Persistent phosphaturic mesenchymal tumor causing tumor-induced osteomalacia treated with image-guided ablation.

Phosphaturic mesenchymal tumors (PMTs) can present with vague symptoms of diffuse bone pain with pathologic fractures that often lead to a delayed diagnosis. We present a 60-year-old patient with a PMT that was persistently hypophosphatemic after resection, who was then successfully treated with cryoablation of the tumor. Tumor-induced osteomalacia (TIO) is a rare cause of hypophosphatemia characterized by vague symptoms of gradual muscle weakness and diffuse bone pain with pathologic fractures that often lead to a delayed diagnosis. This condition is usually caused by benign phosphaturic mesenchymal tumors (PMTs). Here, we present a case of persistent PMT after surgical resection treated with image-guided ablation. We present the patient's clinical examinations and laboratory findings (phosphorus, 1,25 (OH)2D, FGF-23, Intact PTH). Representative histologic images of a PMT are also presented. A 61-year-old male was evaluated for persistent hypophosphatemia and presumed osteomalacia. Six years earlier, he underwent surgical excision of a left ischial mass after presenting with TIO. The pathology was consistent with a PMT; however, hypophosphatemia persisted suggesting incomplete resection. He was treated with calcitriol and phosphate salts. A PET Ga68 dotatate scan of the patient revealed an avid left ischial mixed lytic and sclerotic lesions with marked amount of radiotracer uptake, suggesting persistent tumor. The patient was resistant to re-excision of the tumor due to the extended recovery period from his prior surgery and was treated instead with cryoablation of the tumor. His biochemical findings of hypophosphatemia and elevated FGF23 resolved after the ablation and have remained normal for 5 months after surgery. In patients with TIO, wide surgical excision is the treatment of choice. When this is not possible, image-guided ablation is an alternative therapeutic option.

Gout as a risk factor for osteoporosis: epidemiologic evidence from a population-based longitudinal study involving 108,060 individuals.

Is gout a risk factor for future osteoporosis? This large population-based study comprising two matched groups of individuals with and without gout demonstrates that patients with gout have a 20% increase in the risk of developing osteoporosis in future through an 8-year follow-up. INTRODUCTION: To examine if gout is associated with an increased risk of osteoporosis. METHODS: We conducted a nationwide population-based retrospective matched-cohort study. Two matched cohorts (n = 36,458 with gout and 71,602 without gout) assembled and recruited from the Longitudinal Health Insurance Dataset containing 1 million subjects. Exclusion criteria were missing data, age < 20 years, short follow-up period, and pre-existing osteoporosis. Both cohorts were followed up until incident osteoporosis, death, or the end of the study. Person-year data and incidence rates were evaluated. A multivariable Cox model was used to derive an adjusted hazard ratio (aHR) after controlling for socioeconomic proxy, geographical difference, glucocorticoid and allopurinol exposure, various prespecified medical conditions, and comorbidities. RESULTS: Men comprised 72.8% of the cohorts. With a follow-up of 183,729 and 359,900 person-years for the gout and non-gout cohorts, 517 and 811 incidents of osteoporosis occurred, respectively, after excluding osteoporosis incidents in the first 3 years of follow-up. The cumulative incidence of osteoporosis was statistically higher in the gout cohort than in the non-gout cohort, at 3.3 versus 2.1% (P = 0.0036, log-rank). Our Cox model showed a 1.2-fold increase in the incidence of osteoporosis in the gout cohort, with an aHR of 1.2 (95% confidence interval, 1.06-1.35). CONCLUSIONS: This first population-based epidemiologic study supports the hypothesis that compared with individuals without gout; those with gout have a modest increase in the risk of developing osteoporosis in future.

Effect of adjunct thoracoplasty on Adolescent Idiopathic Scoliosis patients' 3D back contour.

The aims of this study were to evaluate the effect of a thoracoplasty procedure in addition to a posterior spinal fusion and instrumentation on an Adolescent Idiopathic Scoliosis (AIS) patient's 3D back contour as measured by surface topography. We performed a retrospective review to identify patients who were treated with posterior spinal fusion with spinal instrumentation and those who were treated with an additional thoracoplasty procedure. We analyzed changes in surface topography measurements between these two groups using t-test and ANCOVA statistical analyses. Although there were no statistically significant differences in 11 of 12 variables, thoracoplasty-posterior spinal fusion (n=10) group had a mean 6.6 unit reduction in trunk asymmetry while the posterior spinal fusion group (n=26) had a mean 22.8 unit reduction in trunk asymmetry (p-value<0.05). The posterior spinal fusion group and thoracoplasty-posterior spinal fusion group were not shown to have clinically significant differences in 3D back contour correction. An additional thoracoplasty procedure does not provide better correction in the transverse plane and in fact had a smaller degree of trunk asymmetry correction. This supports the current trends of decreasing use of thoracoplasty in AIS patients to address severe rib hump deformities given concerns for decreased post-operative lung function and alternative methods of vertebral body derotation, such as thoracic pedicle screws.

Evaluation of plantar pressures and center of pressure trajectories in Adolescent Idiopathic Scoliosis.

Adolescent idiopathic scoliosis (AIS) has been postulated to affect gait patterns and postural stability due to its effect on center of body mass. 1) Determine the correlation between Cobb angle and COP in the anterior-posterior (AP) direction, COP in the medial-lateral (ML) direction, COP oscillation (COP-O) from midline walking, peak pressures, and pressure-time integrals (loading) at 10 anatomic foot segments; 2) Determine the differences in COP-AP, COP-ML, COP-O, and peak plantar pressures at 10 anatomic foot segments between the normal group and the AIS group. All patients wore a gown to expose the posterior trunk and underwent evaluation with Formetric 4D (DIERS International GmbH, Schlangenbad, Germany) while walking on the treadmill at 2 km/hour for 15 seconds. A total of 24 pressure metrics at 10 anatomic foot segments were evaluated. We then analyzed the data using t-test and linear regression analyses.16 patients were assigned to a normal group (Cobb angle 10° or less, n=4) or AIS group (Cobb greater than 10°, n=12). Of note, AIS patients had statistically significant lower max. pressures at the hallux and the 2nd, 4th, 5th metatarsal head compared to the normal group. Additionally, there was a statistically significant linear association between Cobb angle and both hallux max. pressure and hallux pressure-time integral (P<0.05). Reduced peak plantar pressures before the toe-off phase of gait cycle indicate that AIS patients may lean backwards and have posterior postural sway, which may be associated with hypokyphosis during walking.

A powerful two-stage association test using case-control and case-parents genotype data.

OBJECTIVE: The performance of association tests based on case-control or case-parents substudy alone can be improved by jointly using genetic data from two substudies. However, genetic data from different sources may not be combinable due to population stratification. We propose a two-stage association test based on using combinability tests in stage 1 and association tests in stage 2. METHODS: The combinability tests are designed for testing that genotype data from different sources have same genotype frequencies and relative risks. The association tests are well known tests in the literature. We propose a method to adjust the significance levels at two stages so that the overall type I error rate of the two-stage test can be controlled at the desired level. RESULTS: The simulation results confirm that the two-stage test has empirical type I error rates approximately equal to the predetermined levels while making substantially fewer false negatives than the usual test based only on case-parents substudy. CONCLUSION: It is advantageous to combinecase-control and case-parents data into a single analysis.The two-stage test has significant power improvement when the family-based test has weak or moderate power performance and is robust to the effect of population stratification.

ADP ribosylation factor 1 is required for synaptic vesicle budding in PC12 cells.

Carrier vesicle generation from donor membranes typically progresses through a GTP-dependent recruitment of coats to membranes. Here we explore the role of ADP ribosylation factor (ARF) 1, one of the GTP-binding proteins that recruit coats, in the production of neuroendocrine synaptic vesicles (SVs) from PC12 cell membranes. Brefeldin A (BFA) strongly and reversibly inhibited SV formation in vivo in three different PC12 cell lines expressing vesicle-associated membrane protein-T Antigen derivatives. Other membrane traffic events remained unaffected by the drug, and the BFA effects were not mimicked by drugs known to interfere with formation of other classes of vesicles. The involvement of ARF proteins in the budding of SVs was addressed in a cell-free reconstitution system (Desnos, C., L. Clift-O'Grady, and R.B. Kelly. 1995. J. Cell Biol. 130:1041-1049). A peptide spanning the effector domain of human ARF1 (2-17) and recombinant ARF1 mutated in its GTPase activity, both inhibited the formation of SVs of the correct size. During in vitro incubation in the presence of the mutant ARFs, the labeled precursor membranes acquired different densities, suggesting that the two ARF mutations block at different biosynthetic steps. Cell-free SV formation in the presence of a high molecular weight, ARF-depleted fraction from brain cytosol was significantly enhanced by the addition of recombinant myristoylated native ARF1. Thus, the generation of SVs from PC12 cell membranes requires ARF and uses its GTPase activity, probably to regulate coating phenomena.

Pharmacologic effects in man of a specific serotonin-reuptake inhibitor.

Fluoxetine (Li-ly 110140) caused a 63 percent inhibition of [3H]serotonin uptake into platelets obtained from normal volunteers to whom the drug was administered daily for 7 days. This dose had no effect on the usual pressor response produced by injections of norepinephrine or tyramine.

A v-SNARE participates in synaptic vesicle formation mediated by the AP3 adaptor complex.

Reconstitution of synaptic vesicle formation in vitro has revealed a pathway of synaptic vesicle biogenesis from endosomes that requires the heterotetrameric adaptor complex AP3. Because synaptic vesicles have a distinct protein composition, the AP3 complex should selectively recognize some or all of the synaptic vesicle proteins. Here we show that one element of this recognition process is the v-SNARE, VAMP-2, because tetanus toxin, which cleaves VAMP-2, inhibited the formation of synaptic vesicles and their coating with AP3 in vitro. Mutant tetanus toxin and botulinum toxins, which cleave t-SNAREs, did not inhibit synaptic vesicle production. AP3-containing complexes isolated from coated vesicles could be immunoprecipitated by a VAMP-2 antibody. These data imply that AP3 recognizes a component of the fusion machinery, which may prevent the production of inert synaptic vesicles.

Effects of Ti-C:H coating and plasma nitriding treatment on tribological, electrochemical, and biocompatibility properties of AISI 316L.

Ti-C:H coatings were deposited on original, nitrided, and polished-nitrided AISI 316L stainless steel substrates using a closed field unbalanced magnetron sputtering system. Sliding friction wear tests were performed in 0.89 wt.% NaCl solution under a load of 30 N against AISI 316L stainless steel, Si3N4, and Ti6Al4V balls, respectively. The electrochemical properties of the various specimens were investigated by means of corrosion tests performed in 0.89 wt.% NaCl solution at room temperature. Finally, the biocompatibility properties of the specimens were investigated by performing cell culturing experiments using purified mouse leukemic monocyte macrophage cells (Raw264.7). In general, the results showed that plasma nitriding followed by Ti-C:H coating deposition provides an effective means of improving the wear resistance, anti-corrosion properties, and biocompatibility performance of AISI 316L stainless steel.

Pre-pubertal and adolescent germ cell neoplasms in Taiwan: time trends and geographic variation.

Evidence from our previous study suggested that the incidence of germ cell neoplasms in children and adolescents is increasing. The objectives of this analysis were to quantify this trend in patients aged 0-9 and 10-19 years (pre-pubertal and adolescent groups, respectively) and compare rates in Taiwan according to geographic distribution. Germ cell neoplasm frequencies among 1267 patients aged 0-19 years spanning 1995-2009 were obtained from the population-based Taiwan Cancer Registry. The incidence patterns according to sex, age, disease subgroup, and geographic distribution were analyzed. The incidence rates in the pre-pubertal and adolescent groups were 10.58 and 16.06 per million person-years, respectively. The overall rates increased significantly by 3.2% annually in the adolescent group during the 15-year study period, and increased only among the males. In contrast, no change in trend was observed in the pre-pubertal group. Subgroup analysis showed significant upward trends in the incidence rates of intracranial/intraspinal and testicular germ cell tumors (GCTs) in the adolescent males and extracranial/extragonadal GCTs in the pre-pubertal boys. The most striking differences between the study population and white Americans were that the rates of testicular GCTs were 5-fold higher and 4-fold lower in the Taiwanese pre-pubertal and adolescent groups, respectively. Significantly higher rates were found in Hualien and Chiayi Counties compared with the other areas of Taiwan. The upward trend of testicular GCTs in the adolescent males is consistent with findings from Western countries. The underlying causes that led to the high rate of testicular GCTs in the pre-pubertal boys and significantly higher rates in specific counties warrant further investigation.

Cloning and functional analysis of a beta-tubulin gene from a benomyl resistant mutant of Aspergillus parasiticus.

A genomic DNA library prepared from a benomyl resistant strain of Aspergillus parasiticus was screened with a Neurospora crassa beta-tubulin gene probe. A unique A. parasiticus genomic DNA fragment, thought to carry a mutant beta-tubulin gene (benr), was isolated. Two plasmids, pYT1 and pYTPYRG, carrying the putative benr gene or benr plus a second selectable marker (pyrG), respectively, were used to transform a benomyl sensitive strain of A. parasiticus (CS10) to determine if benr conferred benomyl resistance (BenR). BenR colonies were obtained with pYTPYRG, pYT1 or pYT1 cotransformed with pPG3J which carries a functional pyrG gene. No BenR colonies were obtained without added DNA or with pPG3J only (controls). Southern hybridization analysis of BenR and BenS transformants suggested that plasmid integration occurred most frequently at the chromosomal bens locus, however evidence for gene conversion and heterologous recombination was also observed. The predicted amino acid sequence of benr displayed a high degree of identity (> 93%) with other fungal beta-tubulin genes which confer benomyl resistance. Sequence analysis together with the genetic data suggested that benr encodes a functional mutant beta-tubulin.

Ergolines as selective 5-HT1 agonists.

The synthesis and serotonin receptor subtype affinity of a series of ergolines are described. High selectivity for the 5-HT1 subtype was found with a number of 8-substituted (3 beta, 5 beta)-9,10-didehydro-6-methylergolines. The more potent and selective of these compounds increased the concentration of serotonin and decreased the concentration of 5-HIAA in rat brain and increased corticosterone concentration in rat serum. Oral administration of 13, (3 beta)-2,3-dihydrolysergine, produced long-lasting decreases in serotonin turnover. Compound 13 lacked substantial dopaminergic activity as measured by its effects on dopamine turnover in whole brain or striatum and its affinity for alpha-adrenergic binding sites was significantly less than for 5-HT1 binding sites. The increases in serum corticosterone concentrations produced by 13 were not blocked by the serotonin uptake inhibitor fluoxetine or by the serotonin synthesis inhibitor p-chlorophenylalanine, suggesting that 13 exerts its effects through direct stimulation of serotonin receptors.

The 3,4-catechol derivative of propranolol, a minor dihydroxylated metabolite.

The O,O-dibenzyl ether of the 3,4-catechol derivative of propranolol (11) was prepared to determine whether the catechol is a product of metabolic hydroxylation. 4-(Allyloxy)-1,2-naphthoquinone (5) was reduced with sodium dithionite and alkylated with benzyl chloride to produce ether 7. Osmium tetroxide oxidation of 7 afforded glycol 8. Subsequent monotosylation, oxirane formation with KOH, and opening with isopropylamine afforded benzyl ether 11. Although hydrogenolysis was successful, catechol 3 was rapidly oxidized to the corresponding o-quinone (12). Reduction of 12 with sodium bisulfite afforded 3, which was derivatized with N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) to serve as a standard for the metabolic experiments. Gas chromatography-mass spectrometry of the Me3Si ethers of the products of metabolism of pseudoracemic propranolol (made up of equal molar (2R)-propranolol-d0/(2S)-propranolol-3',3'-d2) in the presence of the rat liver 9000g supernatant fraction showed four dihydroxylated metabolites, of which catechol 3 was in smallest amount, approximately 9% of the sum of dihydroxylated metabolites. Each of the four dihydroxylated propranolols arises stereoselectively from the 2R enantiomer of propranolol (by 1.15- to 2-fold), as determined by parent ion intensities at m/z 507 vs. 509. Quinone 12 was a nonselective competitive beta-adrenoceptor antagonist, being about 16-fold less potent than propranolol in both beta 1 and beta 2 assays.

Atrial natriuretic peptide receptor modulators: effects of disubstituted quinazolines on receptor binding and in vitro biological activity.

Prazosin (25 microM) was found to increase 125I-labeled rat atrial natriuretic peptide ([125I]rANP) receptor binding by 50% (SC50) in bovine adrenal zona glomerulosa membranes. A series of 2,4-disubstituted quinazolines was prepared in order to identify more potent analogues for additional in vitro testing. Compound 7 (N-[3-[[2-(diethyl-amino)-4-quinazolinyl]amino]propyl] guanidine dinitrate) from this series (3 microM) significantly decreased the EC50 for rANP-mediated inhibition of ACTH-stimulated aldosterone synthesis in rat adrenal glomerulosa cells. At a higher concentration (20 microM), compound 7 had no effect on particulate guanylate cyclase from rabbit glomeruli in either the presence or absence of rANP.

N-substituted imidazolines and ethylenediamines and their action on alpha- and beta-adrenergic receptors.

A series of N-substituted imidazolines and ethylenediamines were synthesized and examined for their activity in alpha- and beta-adrenergic systems. The length of the intermediate side chain between the catechol and imidazoline ring or the amine of the ethylenediamine segment was shown to affect the adrenergic activity. N-[2-(3,4-Dihydroxyphenyl)ethyl]imidazoline hydrochloride (2) and N-[2-(3,4-dihydroxyphenyl)ethyl]ethylenediamine dihydrochloride (4), both with two methylene groups between the catechol and amine segment, were found to be somewhat selective for alpha 2-adrenergic receptors while 1-(3,4-dihydroxybenzyl)imidazoline hydrochloride (1) and N-2-(3,4-dihydroxybenzyl)ethylenediamine dihydrochloride (3), both with one methylene group between the catechol and amine segment, were more selective for alpha1-adrenergic receptors in a pithed rat model. Of the four compounds examined, only compound 2 showed significant direct activity on beta1- and beta2-adrenergic receptors.

Phenothiazines as lipid peroxidation inhibitors and cytoprotective agents.

A series of phenothiazines was synthesized and evaluated as in vitro inhibitors of iron-dependent lipid peroxidation. The MIC (minimum tested concentration that gave greater than or equal to 50% inhibition) for 2-(10H-phenothiazin-2-yloxy)-N,N-dimethylethanolamine methanesulfonate (6) was 0.26 microM. Whereas methyl substitution at N-10 diminished activity nearly 100-fold, other structural modifications such as varying the amine group, the distance separating the amine substituent from the phenothiazine nucleus, and the linking group had little effect. Compound 6 was more effective than probucol, a known antioxidant, in blocking Cu2+ catalyzed oxidation of low-density lipoprotein (LDL) as measured by competitive scavenger receptor mediated degradation of 125I-labeled acetyl-LDL by mouse peritoneal macrophage cells in vitro. At a concentration of 5 microM, compound 6 also protected primary cultures of rat hippocampal neurons exposed to hydrogen peroxide (50 microM) when assessed 18 h later by fluorescein diacetate and propidium iodide uptake.

Vergence eye movements under natural viewing conditions.

PURPOSE: To determine whether there are any fundamental differences in vergence dynamics under different viewing conditions, both in instrument space and free space. METHODS: Symmetric vergence responses were measured for a variety of conditions under the traditional instrument space as well as the more natural free space viewing environment. Vergence eye movements were recorded objectively in three subjects using the infrared reflection technique. Within each environment, four conditions were tested: aperiodic self-initiated voluntary gaze shifts between two simultaneously viewed targets; periodic (0.33 Hz) voluntary gaze shifts between the same two targets; gaze shifts in total darkness to the near target following initial far target fixation in the light; and gaze shifts in total darkness to the two remembered target positions. In addition, an experiment was performed in instrument space using randomized step changes of target disparity, in which the responses served as the standard for comparison. For all conditions, target disparities ranged from 0.5 degrees to 10 degrees. The peak velocity of each vergence response was calculated and plotted versus its amplitude. RESULTS: It was found that the data for all conditions tested fell within the standard "main sequence" cluster, indicating similarity in dynamics and thus similarity in the motoneuronal controller signal. Also, the data from investigators who claimed differences in dynamics were also typically found to fall within the normal cluster. CONCLUSIONS: This indicates that the vergence motoneuronal controller signal produced the same dynamics for a particular response amplitude, independent of both viewing environment and test condition.

Primary structure and developmental expression of zebrafish sodium channel Na(v)1.6 during neurogenesis.

A zebrafish sodium channel cDNA encoding a 1949-amino acid polypeptide, Na(v)1.6, was isolated. Two transcripts were detected in zebrafish adult brain but not in cardiac or skeletal muscle. The RNase protection analysis confirmed the neural specificity of zebrafish Na(v)1.6 24 hours postfertilization (hpf) Na(v)1.6 was expressed in the trigeminal ganglion, anterior and posterior lateral line ganglia, rhombomeres, and Rohon-Beard neurons. This preferential localization suggests that Na(v)1.6 plays an important role in tactile sensitivity. The abundance of zebrafish Na(v) 1.6 mRNA in the central and peripheral nervous systems increased markedly between 48 and 72 hpf, during the maturation of the nervous system.

Interactions of three inotropic agents, ASL-7022, dobutamine and dopamine, with alpha- and beta-adrenoceptors in vitro.

Three inotropic agents, ASL-7022, dobutamine and dopamine, were evaluated for their alpha- and beta-adrenoceptor mediated effects in vitro in a variety of isolated organs and in radioligand binding studies. All compounds were alpha 1-adrenoceptor agonists in rat and guinea pig aortae, but the rank orders of potency were exactly opposite in these two tissues. Only the rank potency order of dobutamine greater than ASL-7022 greater than dopamine obtained in rat aorta was consistent with the results obtained in radioligand binding studies to alpha 1-adrenoceptors in rat cerebral cortex and to previous results obtained in vivo in the pithed rat. The results obtained in guinea pig aorta did not parallel the radioligand binding studies in rat brain or our previous results in pithed rat, and suggests that species differences exist between postsynaptic vascular alpha 1-adrenoceptors in rat and guinea pig aorta, consistent with previous conclusions. ASL-7022 was found to be a potent alpha 2-adrenoceptor agonist in field-stimulated guinea pig ileum, and was approximately 10-fold more potent than dobutamine in this respect, which was also confirmed by radioligand binding studies to alpha 2-adrenoceptors in rat cerebral cortex. The beta 1-adrenoceptor mediated effects of these compounds were evaluated in guinea pig atria, where the rank order of potency was dobutamine greater than ASL-7022 greater than dopamine. An identical rank order of affinity was established for these compounds by displacement of 3H-dihydroalprenolol from beta 1-adrenoceptors in rat cerebral cortex. The beta 1-adrenoceptor mediated effects of dobutamine and ASL-7022 in guinea pig atria were completely direct in nature and not secondary to the release of endogenous catecholamines. In contrast, a major component of the beta 1-adrenoceptor mediated tachycardia produced by dopamine in guinea pig atria was indirect in nature as evidenced by the marked attenuation in potency that occurred following catecholamine depletion with reserpine. All three compounds elicited beta 2-adrenoceptor mediated inhibition of tone in rat uterus, with the rank order of potency being ASL-7022 greater than dobutamine greater than dopamine. Again, this rank order of beta 2-adrenoceptor potency was also reflected in beta 2-adrenoceptor affinity as assessed by displacement of 3H-dihydroalprenolol from beta 2-adrenoceptors in rat cerebellum. Based on these results, it may be concluded that for alpha-adrenoceptors, dobutamine is a selective alpha 1-adrenoceptor agonist, ASL-7022 is a selective alpha 2-adrenoceptor agonist, and dopamine is a nonselective alpha-adrenoceptor agonist.(ABSTRACT TRUNCATED AT 400 WORDS)

Interactions of the enantiomers of 3-O-methyldobutamine with alpha- and beta-adrenoceptors in vitro.

The enantiomers of 3-O-methyldobutamine, a metabolite of dobutamine, were evaluated for their alpha- and beta-adrenoceptor mediated effects in vitro in a variety of isolated organs and in radioligand binding studies. Neither enantiomer of 3-O-methyldobutamine possessed alpha 1-adrenoceptor agonist activity in isolated guinea pig aorta. However, both enantiomers of 3-O-methyldobutamine were competitive alpha 1-adrenoceptor antagonists, with the (+)-enantiomer being approximately 10-fold more potent than the (-)-enantiomer as assessed either in guinea pig aorta or by displacement of 3H-prazosin binding from alpha 1-adrenoceptors in rat cerebral cortex. The alpha 1-adrenoceptor blocking activity of (+)-3-O-methyldobutamine was relatively potent and corresponded to a pA2 of 7.33 in guinea pig aorta and a -log Ki of 7.72 in radioligand binding studies. Neither enantiomer of 3-O-methyldobutamine possessed alpha 2-adrenoceptor agonist activity in field-stimulated guinea pig ileum. Although (+)-3-O-methyldobutamine weakly inhibited the twitch response in field-stimulated guinea pig ileum, the response was not blocked by the selective alpha 2-adrenoceptor antagonist, yohimbine, and was found to result from weak anticholinergic activity (pA2 = 5.06). Neither enantiomer of 3-O-methyldobutamine possessed beta 1-adrenoceptor agonist activity in guinea pig atria, however the (+)-enantiomer was a weak noncompetitive antagonist at beta 1-adrenoceptors. In contrast, both enantiomers of 3-O-methyldobutamine were weak beta 2-adrenoceptor agonists in rat uterus, however these weak effects were not highly stereoselective, which was also confirmed in radioligand binding studies.(ABSTRACT TRUNCATED AT 250 WORDS)