Utility of the Japanese Glomerular Filtration Rate Equation in Estimating Glomerular Filtration Rate of Donor Kidney.

BACKGROUND: An equation for the estimated glomerular filtration rate (eGFR) is generally used for evaluating renal function in Japan. OBJECTIVE: To assess the accuracy of the preoperative eGFR for estimating kidney donors' measured glomerular filtration rate (mGFR). METHODS: Between April 2009 and August 2014, 91 Japanese living kidney donors were included in this study. The eGFR was calculated as follows: eGFR = 194 × serum creatinine(-1.094) × Age(-0.287) (and × 0.739 for women), and the mGFR was evaluated using inulin clearance. The preoperative eGFR was then compared with the mGFR. RESULTS: Patients included 27 men and 64 women with a mean age of 56.8 ± 9.5 years (range, 36-79 years), mean body surface area of 1.56 ± 0.14 m(2) (range 1.27-1.92 m(2)), mean body mass index of 22.3 ± 2.3 kg/m(2) (range 14.0-27.0 kg/m(2)), and mean serum creatinine level of 0.66 ± 0.14 mg/dL (range 0.39-0.97 mg/dL). The mean eGFR was 81.3 ± 14.2 mL/min/1.73 m(2) (range 45.5-125.9 mL/min/1.73 m(2)), and the mean mGFR was 89.0 ± 15.5 mL/min/1.73 m(2) (range 45.4-130.7 mL/min/1.73 m(2)). The eGFR was significantly lower than the mGFR (P < .001). The correlation coefficient for the relationship between the eGFR and mGFR values was 0.503, and the mean difference between the 2 values was -7.8 (8.7%). CONCLUSIONS: Although the eGFR correlated with the mGFR, the eGFR values did not accurately estimate the mGFR in living kidney donors. Therefore, it is necessary to evaluate the mGFR, especially in marginal kidney donors.

Possible involvement of cyclic adenosine monophosphate-independent mechanism in the positive chronotropic effect of norepinephrine in the isolated guinea pig right atrium.

BACKGROUND: Although both positive chronotropic and inotropic effects of beta-adrenergic stimulation are thought to be mediated by cyclic adenosine 3'5'-monophosphate, phosphodiesterase III inhibitors such as amrinone and milrinone potentiate the positive inotropic effect of catecholamines with minimum influence on the heart rate in clinical setting. The aim of the current study was to compare the positive chronotropic effect of norepinephrine with that of forskolin to elucidate whether cyclic adenosine monophosphate is relevant to the chronotropic effect of norepinephrine. METHODS: Concentration-response curves for the positive chronotropic effects of norepinephrine and forskolin on the spontaneously beating right atria of guinea pigs were determined in the absence and presence of phosphodiesterase inhibitors or ion channel inhibitors. In some experiments, the left atria driven electrically were used to determine the positive inotropic effect of norepinephrine. RESULTS: Norepinephrine and forskolin increased the beating rate in a concentration-dependent manner. The positive chronotropic effect of forskolin was potentiated by amrinone and 3-isobutyl-1-methylxanthine, whereas the positive chronotropic effect of norepinephrine was not potentiated by the phosphodiesterase inhibitors. In contrast, the positive inotropic effect of norepinephrine was potentiated by amrinone. The hyperpolarization-activated inward current inhibitor cesium chloride and L-type voltage-dependent Ca2+ current inhibitor verapamil suppressed the chronotropic effect of norepinephrine, whereas these inhibitors did not affect the chronotropic effect of forskolin. CONCLUSION: Norepinephrine increases the spontaneously beating rate by a different mechanism from that of forskolin, suggesting that cyclic adenosine monophosphate is causally unrelated to the positive chronotropic effect of norepinephrine in the guinea pig heart.

Interaction of edrophonium with muscarinic acetylcholine M2 and M3 receptors.

BACKGROUND: It has been reported that edrophonium can antagonize the negative chronotropic effect of carbachol. This study was undertaken to evaluate in detail the interaction of edrophonium with muscarinic Mz and M3 receptors. METHODS: A functional study was conducted to evaluate the effects of edrophonium on the concentration-response curves for the negative chronotropic effect and the bronchoconstricting effect of carbachol in spontaneously beating right atria and tracheas of guinea pigs. An electrophysiologic study was conducted to compare the effects of edrophonium on carbachol-, guanosine triphosphate (GTP)gama S-, and adenosine-induced outward K+ currents in guinea pig atrial cells by whole cell voltage clamp technique. A radioligand binding study was conducted to examine the effects of edrophonium on specific [3HIN-methylscopolamine (NMS) binding to guinea pig atrial (M2) and submandibular gland (M3) membrane preparations, and on atropine-induced dissociation of [3H]NMS. RESULTS: Edrophonium shifted rightward the concentration-response curves for the negative chronotropic and bronchoconstricting effects of carbachol in a competitive manner. The pA2 values for cardiac and tracheal muscarinic receptors were 4.61 and 4.03, respectively. Edrophonium abolished the carbachol-induced outward current without affecting the GTPgamma S- and adenosine-induced currents in the atrial cells. Edrophonium inhibited [3H]NMS binding to M2 and M3 receptors in a concentration-dependent manner. The pseudo-Hill coefficient values and apparent dissociation constants of edrophonium for M2 and M3 receptors were 1.02 and 1.07 and 21 and 34 microM, respectively. Edrophonium also changed dissociation constant values of [3H]NMS without affecting its maximum binding capacities. CONCLUSION: Edrophonium binds to muscarinic M2 and M3 receptors nonselectively, and acts as a competitive antagonist.

Food-deprived activity stress decreased the activity of the histaminergic neuron system in rats.

The hypothalamus, which is rich in histaminergic neurons, is highly sensitive to aversive stimuli such as stress. Histamine H3 receptors, which regulate histamine release from the presynaptic site, are associated with stress-induced brain activity. In this study, we investigated the changes of histamine content and histamine H1 and H3 receptors in the brains of rats subjected to stress induced through food deprivation and physical activity on a running wheel (food-deprived activity stress). For purposes of comparison, we also examined the stressful effects of forced swimming on the histaminergic neuron system of rats. The H3 receptor density rapidly declined in the acute phase of stress but gradually returned to the control level in the chronic phase. On the other hand, the H1 receptor slowly decreased and remained at a low level during the chronic phase. These results reveal that there is a discrepancy between the levels of H1 and H3 receptors in the acute and chronic phases of stress. Brain histamine content gradually increased during the late phase of both food-deprived activity stress and forced swimming stress. These changes presumably resulted in the inhibition of histaminergic neuronal activity in the chronic stress condition. In accordance with this hypothesis, the intraventricular administration of histamine significantly reduced the hyperactivity caused by food-deprived activity stress. Since extensive exercise and restricted feeding are thought to be associated with anorexia nervosa, the abnormalities in the histaminergic neuron system might contribute to trait status in anorexia nervosa.

[Focal segmental glomerulosclerosis associated with type C virus hepatitis and decrement of proteinuria by interferon-alpha therapy].

Focal segmental glomerulosclerosis (FSGS) associated with type C virus (HCV) hepatitis has not been described in the literature to date. However, we experienced a 30-year-old man, who had had HCV hepatitis, developed nephrotic syndrome and was admitted to our hospital. The first renal biopsy showed FSGS which was diagnosed by light, immunofluorescent, and electron microscopic study. FSGS diagnosis was based upon the findings of focal segmental glomerular sclerosis associated with hyalinosis and foam cells, segmental deposition of IgM and C3 on glomeruli, and epithelial cell vacuolization in the Bowman's space. HCV hepatitis was treated with interferon-alpha (INF-alpha) over 6 months. The treatment brought the disappearance of not only HCV-RNA from the blood, but also the manifestation of nephrotic syndrome. Therefore, the second renal biopsy was performed, but did not reveal any great pathological improvement. Five months later after the remission, he again had an elevated HCV-RNA level and a relapse of nephrotic syndrome. He was retreated with the same therapy and achieved a second remission of nephrotic syndrome. FSGS associated with HCV hepatitis is described first and the implication of INF-therapy in the improvement of proteinuria is discussed.

Production of exfoliative toxin A by Staphylococcus aureus isolated from mastitic cow's milk and farm bulk milk.

The production of exfoliative toxins A and B (ETA and ETB) by Staphylococcus aureus isolated from mastitic cow's milk and farm bulk milk was examined by the reverse passive latex agglutination method (RPLA). ETA was detected in 2 (1.2%) of 162 isolates from mastitic cow's milk and in 1 (0.6%) of 166 isolates from farm bulk milk. RPLA titers of these isolates were much lower than in human isolates. No ETB was detected in any of the isolates tested. These ETA-positive isolates belonged to bovine ecovar. They were non-typable using the international phage set for human strains. When these ETA-positive isolates were subcutaneously inoculated into neonatal mice, general exfoliation of the epidermis accompanied by the so-called Nikolsky sign was not recognized. By the immunoblotting and PCR methods, however, ETA and eta gene were recognized in the ETA-positive isolates from mastitic cow's milk and farm bulk milk. These data suggest that ETA is also produced by bovine isolates of S. aureus, but in smaller quantities.

Involvement of barium-sensitive K+ channels in endothelium-dependent vasodilation produced by hypercapnia in rat mesenteric vascular beds.

1. We examined the vasodilatory effect of hypercapnia in the rat isolated mesenteric vascular bed. The preparation was perfused constantly (5 ml min(-1) with oxygenated Krebs-Ringer solution, and the perfusion pressure was measured. In order to keep the extracellular pH (pHe) constant (around 7.35) against a change in CO2, adequate amounts of NaHCO3 were added to Krebs-Ringer solution. 2. In the endothelium intact preparations, an increase in CO2 from 2.5% to 10% in increments of 2.5% decreased the 10 microM phenylephrine (PE)-produced increase in the perfusion pressure in a concentration-dependent manner. Denudation of the endothelium by CHAPS (3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulphonate) (5 mg l(-1), 90 s perfusion) abolished the vasodilatory effect of hypercapnia. 3. An increase in CO2 from 5% to 10% reduced the increases in the perfusion pressure produced by 10 microM PE and 400 nM U-46619 by 48% and 44%, respectively. NG-monomethyl-L-arginine (100 microM) and indomethacin (10 microM) did not affect the vasodilatory effect of hypercapnia, whereas the vasodilatory response of the preparation to hypercapnia disappeared when the preparation was contracted by 60 mM K+ instead of PE or U-46619. 4. The vasodilatory effect of hypercapnia observed in the PE- or U-46619-precontracted preparation was affected by neither tetraethylammonium (1 mM), apamin (500 microM), glibenclamide (10 microM), nor 4-aminopyridine (1.5 mM). On the other hand, pretreatment with Ba2+ at a concentration of 0.3 mM abolished the hypercapnia-produced vasodilation. 5. An increase in the concentration of K+ in Krebs-Ringer solution from 4.5 mM to 12.5 mM in increments of 2 mM reduced the PE-produced increase in the perfusion pressure in a concentration-dependent manner. Pretreatment of the preparations with not only Ba2+ (0.3 mM) but also CHAPS abolished the vasodilatory effect of K+. 6. The results suggest that an increase in CO2 produces vasodilation by an endothelium-dependent mechanism in the rat mesenteric vascular bed. The membrane hyperpolarization of the endothelial cell by an activation of the inward rectifier K+ channel seems to be the mechanism underlying the hypercapnia-produced vasodilation. Neither nitric oxide nor prostaglandins are involved in this response.

Behavioural characterization and amounts of brain monoamines and their metabolites in mice lacking histamine H1 receptors.

Behavioural assessments were made of mutant mice lacking histamine H1 receptors to reveal the function of H1 receptors in the behaviour of mice. Exploratory behaviour of mice in a new environment was examined to discover whether the absence of H1 receptors in mice affects actions relating to their emotions. The H1 receptor-deficient mice showed a significant decrease in ambulation in an open field and on an activity wheel. Cognitive functions and anxiety were examined using passive avoidance response test and the elevated plus-maze test, respectively. The passive avoidance test did not show any change in latency. The elevated plus-maze test revealed that the transfer latency of the mutant mice was significantly prolonged, indicating that H1 receptors are partly associated with the control of anxiety. Aggressive behaviour was examined by a resident-intruder aggression test. When confronted with an intruder, the mutant mice attacked the intruder significantly slower and less frequently than did wild-type mice after a six-month isolation period. A formalin test and a forced swimming test were used to evaluate the nociceptive response and depressive or despairing state, respectively, of both groups. The mutant mice showed a significant decrease of nociceptive response in the late phase without affecting the early phase. There was no significant difference in the forced swimming test between the two groups. The brain content of monoamines and their metabolites was measured in the H1 receptor null and wild-type mice. The turnover rate of 5-hydroxytryptamine defined by the ratio of 5-hydroxyindoleacetic acid and 5-hydroxytryptamine was significantly increased in the cerebral cortex and hippocampus of H1 receptor null mice. These results support the previous pharmacological findings that histamine modulates various neurophysiological functions such as locomotor activity, emotion, memory and learning, nociception and aggressive behaviour through H1 receptors.

ATP-induced ventricular asystole and hypotension during endovascular stenting surgery.

PURPOSE: To describe four cases of endoluminal stenting surgery in which adenosine 5'-triphosphate (ATP) was used to arrest the heart for accurate placement of the stent-graft. CLINICAL FEATURES: Four patients with descending thoracic aortic aneurysm were anaesthetized for deployment of a self-expanding stent-graft. Maintenance of general anaesthesia was performed with isoflurane and nitrous oxide in three patients, and with fentanyl and propofol in another. An initial trial of 20 mg ATP was administered via a central venous catheter as rapidly as possible, and produced third degree AV block of 8 +/- 1.7 sec and 59.7 +/- 17.5 sec hypotension, mean blood pressure < 60 mmHg, in three patients. The time to onset of AV block was 15.7 +/- 6.7 sec. In these patients, deployment of the stent-graft was performed during ventricular asystole produced by 30 mg ATP, which produced 16.3 +/- 2.1 sec third and second degree AV block. In one patient anaesthetized with fentanyl and propofol, 20 mg ATP did not change AV conduction. However, after 10 mg edrophonium, 20 mg ATP produced 9 sec third degree AV block. In all cases, heart rate and PQ interval were restored to the pre-drug control level within 50 sec after the commencement of AV block. There were no clinical complications related to this procedure in any patient. CONCLUSION: ATP is a convenient and suitable agent to produce transient ventricular asystole for the precise deployment of a self-expanding stent-graft. Co-administration of a parasympathomimetic agent might potentiate the inhibitory effect of ATP on AV conduction.

Targeting disruption of histamine H1 receptors in mice: behavioral and neurochemical characterization.

With gene targeting, one can practically knock out a gene in vivo and create a mutant organism that completely lacks the gene product. The mutant mice lacking histamine H1 receptors was generated by the method of gene targeting. In brains of homozygous mutant mice, no specific binding of [3H]pyrilamine was seen. The mutant mice showed impaired locomotor activity and exploratory behavior in an open field and activity wheel. Behaviors of the mutant mice were examined with several other tasks such as passive avoidance test, resident-intruder aggression test and formalin test to clarify the role for the H1 receptors in behaviors. Behavioral changes observed in the mutant mice are almost compatible with those obtained by the classical pharmacological tools. In correlation to the behavioral changes in the mutant mice, 5-hydroxytryptamine release was significantly increased in the brains of mutant mice.

A comparison between chronotropic effects of neostigmine and edrophonium in isolated guinea pig right atrium.

Bradycardia is one of the inevitable and undesirable responses when the muscle weakness induced by nondepolarizing muscle relaxants is reversed by AChE inhibitors. The current study was designed to compare the bradycardiac effects of the two AChE inhibitors used widely in clinical anesthesia, neostigmine and edrophonium. Isolated, spontaneously beating guinea pig right atrial preparations were used as the experimental model, and in some cases, electrical field stimulation was utilized to stimulate parasympathetic nerve terminals within the atria. Neostigmine decreased the spontaneously beating rate in a concentration-dependent manner at concentrations up to 10 microM. At higher concentrations, the agent restored the beating rate to the predrug control level. Atropine abolished the biphasic response of the atrium to neostigmine. In contrast, edrophonium had no effect on the spontaneous beating rate. However, edrophonium (3 microM) potentiated the field stimulation-induced negative chronotropic effect. Tetrodotoxin did not inhibit the chronotropic effect of neostigmine. Both neostigmine and edrophonium at higher concentrations inhibited the negative chronotropic effect of carbachol. In conclusion, neostigmine possesses potential dual effects on cardiac muscarinic ACh receptors. Low concentrations of neostigmine may stimulate the receptors directly, and at higher concentrations neostigmine may act as an antimuscarinic agent. On the other hand, edrophonium may inhibit the cardiac muscarinic ACh receptors exclusively without stimulating the receptors. These results could at least partially explain the difference between the bradycardiac effects of the agents observed clinically.

Microangiopathy without hemolysis in a patient following allogeneic bone marrow transplantation.

Thrombotic microangiopathy (TMA) is one of the complications of bone marrow transplantation (BMT) which includes hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). Red cell fragmentation is the most consistent laboratory finding. We present a case of TMA with endothelial damage but without the signs of hemolysis. The patient was not receiving cyclosporine. Partial activation of platelets was also observed. This case represents a new form of TMA in transplant recipients.

Prostaglandin E1 potentiation of the spontaneous phasic contraction of rat isolated portal vein by a cyclopiazonic acid-sensitive mechanism.

1. The effect of prostaglandin E1 (PGE1) on the spontaneous phasic contraction of the rat isolated portal vein was studied. 2. The isolated portal vein exhibited spontaneous phasic contractions. Removal of Ca2+ from Krebs-Ringer solution or application of nifedipine abolished the spontaneous contraction, indicating that the contraction depends exclusively on Ca2+ influx through L-type Ca2+ channels. On the other hand, cyclopiazonic acid (CPA), a specific inhibitor of Ca(2+)-ATPase of sarcoplasmic reticulum (SR) increased the amplitude of the contractions, suggesting that the SR regulates the spontaneous contractions negatively by sequestration of Ca2+ entering through L-type Ca2+ channels and buffering the rise in cytosolic Ca2+. 3. PGE1 increased the amplitude of the spontaneous contraction in a concentration-dependent manner without affecting the resting tension. The effect was completely abolished by nifedipine. Bay K 8644 and phenylephrine (PE) also increased the amplitude of the contraction in a concentration-dependent manner. PGE1 at a concentration of 1 microM. Bay K 8644 at 100 nM and PE at 30 nM doubled the amplitude, respectively. 4. Pretreatment with 1 microM CPA abolished the effect of PGE1, but the effects of Bay K 8644 and PE were not inhibited by pretreatment with CPA. In contrast, 10 microM ryanodine attenuated the effect of PE without affecting the contractile effect of PGE1. 5. When the SR was depleted of Ca2+ by repeated applications of caffeine in a nominally Ca(2+)-free Krebs-Ringer solution, it took about 120 s to restore the spontaneous contraction after addition of Ca2+ into the solution. In CPA-treated veins, the time taken to restore the contraction was shortened significantly. Pretreatment with 1 microM PGE1 shortened the time to the same extent as pretreatment with CPA did. 6. These results suggest that PGE1 increases the amplitude of the spontaneous phasic contraction by a different mechanism from those by which PE and Bay K 8644 increase it. Inhibition of Ca(2+)-ATPase of the SR might be involved in the vasoactive effect of PGE1.

Giant epiphrenic diverticulum with achalasia occurring 20 years after Heller's operation.

We report a case of giant epiphrenic diverticulum in a 43-year-old woman who underwent Heller's myotomy because of achalasia 20 years earlier. She complained of heartburn and dysphagia from March of 1991 and was hospitalized in our institution. An upper gastrointestinal X-ray examination with contrast medium revealed a large hemispheric lesion (7.8 x 4.8 cm) occupying the right posterior wall of the lower thoracic and abdominal esophagus. Manometry revealed a motility disorder and high pressure of the lower esophageal sphincter due to achalasia. Therefore she was diagnosed as having a giant diverticulum with achalasia after Heller's operation. She underwent transhiatal esophagectomy and reconstruction with placement of a gastric tube on June 4, 1992. Pathology results on the resected specimen revealed a false diverticulum. She has been doing well for 4 years since the operation. It has been said that a complication of incomplete long myotomy causes pulsion diverticulum, but we could not find a case of epiphrenic diverticulum after myotomy for achalasia reported in the literature in the last 10 years.

Generalized peritonitis caused by spontaneous intraperitoneal rupture of the urinary bladder.

We report a case of generalized peritonitis caused by spontaneous intraperitoneal rupture of the urinary bladder. A 74-year-old female was admitted with abdominal pain and biochemical findings of acute renal failure (ARF). She had recently complained of macrohematuria. She had a past history of radiotherapy for uterine cervical cancer and Parkinson's disease treated with levodopa and amantadine. We diagnosed this case as intraperitoneal rupture of the bladder by cystogram. Biochemical findings of ARF might have resulted from urine reabsorption. Intraperitoneal rupture of the bladder should be considered in all cases of peritonitis, especially in patients with urological symptoms and features of ARF.

[Hepatic intra-arterial 5-fluorouracil and CDDP administration in patients with colorectal cancer metastasis to the liver].

Eleven patients with hepatic metastasis from colorectal cancer were treated by combined chemotherapy with 5-FU and CDDP. Metastatic tumor was not resected or incompletely removed in all cases. 5-FU (180 mg/m2/day) as a 7-day continuous hepatic arterial infusion (HAI) with CDDP (10 approximately 20 mg/2 weeks) or intermittent high dose 5-FU HAI (1,000 mg/m2/5 h) with CDDP (10 approximately 20 mg/2 weeks) was administered, followed by a one-week rest. The overall response rate was 63.8%. There was a significant prolongation in overall survival compared with controls. Drug-related toxicity was observed in 10 cases (91.0%), but nothing serious. Survival can be prolonged with almost normal quality of the life in patients with colorectal liver metastasis.

Nonstereospecific actions of ketamine isomers on the force of contraction, spontaneous beating rate, and Ca2+ current in the guinea pig heart.

Ketamine possesses stereospecific actions of anesthesia with the S(+)-isomer being three to four times as potent an anesthetic as the R(-)-isomer. We investigated the mechanical and electrophysiologic effects of ketamine isomers in guinea pig cardiac preparations. Both isomers decreased the contractile force of electrically driven papillary muscles and the spontaneously beating rate of the right atria in a concentration-dependent manner. There were no significant differences between the S(+)- and R(-)-isomers for these measured variables. Consistent with the results from mechanical experiments, electrophysiologic experiments using whole cell voltage clamp techniques revealed that both isomers suppressed identically the transsarcolemmal Ca2+ current (ICa), which plays a role in the generation of the force of contraction and the spontaneous firing of sinoatrial node cells. In conclusion, the optical isomers of ketamine have equipotent cardiodepressant effects in the guinea pig. Inasmuch as the S(+)-isomer is the more potent anesthetic, it could offer significant clinical advantage over the R(-)-isomer or the racemate, in terms of impairment of cardiac functions, if the present results could be extrapolated to the clinical setting.

Interaction of class III antiarrhythmic drugs with muscarinic M2 and M3 receptors: radioligand binding and functional studies.

We have recently reported that class III antiarrhythmic drugs inhibit the muscarinic acetylcholine (ACh) receptor-operated K+ current (IK,ACh) in guinea-pig atrial cells by different molecular mechanisms. The data obtained from the patch-clamp study suggest that D,L-sotalol inhibits IK,ACh by blocking the muscarinic receptors, whereas MS-551 inhibits the K+ current by blocking the muscarinic receptors and depressing the function of the K+ channel itself and/or the guanine nucleotide-binding protein (G protein). This study was undertaken to determine whether the class III antiarrhythmic drugs D,L-sotalol and MS-551 interact with the muscarinic receptors of cardiac and peripheral tissues. Both drugs inhibited concentration dependently the specific [3H]N-methylscopolamine ([3H]-NMS) binding to membrane preparations obtained from guinea-pig atria and submandibular glands. The competition curves of these drugs for [3H]-NMS binding to glandular membranes were monophasic, suggesting competition with [3H]-NMS at a single site. Although the competition curve of D,L-sotalol for [3H]-NMS binding to atrial membranes was monophasic, that of MS-551 was biphasic and showed high- and low-affinity states of binding. D,L-Sotalol showed slightly, but significantly, higher affinity for cardiac-type muscarinic receptors (M2) than for glandular-type muscarinic receptors (M3). The inhibition constant (Ki) for MS-551 in glandular membranes was also slightly greater than the high-affinity Ki value for the drug in atrial membranes. In guinea-pig left atria and ilea, D,L-sotalol shifted the concentration-response curves for the negative inotropic effect and the contracting effect of carbachol in a parallel manner. The slopes of Schild plot were not significantly different from unity, suggesting competitive antagonism, and the pA2 for D,L-sotalol in left atria was slightly greater than that in ilea. MS-551 also shifted the concentration response curve for the negative inotropic effect of carbachol in atrial preparations to a greater extent than that for the contracting effect in ileal preparations, although MS-551 failed to show a pure competitive antagonism. These results suggest that both D,L-sotalol and MS-551 interact with cardiac M2 and peripheral M3 receptors, and that at high concentrations they exert anticholinergic activity in cardiac and peripheral tissues.