by using a combined (in vivo and in vitro) approach. ROT (1, 5, 10, 20 and 30 mg kg(-1) i. v.) induced a significant and dose-dependent hypotension and bradycardia in non-anaesthetized normotensive rats. The hypotensive effect was significantly attenuated by pre-treatment of the rats with atropine (2 mg kg(-1) i. v.) or L-NAME (20 mg kg(-1) i. v.). Furthermore, the bradycardic effect was abolished by atropine. In isolated rat atrial preparations, ROT (10, 100, 300 and 500 microg ml(-1)) produced concentration-related negative inotropic and chronotropic effects. In isolated intact aortic rings, increasing concentractions of ROT (0.3, 1, 10, 100, 300 and 500 microg ml(-1)) were able to antagonize the contractile effect of phenylephrine (1 microM) (IC50 = 184 +/- 6 microg ml(-1)). The smooth muscle-relaxant activity of ROT was inhibited by either removal of vascular endothelium, atropine (1 microM), L-NAME (100 and 300 microM) or indomethacin (10 microM) (IC50 values = 235 +/- 7, 247 +/- 8, 387 +/- 21, 723 +/- 75 and 573 +/- 38 microg ml(-1), respectively). These results suggest that rotundifolone markedly lowers arterial pressure and heart rate in non-anaesthetized animals. The hypotensive action of rotundifolone can be a consequence of a decrease in heart rate and peripheral vascular resistance, probably due to a non-selective muscarinic receptor stimulation.

Acetylcholine receptors do not mediate the immobilization produced by inhaled anesthetics.

Abstract: Acetylcholine receptors transmit excitatory impulses, are broadly distributed throughout the central nervous system, and are particularly sensitive to the depressant effects of inhaled anesthetics. Thus these receptors are potential mediators of the immobility produced by inhaled anesthetics. We tested this potential in rats by giving intraperitoneal atropine, scopolamine, and mecamylamine to block muscarinic (atropine and scopolamine) and neuronal nicotinic (mecamylamine) acetylcholine receptors. Block with scopolamine (up to 100 mg/kg), atropine (10 mg/kg), mecamylamine (up to 4 mg/kg), or atropine (10 mg/kg) plus mecamylamine (up to 4 mg/kg) did not significantly decrease the isoflurane concentration required to suppress movement to noxious stimulation (minimum alveolar anesthetic concentration). We also gave atropine intrathecally, finding that the infusions that did not cause permanent paralysis produced slight or no decreases in the minimum alveolar anesthetic concentration. We conclude that acetylcholine receptors do not seem to play a role as mediators of immobilization by inhaled anesthetics.

Intravenously administered oxotremorine and atropine, in doses known to affect pain threshold, affect the intraspinal release of acetylcholine in rats.

Abstract: :Both systemically and intrathecally administered cholinergic agonists produce antinociception while cholinergic antagonists decrease pain threshold. The mechanism and the site of action of ...

Cholinergic and purinergic contribution to the micturition reflex in conscious rats with long-term bladder outlet obstruction.

Abstract: The urethra of female Wistar rats was partially obstructed for 15 weeks. The effects of atropine (1 mg/kg i.v.), suramin (100 mg/kg i.v.), and a combination of atropine and suramin on the peak micturition pressure (MP) were compared during cystometry in conscious rats controls or subjected to outlet obstruction. On the isolated bladder dome, we studied the inhibitory effect of 1 micromol/L atropine, 1 mmol/L suramin, and the combination of the two drugs on contractions induced by electrical field stimulation (EFS). We studied also the contractile response to 80 mmol/L KCl and the concentration-response curves to noradrenaline, phenylephrine, and carbachol on the bladder dome and bladder neck and alpha, beta-methylene adenosine triphosphate on the bladder dome. In conscious rats, the MP, bladder capacity, and micturition volume were significantly higher in obstructed rats than in controls. Suramin induced the same inhibition in the two groups of animals (-30.7 +/- 13.3% in controls and -29.2 +/- 8.5% in obstructed rats). Atropine decreased the MP, but this effect was twofold greater in obstructed animals (-28.1 +/- 3.1% and -65.1 +/- 6.9% in control and obstructed animals, respectively). However, the combined effect of atropine and suramin was additive in controls but not in obstructed (-56.7 +/- 5.4% and -55.9 +/- 9.4%, respectively). Similar results were obtained in vitro using 1 micromol/L atropine and 1 mmol/L suramin. In the obstructed bladder dome and bladder neck, we found a great reduction in KCl- and carbachol-induced contractility but no difference in the response to EFS. Responses to noradrenaline and phenylephrine were moderately reduced in the bladder neck only, whereas responses to alpha, beta-methylene adenosine triphosphate in the bladder dome were not reduced except at the concentration of 300 micromol/L. We conclude that long-term obstruction in rats could induce cholinergic nerve fiber proliferation as suggested by the decrease in M(3) muscarinic receptor contractility (desensitization) and by a greater sensitivity of the MP to atropine.

Cyclosporine attenuates the autonomic modulation of reflex chronotropic responses in conscious rats.

Abstract: Cyclosporine A (CyA), an immunosuppressant drug, has been shown to attenuate the baroreflex control of heart rate (HR). This study investigated whether or not the CyA-induced baroreflex dysfunction is due to alterations in the autonomic (sympathetic and parasympathetic) control of the heart. We evaluated the effect of muscarinic or beta-adrenergic blockade by atropine and propranolol, respectively, on reflex HR responses in conscious rats treated with CyA (20 mg·kg–1·day–1 dissolved in sesame oil) for 11–13 days or the vehicle. Baroreflex curves relating changes in HR to increases or decreases in blood pressure (BP) evoked by phenylephrine (PE) and sodium nitroprusside (NP), respectively, were constructed and the slopes of the curves were taken as a measure of baroreflex sensitivity (BRSPE and BRSNP). Intravenous administration of PE and NP produced dose-related increases and decreases in BP, respectively, that were associated with reciprocal changes in HR. CyA caused significant (P < 0.05) reductions in ...

Heart rate response to intravenous atropine during propofol anesthesia.

Abstract: UNLABELLED We studied the dose-response relationships for atropine-induced heart rate (HR) changes in 61 patients during propofol anesthesia The control group (n = 15) received no propofol Group P-5 (n = 22) received IV propofol 125 mg/kg over 1 min followed by propofol at 5 mg kg(-1) h(-1) After tracheal intubation, anesthesia was maintained with propofol 5 mg kg(-1) h(-1) and 67% nitrous oxide in oxygen Group P-10 (n = 24) received IV propofol 25 mg/kg over 1 min followed by propofol at 10 mg kg(-1) h(-1) The P-10 protocol was otherwise identical All patients received incremental doses of IV atropine 5 microg/kg over 5 s at 2-min intervals until HR increased >20 bpm from baseline values Heart rate response to atropine 10 microg/kg was attenuated in Groups P-5 (12 +/- 7 bpm) and P-10 (9 +/- 6 bpm) compared with the control group (28 +/- 13 bpm, P 20 bpm in all patients of the control group, but in only 43% and 13% of patients in Groups P-5 and P-10, respectively (P<005) These results indicate the decreased HR responsiveness to IV atropine in patients receiving propofol, which cannot be effectively overcome by a large dose of atropine, is possibly attributable to propofol-induced suppression of the sympathetic nervous system IMPLICATIONS Heart rate response to IV atropine is attenuated during propofol anesthesia, and the decreased responsiveness to atropine cannot be effectively overcome by a large dose of atropine

Comparative antidotal effects of diphenhydramine and atropine against dichlorvos-induced acute toxicosis in rats

Abstract: The antidotal effect of diphenhydramine against acute toxicosis induced by the organophosphorus insecticide dichlorvos in male rats was evaluated and compared with that of the standard antidote atropine. Dichlorvos at 45 mg/kg orally induced cholinergic toxicity in the rats with cholinesterase inhibition in the plasma (62%), erythrocytes (59%) and whole brain (37%) in comparison with the control group. Intraperitoneal administration of diphenhydramine or atropine at 20 mg/kg 5 minutes after the dichlorvos dosing significantly decreased the incidences of toxic manifestations and gradually decreased the severity of toxicosis during a 60-minute observation period. The antidotal effect of diphenhydramine appeared to be comparable with that of the atropine. However, addition of diazepam did not improve the antidotal efficacy of diphenhydramine. The reductions in blood and brain cholinesterase activities occurred in all the dichlorvos-treated rats regardless of antidotal therapy. The data indicate the antidotal efficacy of diphenhydramine against dichlorvos-induced poisoning in rats in a manner comparable with that of atropine.

The attenuating effect of intraglossal atropine on the oculocardiac reflex.

Abstract: INTRODUCTION Bradycardia during strabismus surgery is reduced better by intravenous than by intramuscular (deltoid) anticholinergics, but recent studies suggest that injection into the tongue works faster than into the deltoid. We sought to study this using the suppression of the oculocardiac reflex during eye surgery as a parameter. METHODS 804 children and adults underwent calibrated extraocular muscle tensioning during controlled, inhalational general anesthesia. A systemic anticholinergic agent was distributed by different routes to patient-subject sub-groups: preoperative oral, or induction intravenous, intramuscular (deltoid) and intraglossal (submucosal at the base of the tongue). A large control group received no anticholinergic. RESULTS The control group had an oculocardiac reflex averaging 17.2% heart rate reduction (bradycardia), 6% of whom had greater than a 50% heart rate reduction. This oculocardiac reflex bradycardia was reduced to only a 6.7% heart rate reduction by oral and intradeltoid routes and was essentially eliminated by both intravenous (-2.3%) and intraglossal (-0.9%) routes. CONCLUSION Intraglossal atropine is an effective alternative for oculocardiac reflex prophylaxis when intravenous access is not readily available in strabismus surgery. The intraglossal route is in fact slightly more effective in this regard that the intravenous route per se.

Constitutive inhibitory action of muscarinic receptors on adenylyl cyclase in cardiac membranes and its stereospecific suppression by hyoscyamine.

Abstract: Muscarinic acetylcholine receptors in the heart have been shown to display agonist-independent spontaneous (constitutive) activity which causes changes in the opening of cardiac ion channels and in the activity of G proteins. We investigated whether an inhibition of the constitutive activity of muscarinic receptors induced by the binding of antagonist brings about a change in the synthesis of cyclic AMP in rat cardiac membranes, and whether the action ofthe antagonist is stereospecific. Atropine and S-(-)-hyoscyamine were indeed found to enhance the forskolin-stimulated synthesis of cyclic AMP in rat cardiac (both atrial and ventricular) membranes by up to 24%. The effect was stereospecific and the potency of R-(+)-hyoscyamine was 30 fold lower than that of the S-(-) enantiomer, confirming that the action of hyoscyamine is receptor-mediated. The effect did not depend on the presence of endogenous acetylcholine in the system used. The results strongly suggest that the adenylyl cyclase in the heart is exposed to continuous mild inhibition by constitutively active muscarinic receptors in the membranes of cardiomyocytes.

Mechanism of vascular relaxation by cholinomimetic drugs with special reference to pilocarpine and arecoline.

Abstract: The muscarinic receptor-mediated and non-muscarinic vascular effects of cholinomimetic drugs used in glaucoma were quantified. On the isolated rat aorta, the vascular tone induced by phenylephrine is functionally antagonized by cholinomimetic drugs. Based on EC50, the relative order of potency for the endothelium-dependent vascular relaxation was acetylcholine (0.05 microM) 1 > (+/-)-methacholine (0.35 microM) 1/7 > carbachol (0.63 microM) 1/12 > (+/-)-aceclidine (1.26 microM) 1/25. The maximal effects of the four agonists varied between 82-87%. The muscarinic vascular relaxation of 0.03 microM to 100 microM pilocarpine was less than 15%. At high concentrations, pilocarpine had 1/20.000 the vascular activity of acetylcholine. Physostigmine failed to potentiate the vascular relaxation of exogenous acetylcholine, indicating the absence of acetylcholine esterase in the tissue. Arecoline, with an EC50 of 7.76 microM, was partly sensitive to the removal of the endothelium. Atropine treatment did not block the vascular effect of high concentrations of pilocarpine. Atropine, as expected, blocked the vascular effects of carbachol with K(B) = 3.2 nM. Pilocarpine produces vascular relaxation by its competition with spasmogens like phenylephrine, oxymetazoline, vasopressin or latanoprost. Arecoline also shares these properties with pilocarpine in the blood vessel. The molecular mechanism of the vascular effects as well as ocular clinical implications of cholinomimetic drugs is discussed.

The influence of anticholinergic drug and oxime selection on the effectiveness of antidotal treatment against tabun-induced poisoning in mice.

Abstract: 1. The influence of oximes (pralidoxime, obidoxime, HI-6) and anticholinergic drugs (atropine, benactyzine, biperiden, scopolamine) on the effectiveness of antidotal treatment to eliminate tabun-induced lethal effects was studied in mice. 2. Obidoxime seems to be the most efficacious oxime for the elimination of tabun-induced lethal effects in mice, although the difference in the efficacy of obidoxime and HI-6 is not significant when they are combined with atropine. 3. Obidoxime and HI-6 when combined with centrally acting anticholinergic drugs (benactyzine, biperiden and scopolamine) seem to be more efficacious in the elimination of toxic effects of the lethal dose of tabun than their combination with atropine. 4. The findings support the hypothesis that the choice of acetylcholinesterase reactivators as well as the anticholinergic drug selection are important for the effectiveness of antidotal mixture in the case of antidotal treatment of tabun-induced acute poisoning.

Neurochemical regulation of cough response to capsaicin in guinea-pigs

Abstract: 1. Although monumental efforts have been made to define the action sites of cough, the importance of neurotransmitter systems in the cough reflex has received limited attention. We studied the roles for four major neurotransmitters [acetylcholine, histamine, serotonin (5-hydroxytryptamine, 5-HT) and dopamine] in the modulation of the cough reflex. 2. Atropine (muscarinic cholinergic blocking agent), pyrilamine maleate (PM, histamine H1 blocker), cimetidine (histamine H2 blocker), 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT, specific 5-HT1A receptor agonist) and SCH-23390 (selective dopamine D1 receptor antagonist) were examined on the cough response to inhaled capsaicin in conscious guinea-pigs. 3. All the drugs significantly decreased the number of capsaicin-induced coughs in a dose-dependent manner. To compare the sensitivity of these drugs on cough response, we calculated the effective doses for 50% inhibition of cough (ED50) when the animals were exposed to 3 x 10-4 m capsaicin. The ED50 values were 0.03 microm kg-1 for atropine, 0.2 microm kg-1 for 8-OH-DPAT, 6.2 microm kg-1 for SCH-23390, 8.5 microm kg-1 for PM and 13.9 microm kg-1 for cimetidine. 4. These findings indicated that all these four neurotransmitters may be involved in the regulation of the cough reflex. Multiple changes of these neurotransmitters in disorders of the central nervous system might synergically affect the cough reflex.

General pharmacological profile of the novel muscarinic receptor agonist SNI-2011, a drug for xerostomia in Sjögren's syndrome. 3rd communication: effects on respiratory and cardiovascular systems.

Abstract: A novel muscarinic receptor agonist, SNI-2011 ((+/-)-cis-2-methylspiro[1,3-oxathiolane- 5,3'-quinuclidine]monohydrochloride hemihydrate, cevimeline, CAS 153504-70-2), is a candidate therapeutic drug for xerostomia in Sjogren's syndrome. The general pharmacological properties of this drug on the respiratory and cardiovascular systems were investigated in guinea pigs and dogs. SNI-2011 reduced the contractile force and beating rate of isolated right guinea pig atrium at 1 x 10(-6) mol/l or higher and 3 x 10(-6) mol/l or higher, respectively. SNI-2011 reduced the contractile force of isolated left atrium induced by electric stimulation at 1 x 10(-6) mol/l or higher. In anesthetized dogs, SNI-2011 caused a transient decrease in blood pressure, tachycardia and an increase in femoral arterial blood flow at 0.01 mg/kg i.v. or higher. At 1 mg/kg it caused continuous bradycardia, a decrease in femoral arterial blood flow and an increase in respiration rate in addition to the changes observed immediately after injection. A transient negative T-wave was observed as the only change in the ECG immediately after injection at 1 mg/kg. However, when SNI-2011 was injected intraduodenally, a decrease in femoral arterial blood flow, bradycardia and a tendency to increase respiration rate were observed at doses of 1 to 3 mg/kg. All these events in dogs were antagonized by atropine. These results suggest that oral administration of SNI-2011, that is the clinical administration route, can distinctly reduce the muscarinic effects on the respiratory and cardiovascular systems compared to intravenous administration.