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PubMed2006

Compartment volume influences microtubule dynamic instability: a model study.

Microtubules (MTs) are cytoskeletal polymers that exhibit dynamic instability, the random alternation between growth and shrinkage. MT dynamic instability plays an essential role in cell development, division, and motility. To investigate dynamic instability, simulation models have been widely used. However, conditions under which the concentration of free tubulin fluctuates as a result of growing or shrinking MTs have not been studied before. Such conditions can arise, for example, in small compartments, such as neuronal growth cones. Here we investigate by means of computational modeling how concentration fluctuations caused by growing and shrinking MTs affect dynamic instability. We show that these fluctuations shorten MT growth and shrinkage times and change their distributions from exponential to non-exponential, gamma-like. Gamma-like distributions of MT growth and shrinkage times, which allow optimal stochastic searching by MTs, have been observed in various cell types and are believed to require structural changes in the MT during growth or shrinkage. Our results, however, show that these distributions can already arise as a result of fluctuations in the concentration of free tubulin due to growing and shrinking MTs. Such fluctuations are possible not only in small compartments but also when tubulin diffusion is slow or when many MTs (de)polymerize synchronously. Volume and all other factors that influence these fluctuations can affect MT dynamic instability and, consequently, the processes that depend on it, such as neuronal growth cone behavior and cell motility in general.

Animals↗
PubMed2002

Microsatellite instability and cytogenetic survey in myeloid leukemias.

Microsatellites are short tandem repeat sequences dispersed throughout the genome. Their instability at multiple genetic loci may result from mismatch repair errors and it occurs in hereditary nonpolyposis colorectal cancer. This instability is also found in many sporadic cancers. In order to evaluate the importance of this process in myeloid leukemias, we studied five loci in different chromosomes of 43 patients, 22 with chronic myelocytic leukemia (CML) in the chronic phase, 7 with CML in blast crisis, and 14 with acute myeloid leukemia (AML), by comparing leukemic DNA extracted from bone marrow and constitutional DNA obtained from buccal epithelial cells. Only one of the 43 patients (2.1%), with relapsed AML, showed an alteration in the allele length at a single locus. Cytogenetic analysis was performed in order to improve the characterization of leukemic subtypes and to determine if specific chromosome aberrations were associated with the presence of microsatellite instability. Several chromosome aberrations were observed, most of them detected at diagnosis and during follow-up of the patients, according to current literature. These findings suggest that microsatellite instability is an infrequent genetic event in myeloid leukemias, adding support to the current view that the mechanisms of genomic instability in solid tumors differ from those observed in leukemias, where specific chromosome aberrations seem to play a major role.

Adolescent↗
PubMed2003

DNA repair and trinucleotide repeat instability.

enes harboring certain trinucleotide repeat (TNR) sequences are at risk for high-frequency mutations that expand or contract the repeat tract. The triplet sequences CNG (where N = any nucleotide) and GAA are known to cause human disease when they expand by more than a few repeats in certain key genes. One of the crucial questions in the field is the mechanism (or, more likely, mechanisms) of triplet repeat expansions and contractions. The available evidence indicates that TNRs can change length as a result of aberrant DNA replication in proliferating cells. In addition, TNR instability can arise from gene conversion or by error-prone DNA repair whether the cell is dividing or not, since most cell types have recombination and repair activities. The latter of these three sources, DNA repair, is the subject of this review because of some recent provocative findings. Two non-mutually exclusive views of DNA repair and TNR instability predominate at this time. One idea is that aberrant DNA structure within TNRs blocks repair. Thus even cells with normal repair activities are inhibited from preventing expansions or contractions, due to local DNA structures formed by TNR sequences. A pernicious second model is that DNA repair actually contributes to TNR instability. This idea of pro-mutagenic DNA repair, although seemingly counterintuitive, has support from a number of studies. A simple explanation is that repair is triggered either by DNA damage in or near the TNR, or perhaps by the aberrant TNR-DNA structure itself. Subsequent excision of nucleotides is followed by error-prone repair synthesis. The idea that repair synthesis is a culprit in expansions or contractions ties into the established ideafz that DNA replication through TNRs gives rise to instability. Since DNA synthesis also occurs during gene conversion, a common source of TNR instability could well be the errors that arise when DNA polymerases attempt to synthesize the problematic triplet repeat sequence.

Animals↗
PubMed1978

Demonstration of rotatory instability in injured knees by stress radiography.

Rotatory instability of injured knees may be demonstrated by stress radiography by recording the different movements of the medial and lateral tibial condyle at pull or push with the knee in 90 degrees flexion. The displacements of the condyles are expressed in millimetres, not degrees. Comparison with the healthy knee is always used. The displacement of a tibial condyle has to exceed 3.0 mm in relation to the healthy knee to be defined as pathological. If the movements of both condyles exceed the movements in the healthy knee by more than 3.0 mm in the same direction a drawer sign is present--if only one of them moves, an abnormal rotation is present. When a drawer sign is present there may still be a greater displacement of one of the tibial condyles which means a rotatory instability added to the drawer sign, designated a complex rotatory instability. All types of rotatory instabilities, simple and complex, are defined and discussed, in relation to the classification of Nicholas, Trickey and Slocum & Larson. Forty-one cases of abnormal rotation were demonstrated in this series by stress radiography. The direction of rotation and the type of instability are described and compared with the operative findings. The findings are in agreement with those of the above-mentioned authors and the experimental work of Warren et al.

Humans↗
PubMed1998

Microsatellite instability, chemosensitivity and mutant frequency in a series of 1,2-dimethylhydrazine induced murine colon adenocarcinoma models.

Loss of DNA mismatch repair has been described in a number of tumour types such as colorectal adenocarcinoma and leads to microsatellite instability. This may have clinical relevance due to mismatch repair defects altering chemosensitivity towards certain classes of anti-tumour agent. This study has examined microsatellite instability of eight murine colon adenocarcinoma tumour models induced by 1,2-dimethylhydrazine. Four microsatellite regions were examined suggesting that four of the tumour models exhibit a low level of microsatellite instability. Loss of heterozygosity was found in 5/8 tumours, suggesting that allelic loss may be a relatively common step in the carcinogenesis of these tumour models. Three of the allelic losses involved the D11MIT4 locus which is situated very close to the p53 tumour suppressor locus. Four tumour models are routinely cultured in vitro and these were used to examine whether there was any association between microsatellite instability, mutant frequency and chemo-sensitivity of these tumour models, comparing them with four human adenocarcinoma cell lines of known mismatch repair status. Two cell lines (MAC26 and MAC16) were found to be more chemoresistant towards cisplatin but not 6-thioguanine. No association was found between microsatellite instability and chemosensitivity for either the human or mouse cell lines.

1,2-Dimethylhydrazine↗
PubMed2001

Clonal evolution and progression of 20-methylcholanthrene-induced squamous cell carcinoma of mouse epidermis as revealed by DNA instability and other malignancy markers.

We examined the clonal evolution of skin malignant lesions by repeated topical applications of 20-methylcholanthrene (20-MC) to the skin, which induces hyperplastic epidermis, papillomatous lesion and invasive carcinoma in mice. The lesions were examined histologically and immunohistochemically with anti-single-stranded DNA after acid hydrolysis (DNA-instability test), p53, VEGF, DFF45, PCNA and AgNORs parameters analyses. Multiple clones with increased DNA instability comparable to that of invasive carcinoma were noted in early-stage (2-6 weeks) hyperplastic epidermis, and their number increased in middle (7-11 weeks), and late-stages (12-25 weeks) of hyperplastic epidermis, indicating that they belong to the malignancy category. All papillomatous lesions and invasive carcinomas showed a positive DNA-instability test. Positive immunostaining for various biomarkers and AgNORs parameters appeared in clones with a positive DNA-instability test in early-or middle-stage hyperplastic epidermis, and markedly increased in late-stage hyperplastic epidermis, papillomatous lesions and invasive carcinomas. The percentage of PCNA-positive vascular endothelial cells was significantly higher in VEGF-positive lesions with a positive DNA-instability test and became higher toward the late-stage of progression. Cut-woundings were made to papillomatous and invasive carcinoma lesions, and the regeneration activity of vascular endothelial cells was determined by using flash labeling with tritiated thymidine (3H-TdR). In small papillomatous lesions, vascular endothelial cells showed regenerative response, but the response was weak in large lesions. No such response was noted in invasive carcinomas; rather, cut-wounding induced collapse of blood vessels, which in turn induced massive coagulative necrosis of cancer cells. These responses can be interpreted to reflect exhausted vascular growth activity due to excessive stimulation by VEGF-overexpression, which was persistently seen from hyperplastic epidermis to invasive carcinoma.

Animals↗
PubMedDate not supplied

Dynamics of genetic instability in sporadic and familial colorectal cancer.

Genetic instability is a defining feature of human cancer. In colorectal cancer, two specific types of genetic instabilities have been identified: microsatellite instability (MIN) leads to a 1000-fold increase in the rate of subtle DNA changes, whereas chromosomal instability (CIN) enhances the rate at which gross chromosomal changes occur during cell division. In this paper, we develop a mathematical model for the dynamics of colon cancer initiation. We outline the processes and rate constants that determine the fraction of colon cancers where MIN or CIN mutations precede the inactivation of the first tumor suppressor gene. For a wide range of parameter values, we find support for the radical hypothesis that genetic instability initiates colonic tumorigenesis. We compare sporadic and hereditary forms of colorectal cancer.

Adenomatous Polyposis Coli↗
PubMed1999

Recognising clinical instability in hospital patients before cardiac arrest or unplanned admission to intensive care. A pilot study in a tertiary-care hospital.

OBJECTIVE: To investigate the nature and duration of clinical instability (i.e., abnormalities in simple physical observations or laboratory test results) in hospital patients before a "critical event" (i.e., a cardiac arrest or an unplanned admission to intensive care). DESIGN: Retrospective survey of medical records of all patients having critical events (CEs) over 12 months. Data on hospital and Intensive Care Unit (ICU) patients were obtained for comparison with the study population. SETTING: A 300-bed metropolitan teaching hospital with a seven-bed ICU. PATIENTS: All patients having CEs over a 12-month period (January to December 1997). MAIN OUTCOME MEASURES: Number of patients with clinical instability before a CE; duration of clinical instability before a CE; number of medical reviews of each patient before a CE; mortality rate and length of hospital stay for all patients. RESULTS: There were 122 CEs in 112 patients (median, 1; range, 1-4). Of the CEs, 79 were unplanned ICU admissions (14 subsequent to cardiac arrest calls), and 43 were cardiac arrest calls not resulting in ICU admission. Each CE was preceded by a median of two (range, 0-9) criteria for clinical instability. The median duration of instability before a CE was 6.5 hours (range, 0-432 hours), and in that time a median of two (range, 0-13) medical reviews took place. The incidence of CEs in the total hospital population (122 CEs/19,853 admissions) and in ICU patients (79 unplanned admissions/515 admissions) was 0.6% and 15%, respectively. There were 70 deaths (62%) among the 112 patients, compared with a total of 392 deaths (2% of admissions) in the hospital, of which 107 were in ICU. CONCLUSIONS: Very few patients suffer a CE while in hospital. However, those who do frequently manifest abnormalities in simple physical observations and laboratory test results before the CE. More rapid intervention in response to warning signs might provide a better outcome for these patients.

Adult↗
PubMed1999

[Hidden chromosome instability and risk of laryngeal cancer incidence].

The bleomycin test is a recognised method of evaluation of hidden genetical instability. The concept of the test consists in inducing chromosome aberrations in lymphocytes exposed in vitro to bleomycin and subsequent quantitative analysis of chromosome breaks. The study material was whole venous blood from 61 laryngeal cancer patients and from 30 healthy persons taken as a control. For each patient two parallel cultures where carried out in the standard procedure. Bleomycin was added to one of the cultures to induce chromosome breaks. Then, in microscopic metaphasal plates stained by Giemsa dye, the chromosome instability index estimated as a number of chromosome breaks per cell (b/c) and the percentage of cells with chromosome breaks were calculated. Higher indices of chromosome instability were demonstrated in laryngeal cancer patients in comparison to the controls. The persons with chromosome instability (b/c > 0.8) or with chromosome oversensitivity to mutagens (b/c > 1) were identified only among larynx cancer subjects. Furthermore, it was established that an increased chromosome instability is associated with high aggressiveness recognised by histological grading. The latter finding requires confirmation on an enlarged group of subjects.

Adult↗
PubMed1999

Accumulated frameshift mutations at coding nucleotide repeats during the progression of gastric carcinoma with microsatellite instability.

Microsatellite instability (MSI) and frameshift mutations in genes containing nucleotide repeats have been reported in a subset of gastric carcinomas, but the mutational profiles in precancerous lesions have not been characterized. To characterize the genetic events during gastric carcinogenesis, we analyzed DNA from 56 gastric adenomas and 167 gastric carcinomas for MSI using five microsatellite markers and for frameshift mutations at coding nucleotide repeats of the type II transforming growth factor beta receptor, BAX, hMSH3, hMSH6, IGF II receptor, and E2F-4 genes. On the basis of the number of markers displaying instability per tumor, the tumors were divided into three groups: those with two or more of the five markers showing instability (high MSI [MSI-H]), those with one of the five markers showing instability (low MSI [MSI-L]), and those with no instability. MSI-H was found in 8 adenomas (14%) and 19 carcinomas (11%), and MSI-L was found in 8 adenomas (14%) and 9 carcinomas (5%). These groups were tested for correlations with several clinicopathologic parameters. MSI-H gastric adenomas were related to the high histologic grade of composing dysplastic glands (p = 0.004), and MSI-H gastric carcinomas were associated with exophytic tumor growth (p = 0.005). We found 48 frameshift mutations at coding nucleotide repeats of the six genes, and all mutations except one were found in MSI-H gastric tumors. Only one of the 17 MSI-L tumors showed frameshift mutations at coding nucleotide repeats of the transforming growth factor beta receptor II gene. Compared with MSI-H gastric carcinomas, MSI-H adenomas had no mutations in the hMSH6 and the IGF II receptor genes, less frequent mutations in the transforming growth factor beta receptor II (38% versus 63%), BAX (13% versus 37%), and hMSH3 (13% versus 37%) genes, and more frequent mutations in the E2F-4 (50% versus 37%) gene. Our findings suggest that MSI and E2F-4 mutations are early genetic events and that mutations of the other five genes are accumulated during the progression of gastric carcinomas with MSI.

Adenoma↗
PubMed1999

Genetic instability and darwinian selection in tumours.

Genetic instability has long been hypothesized to be a cardinal feature of cancer. Recent work has strengthened the proposal that mutational alterations conferring instability occur early during tumour formation. The ensuing genetic instability drives tumour progression by generating mutations in oncogenes and tumour-suppressor genes. These mutant genes provide cancer cells with a selective growth advantage, thereby leading to the clonal outgrowth of a tumour. Here, we discuss the role of genetic instability in tumour formation and outline future work necessary to substantiate the genetic instability hypothesis.

Animals↗
PubMed2000

Early progression stage of malignancy of uterine cervical dysplasia as revealed by immunohistochemical demonstration of increased DNA-instability.

The degree of DNA-instability as revealed by the immunohistochemical staining with anti-single-stranded DNA antibody after acid hydrolysis (DNA-instability test) was used as a marker of malignancy. This was applied to mild dysplasia (42 cases), moderate dysplasia (43 cases), severe dysplasia (27 cases), squamous cell carcinoma in situ (CIS) (21 cases), invasive squamous cell carcinoma (SCC) (31 cases) and normal (7 cases) human uterine cervix. The expression of tumour suppressor gene p53 and oncogene bcl-2 was detected immunohistochemically. Proliferative activity was evaluated by PCNA immumohistochemistry and the quantitative analysis of the number, mean area, the largest area and maximum shape irregularities of AgNOR in a nucleus were performed for all these cases. The distribution of numeric chromosomal aberrations of chromosome 17 was also investigated in some of these cases. The results showed that 31 SCC (100%), 21 CIS (100%), 21 severe dysplasia (77.77%), 28 moderate dysplasia (65.11%), and 14 mild dysplasia (33.33%) were positively stained by the DNA-instability test diffusely or sporadically, indicating their malignancy. Reflecting the malignant character, these cases showed a remarkable increase in the PCNA-index with the loss of polarity of PCNA positive cell distribution and also an increase in number, mean and largest sizes and maximum shape irregularity of AgNOR dots. The mean chromosome index for chromosome 17, p53 and bcl-2 immunostaining positivity were also found to be significantly increased in moderate and severe dysplasia and in cancerous cases in comparison to normal and mild dysplasia cases. Moreover, the DNA-instability-test positive dysplasia cases showed statistically significant increased values of PCNA-index, AgNOR parameters, mean chromosome index, p53 and bcl-2 expression in comparison to those of DNA-instability-test negative dysplasia cases. In conclusion, some mild dysplasia (33.33%) and most of the moderate (65.11%) and severe dysplasia (77.77%) were regarded as malignant in nature, existing at an early stage of progression of malignancy.

Carcinoma in Situ↗
PubMed2000

Genomic instability at the BUB1 locus in colorectal cancer, but not in non-small cell lung cancer.

Genomic instability is observed in the majority of human tumors. Dysregulation of the mitotic spindle checkpoint is thought to be one of the mechanisms that facilitate aneuploidy in tumor cells. Mutations in the mitotic spindle checkpoint kinase BLUB1 cause a dominant negative disruption of the spindle, leading to chromosome instability in cancer cell lines. However, little is known about chromosome 2q14, the genomic region containing BUB1, in human tumors. The BUB1 locus was evaluated in 32 colorectal cancer (CRC) and 20 non-small cell lung cancer (NSCLC) primary tumors using a panel of seven microsatellite repeats for 2q, two CA repeats in BUB1, and gene mutation analysis. The 2q locus was allelically stable in NSCLC but relatively unstable in colorectal primary tumors (20 of 32 tumors, 62.5%). In addition, 14.5% of CRC patients displayed instability within BUB1. Previously described BUB1 mutations and polymorphisms were rare (< 1%) in the CRC or NSCLC tumors. Our data demonstrate 2q and BUB1 allelic instability in CRC and indicate that mutations in BUB1 are rare causes of chromosome instability in CRC or NSCLC. Additional investigations may shed light on the mechanistic impact of the mitotic spindle checkpoint pathway in colorectal tumor initiation and progression.

Adenocarcinoma↗
PubMed2001

TP53-dependent chromosome instability is associated with transient reductions in telomere length in immortal telomerase-positive cell lines.

Telomere shortening in telomerase-negative somatic cells leads to the activation of the TP53 protein and the elimination of potentially unstable cells. We examined the effect of TP53 gene expression on both telomere metabolism and chromosome stability in immortal, telomerase-positive cell lines. Telomere length, telomerase activity, and chromosome instability were measured in multiple clones isolated from three related human B-lymphoblast cell lines that vary in TP53 expression; TK6 cells express wild-type TP53, WTK1 cells overexpress a mutant form of TP53, and NH32 cells express no TP53 protein. Clonal variations in both telomere length and chromosome stability were observed, and shorter telomeres were associated with higher levels of chromosome instability. The shortest telomeres were found in WTK1- and NH32-derived cells, and these cells had 5- to 10-fold higher levels of chromosome instability. The primary marker of instability was the presence of dicentric chromosomes. Aneuploidy and other stable chromosome alterations were also found in clones showing high levels of dicentrics. Polyploidy was found only in WTK1-derived cells. Both telomere length and chromosome instability fluctuated in the different cell populations with time in culture, presumably as unstable cells and cells with short telomeres were eliminated from the growing population. Our results suggest that transient reductions in telomere lengths may be common in immortal cell lines and that these alterations in telomere metabolism can have a profound effect on chromosome stability.

Cell Line, Transformed↗
PubMed1998

[Genetic instability of microsatellites Mfd41 and DCC in the evolution of chronic myelogenous leukemia].

OBJECTIVE: To explore the relationship between the genetic instability of microsatellite and the evolution of chronic myelogenous leukemia(CML). METHODS: The loss of heterozygosity(LOH) and the microsatellite instability(MSI) of two polymorphic microsatellite markers, DCC and Mfd41, which located on chromosome 18q and 17p respectively, were assayed by standard PCR-silver staining analysis in bone marrow cells from 17 CML patients progressing from chronic phase to accelerated phase or blast crisis. RESULTS: LOH or MSI of the two microsatellites were demonstrated in 8/17 (47.5%) patients in accelerated/blastic phases. For DCC, genetic instability was revealed in 2 of 9 patients in accelerated phase and in 4 of 8 in blast crisis. For Mfd41, genetic instability was revealed in 1 of 9 patients in accelerated and in 1 of 8 in blast crisis. CONCLUSION: Genetic instability of DCC and Mfd41 may play a role in the evolution of CML.

Adolescent↗
PubMed2001

[Long-term results of interferential current stimulation in the treatment of bladder instability].

OBJECTIVE: To study the late results of interferential current stimulation in the treatment of detrusor instability. MATERIAL AND METHODS: 62 patients with detrusor instability refractory to medical treatment by anticholinergic drugs were treated by interferential current stimulation. This technique combines the advantages of retraining stimulation with external application. This retrospective study was based on 62 patients (43 children, 11 men and 8 women) presenting with detrusor instability between January 1990 and December 1997. All patients were assessed clinically and by a radiological, bacteriological and urodynamic work-up prior to treatment. The mean follow-up was 5 years (range: 18 months to 10 years). RESULTS: The results of this technique were excellent, with 80.9% of cures at one year, but they tended to fade over time to 40% of cures at 5 years. However, results which deteriorate after one year can generally be maintained by performing 5 maintenance sessions every 12 or 18 months. CONCLUSION: Treatment of detrusor instability by interferential current is a reliable technique which constitutes an alternative to the other methods of retraining stimulation and can be performed in cases of instability refractory to anticholinergic drugs, before considering neuromodulation or surgery. Five to 10 maintenance sessions every 12 or 18 months ensure stable long-term results in the majority of cases.

Adolescent↗
PubMed2001

Application of the National Cancer Institute international criteria for determination of microsatellite instability in ovarian cancer.

Recently, the National Cancer Institute (NCI) established criteria for determination of microsatellite instability (MSI) in colorectal tumors. Although the best panel of markers for ovarian tumors is not known, we evaluated epithelial ovarian cancers for MSI based on the NCI recommendations. One hundred and nine ovarian tumors were analyzed for MSI by gel analysis of paired germ-line and tumor DNA. PCR amplification was performed using the panel of five microsatellite markers recommended by the NCI (BAT25, BAT26, D5S346, D2S123, and D17S250) and nine additional markers picked based on their genomic location (NME1, D10S197, D11S904, D13S175, DXS981, DXS6800, DXS6807, AR, and D3S1611). Tumors were characterized on the basis of: high-frequency MSI (MSI-H) if two or more of the five NCI markers showed instability or there was instability at 30% or more of all markers tested; or low-frequency MSI (MSI-L) if only one of the five NCI markers showed instability or <30% of all of the markers. All of the other tumors were considered microsatellite stable. On the basis of the NCI markers, 12 (11%) tumors demonstrated MSI-H, and 8 (7%) additional tumors had MSI-L. When all of the 14 markers were considered together, 13 (12%) tumors demonstrated MSI-H (based on 30% or more unstable loci), and 26 (24%) tumors had MSI-L. A single tumor identified to have MSI-H based upon all of the markers tested would have been classified as MSI-L based upon the NCI markers alone. Inclusion of an additional dinucleotide marker (NME1) to the NCI panel allowed detection of all of the tumors with MSI-H using only six markers. MSI-H occurs in approximately 12% of invasive ovarian tumors. For optimal detection of microsatellite instability in ovarian cancer, an additional marker (NME1) may be required, along with the five recommended by the NCI.

DNA, Neoplasm↗
PubMed2001

Efficacy of the beta3-adrenergic receptor agonist CL-316243 on experimental bladder hyperreflexia and detrusor instability in the rat.

PURPOSE: Recent evidence indicates that in a number of species detrusor relaxation is mediated through activation of the beta3-adrenergic receptor. We determined whether activation of the beta3-adrenergic receptor would be a useful therapeutic approach for bladder instability. We profiled in vitro activity of the beta3-adrenergic receptor agonist CL-616243 and the efficacy of this compound in experimental models of detrusor instability and bladder hyperreflexia. MATERIALS AND METHODS: Isolated rat detrusor strips were contracted by depolarizing the preparations with 20 mM. KCl. CL-316423 was added to the tissue bath in increasing concentrations and contraction inhibition was assessed. Efficacy against bladder instability was evaluated using the obstructed hypertrophied bladder model in the rat. The acetic acid bladder cystometry model was used to assess the efficacy of CL-316423 in bladder hyperreflexia. Isovolumetric contractions were evoked by electrical stimulation using a silver bipolar electrode. Data are expressed as the mean plus or minus standard error of mean. RESULTS: CL-316243 inhibited spontaneously contracting, isolated rat detrusor strips in a concentration dependent manner with a mean concentration inhibiting 50% of maximal response of 2.65 +/- 0.36 nM. Intrinsic activity relative to forskolin was 1. In vivo CL-316243 administered intravenously or orally significantly increased the voiding interval and bladder compliance. In addition, there was a decrease in the number of spontaneous contractions during the filling phase in a model of neurogenic and obstruction induced bladder instability. The amplitude of electrically evoked isovolumetric contractions was significantly smaller after CL-316243 exposure. CONCLUSIONS: These data suggest that activating the beta3-adrenergic receptor in rat bladder using CL-316243 may directly inhibit smooth muscle contractility, experimental hyperreflexia and detrusor instability, and be useful for urge urinary incontinence.

Adrenergic beta-Agonists↗