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PubMed2006

Understanding biodiversity effects on prey in multi-enemy systems.

Biodiversity-ecosystem functioning theory would predict that increasing natural enemy richness should enhance prey consumption rate due to functional complementarity of enemy species. However, several studies show that ecological interactions among natural enemies may result in complex effects of enemy diversity on prey consumption. Therefore, the challenge in understanding natural enemy diversity effects is to predict consumption rates of multiple enemies taking into account effects arising from patterns of prey use together with species interactions. Here, we show how complementary and redundant prey use patterns result in additive and saturating effects, respectively, and how ecological interactions such as phenotypic niche shifts, synergy and intraguild predation enlarge the range of outcomes to include null, synergistic and antagonistic effects. This study provides a simple theoretical framework that can be applied to experimental studies to infer the biological mechanisms underlying natural enemy diversity effects on prey.

Biodiversity↗
PubMed2006

Long-term treatment of pigs with low doses of monoclonal antibodies against porcine CD4 and CD8 antigens.

In vivo depletion of lymphocyte subsets allows investigation of the role of specific subsets in protective immunity. In the present study we evaluated the effects of long-term, low-dose treatment with murine monoclonal antibodies (mAbs) against porcine CD4 and CD8 surface antigens on lymphocyte subsets in pigs. Four-week-old pigs were treated by intramuscular injections of hybridoma cell culture supernatants containing anti-CD mAbs twice a week for a period of 5 weeks. The immunomodulatory effects of the treatments were assessed by flow cytometry (FCM) analysis of peripheral blood lymphocytes. Treatment with the anti-CD4 mAb almost completely eliminated the CD4(+) T-cell subset from the circulation after 2 weeks of therapy. This depletion persisted until the end of the experimental period 5 weeks after initiated therapy. Treatment with the anti-CD8 mAb was less effective, reducing the CD8(+) T-cell subset in peripheral blood by approximately 50% of the initial level after 3 weeks of therapy. Further, the anti-CD8 mAb-treated pigs showed a parallel increase in the CD4(+) T-cell subset from day 7. Two-colour FCM analysis indicated that a shift in phenotype from single-positive CD4(+)/CD8(-) to double-positive CD4(+)/CD8(+) T-cells might have occurred in these pigs. In the present experiment we demonstrated specific modulation of the peripheral blood T-lymphocyte population in pigs with continuous low-dose injections of specific mAb. The ability to modulate individual T-cell subsets should provide a method to elucidate their functionality in protection against infectious disease.

Animals↗
PubMed2002

Structural basis of differences in isoform-specific gating and lidocaine block between cardiac and skeletal muscle sodium channels.

Voltage-gated Na(+) channels underlie rapid conduction in heart and skeletal muscle. Cardiac sodium channels open and close over more negative potentials than do skeletal muscle sodium channels; heart channels are also more sensitive to lidocaine block. The structural basis of these differences is poorly understood. We mutated nine isoform-specific micro1 (rat skeletal muscle) channel residues in domain IV to those at equivalent locations in hH1 (human cardiac) channels. Channel constructs were expressed in tsA-201 cells and screened for changes in gating and lidocaine sensitivity. Only L1373E, located in the linker between the S1 and S2 transmembrane segments, shifted activation gating and use-dependent block by lidocaine toward that seen in hH1. The converse mutation, hH1-E1555L, shifted the phenotype of hH1 to resemble that of micro1. Therefore, we identified a previously unsuspected glutamate-to-leucine isoform-specific variant site (i.e., 1555 in hH1 and 1373 in micro1) that significantly influences gating and drug block in sodium channels. The identification of the residue at this position plays a major role in shaping the responses of sodium channels to voltage and to lidocaine, helping to rationalize the distinctive behavior of cardiac sodium channels.

Amino Acids↗
PubMed2005

Role of erythropoietin for angiogenesis and vasculogenesis: from embryonic development through adulthood.

Erythropoietin (EPO), a stimulator of erythropoiesis, was previously shown to stimulate angiogenesis and proliferation of endothelial cells. Here, we investigated and compared the influence of EPO on cell number, proliferation, apoptosis, migration, and differentiation of endothelial cells in intact mouse embryoid bodies (EB), isolated endothelial cells from EB (EBEC), and adult human endothelial progenitor cells (hEPC). EB were treated with EPO (0.5 U/ml) immediately after plating was completed (day 5+0) or 3 days later. EPO treatment was continued until days 5+3 or 5+6. Cultured EBEC were treated 3 days after being plated, and primary hEPC from young healthy adults were treated 5 days after being plated with EPO for 48 h. Immunohistochemistry was performed with anti-PECAM (CD31), anti-Ki67, anti-CD34, anti-CD133, anti-EphB4, and anti-ephrinB2 antibodies. In all, mouse EB and EBEC and hEPC, EPO-treatment resulted in increased number of endothelial cells, increased proliferation, decreased apoptosis, and enhanced migration. In EB, this EPO effect was most pronounced when treatment was begun early (day 5+0) and was accompanied by an enhanced endothelial tube formation. In EBEC and hEPC, EPO shifted the phenotypic differentiation toward an increased ratio of EphB4-positive cells, i.e., toward a venous phenotype. These results are consistent with an important role of EPO for the number, proliferation, apoptosis, function, and phenotypical development of immature endothelial cells, which persists from early development through adulthood. They provide additional and further evidence for a strong interrelation between hematopoiesis and vasculogenesis/angiogenesis (sharing the same pathways), which may be important in many physiological and pathophysiological conditions.

AC133 Antigen↗
PubMed2005

Pre-B-cell colony-enhancing factor regulates NAD+-dependent protein deacetylase activity and promotes vascular smooth muscle cell maturation.

Conversion of vascular smooth muscle cells (SMCs) from a proliferative state to a nonproliferative, contractile state confers vasomotor function to developing and remodeling blood vessels. Using a maturation-competent human SMC line, we determined that this shift in phenotype was accompanied by upregulation of pre-B-cell colony-enhancing factor (PBEF), a protein proposed to be a cytokine. Knockdown of endogenous PBEF increased SMC apoptosis and reduced the capacity of synthetic SMCs to mature to a contractile state. In keeping with these findings, human SMCs transduced with the PBEF gene had enhanced survival, an elongated bipolar morphology, and increased levels of h-caldesmon, smoothelin-A, smoothelin-B, and metavinculin. Notwithstanding some prior reports, PBEF did not have attributes of a cytokine but instead imparted the cell with increased nicotinamide phosphoribosyltransferase activity. Intracellular nicotinamide adenine dinucleotide (NAD+) content was increased in PBEF-overexpressing SMCs and decreased in PBEF-knockdown SMCs. Furthermore, NAD+-dependent protein deacetylase activity was found to be essential for SMC maturation and was increased by PBEF. Xenotransplantation of human SMCs into immunodeficient mice revealed an increased capacity for PBEF-overexpressing SMCs to mature and intimately invest nascent endothelial channels. This microvessel chimerism and maturation process was perturbed when SMC PBEF expression was lowered. These findings identify PBEF as a regulator of NAD+-dependent reactions in SMCs, reactions that promote, among other potential processes, the acquisition of a mature SMC phenotype.

Apoptosis↗
PubMed1987

Quiescence and increased adhesion after mammalian DNA transfection of human fibrosarcoma cells.

When a population of human fibrosarcoma HT1080 cells was transfected with a mammalian expression vector and DNA pieces representing either the human whole genome or mouse bulk cDNA, there was a transient increase in the number of adhesive cells in the population. The number of cells with increased adhesion was proportional to the amount of transfected DNA; the increase occurred at a maximal frequency of between 10(-4) and 10(-5) per cell. Increased adhesion in these cells persisted for 9-12 days, corresponding to the period of highly efficient transient transfection, and was accompanied by arrest in cell division. Transfection of non-mammalian DNAs, reduction of transfected mammalian sequence length by restriction enzyme digestion, or omission of expression vector DNA did not permit these shifts in phenotype. The effects seen suggest that expression of specific transfected mammalian DNA sequences suppresses certain phenotypic characteristics in these transformed mammalian cells.

Cell Adhesion↗
PubMed1999

Postthymic development of CD28-CD8+ T cell subset: age-associated expansion and shift from memory to naive phenotype.

During human aging, one of the major changes in the T cell repertoire is a dramatic expansion of T cells with the atypical CD28-CD8+ phenotype. In this study, we show that this increase is a consequence not only of an expansion in the CD28-CD8+ population but also of a decrease in the number of CD28+CD8+ T cells. The decrease in circulating CD28+CD8+ T cells is dramatically accelerated after the age of 50 and is not accompanied by an equivalent reduction in the CD28+CD8+ subset. Our findings confirm that aging leads to an accumulation of CD45RO+ T cells within the CD28+CD8+ subset as previously observed. Surprisingly, we found an increase in CD45RA+ expression with age in the CD28-CD8+ subset. Immune-phenotyping for activation markers, measurement of telomere DNA content, and cytokine production analysis indicate that the large majority of CD28-CD8+ T cells are Ag-experienced, despite their CD45RA+ phenotype. Our study further demonstrates that the poor proliferative response displayed by CD28-CD8+ T cells is not a consequence of telomere shortening. Also, analysis of cytokine production at the single cell level revealed that the proportions of IFN-gamma +, IL-4+, and IL-10+ T cells are considerably higher among the CD28-CD8+ than the CD28+CD8+ subset. In summary, these data explain the presence of CD45RA+ T cells in the elderly, shed light on the phylogenetic origin of CD28-CD8+ T cells, and suggest a role for these cells in the immune senescence process.

Adolescent↗
PubMed2003

ERK(MAPK) activity as a determinant of tumor growth and dormancy; regulation by p38(SAPK).

After dissemination from a primary tumor, cancer cells may resume growth, leading to overt metastasis, or enter a state of protracted dormancy. However, mechanisms that determine their fate, or markers that predict it, are mostly unavailable. We previously showed that in HEp3 human head and neck carcinoma, the extracellular signal-regulated kinase (ERK)(MAPK)/p38(SAPK) activity ratio predicts whether the cells will proliferate or enter a state of dormancy in vivo. The proliferative balance of high ERK/p38 ratio was induced by high urokinase (uPA) receptor (uPAR) expression, which activated alpha5beta1-integrin and epidermal growth factor receptor. This signaling pathway was additionally enhanced by uPA binding to uPAR and fibronectin binding to alpha5beta1-integrin. We tested whether the ERK/p38 balance is predictive of in vivo behavior in other cancer cell types and whether altering the balance will shift their phenotype between proliferation and dormancy. ERK and p38 activities were determined using either phospho-specific monoclonal antibodies or a trans-reporting system where GAL4-Elk and GAL4-CHOP trans-activation of luciferase gene served as reporters for ERK and p38 activities, respectively. We show that in breast, prostate, melanoma, and fibrosarcoma cell lines, the level of active phospho-ERK and the ERK/p38 activity ratio predict for the in vivo behavior in approximately 90% of the cell lines tested. Modulation of ERK/p38 activity ratio by multiple pharmacological and genetic interventions confirms that high ERK/p38 ratio favors tumor growth, whereas high p38/ERK ratio induces tumor growth arrest (dormancy) in vivo and that ERK is negatively regulated by p38. A melanoma cell line appeared to have developed an escape mechanism to avoid the growth inhibitory effect of high p38 activity. Mechanistic analysis implicated high uPAR expression and its interaction with and activation of alpha5beta1-integrin as determinants of the in vivo growth promoting high ERK/p38 ratio in several cell lines. The small GTPase, Cdc42, was implicated in activation of p38 and growth arrest. These results suggest that even cells that originate in advanced cancers retain a degree of dependence on surface receptors and matrix for their proliferative signals in vivo and provide a therapeutic opportunity to change their phenotype from tumorigenic to dormant.

Animals↗
PubMed1992

[Participation of mobile element hobo in transposition events in the long-term instability system of Drosophila melanogaster].

The lines with an active hobo elements as well as those without any hobo fragments were hybridized with the y2sc1waG line. This resulted in the appearance of a number of mutations at the white, miniature, and some other loci. The authors analysed, in which way the hobo transposable elements take part in mutagenesis in these crosses. Most of the white mutants obtained were analysed and transpositions of hobo and Stalker elements were demonstrated. Both independent and simultaneous transpositions were found. It was shown by means of the Southern blot analysis that additional hobo or Stalker insertion into or close to the parental unknown waG insertion resulted in mutant white phenotype's shift toward both extreme and partial reversion. Possible participation in mutagenesis of other mobile elements is also under debate.

Animals↗
PubMed2003

[Composition of activated immunocompetent cells of periodontal blood in catarrhal gingivitis (Communication 3)].

Activation composition of lymphocyte population and killer cell phenotype are shifted in patients with catarrhal gingivitis during exacerbation and remission. Our findings indicate high activation of T-cellular immunity and NK cells in patients with exacerbation of catarrhal gingivitis, while remission is characterized by decreased level of activated T cells expressing HLA DR+ molecule on their surface and increased level of killer suppressors expressing IL-2 receptors.

Adolescent↗
PubMed1987

The abundance of alpha-tubulin mRNA increases during ciliary regeneration in Tetrahymena, and this occurs independently of the soluble tubulin content.

Control mechanisms of tubulin synthesis are analyzed during ciliary regeneration of the ciliate Tetrahymena. Titration of the alpha-tubulin mRNA concentrations during the regeneration period reveal that enhancement of tubulin synthesis is preceded and accompanied by increased concentrations of tubulin mRNA molecules. Stimulation of tubulin synthesis is independent of the pool size of soluble tubulin molecules, as suggested by at least two independent lines of evidence: First, like cells of normal phenotype a temperature sensitive size mutant enhances tubulin synthesis as well as tubulin mRNA concentration during ciliary regeneration, although these large mutant cells have a much higher concentration and amount of soluble tubulin molecules in the cytoplasm. Second, slowly regenerating cells of normal phenotype shift-up their concentration of tubulin mRNA molecules already before a time, when ciliary outgrowth might cause a significant depletion of the pool of soluble tubulin molecules. Thus, neither an induction of tubulin synthesis nor an increase in tubulin mRNA molecules is mediated via changes in the pool size of soluble tubulin molecules.

Animals↗
PubMedDate not supplied

Retinoic acid alters epithelial differentiation during palatogenesis.

Retinoids are teratogenic in humans and animals, producing a syndrome of craniofacial malformations that includes cleft palate. This study investigates the mechanism through which retinoic acid induces cleft palate. Murine palatogenesis after exposure to retinoic acid in utero is compared to normal development and to alterations observed after exposure in organ culture to retinoic acid or epidermal growth factor (EGF). Human embryonic palatal shelves were placed in the organ culture system and the responses to retinoic acid and EGF were compared to those of the murine palatal shelves. Growth factors play a role in normal development and are found in the embryonic palate. In other cell culture systems, retinoids alter the expression of EGF receptors. Our results suggest that in the medial epithelial cells of the palate, retinoic acid sustains the expression of the EGF receptor and the binding of EGF at a time when the expression in control medial cells has declined, and these control cells subsequently undergo programmed cell death. The continued DNA synthesis, proliferation, survival, and shift in phenotype of the medial cells is believed to interfere with the adhesion and fusion of opposing palatal shelves, resulting in cleft palate.

Cell Death↗
PubMed1995

Interaction between murine germline mutations in p53 and APC predisposes to pancreatic neoplasia but not to increased intestinal malignancy.

Murine strains which bear constitutive inactivating mutations of either the APC or the p53 tumor suppressor genes are characterised by spontaneous tumors. APC mutated (Min) mice develop large and small bowel adenomas, a small proportion of which, in time, become malignant. p53 deficient mice develop predominantly lymphoma and sarcoma. By interbreeding these strains we have shown that there is co-operativity between these mutations, leading to a shift in phenotype. Most notably, this was characterised by a range of abnormalities of the exocrine pancreas in 83% of animals heterozygous for the APC mutation and constitutively null for functional p53. Dysplasia and preneoplastic foci were seen in 61% of these animals and pancreatic acinar cell adenocarcinoma in 22%. Analysis of these tumors showed them to have lost the remaining wild-type copy of APC. Similar loss of APC was not associated with the development of other extra-intestinal tumors. Surprisingly, given the proposed role for loss of function mutations of the p53 gene in the development of human colorectal cancer, we have found no evidence for either an increase in the rate of adenoma formation in APC +/-, p53 -/- animals, or an increased rate of progression to malignancy compared with APC +/- p53 +/+ mice. These findings highlight striking tissue-specific differences in the tumor suppressor effects of p53.

Adenocarcinoma↗
PubMed1996

Trisomy 7p and malignant transformation of human breast epithelial cells following epidermal growth factor withdrawal.

We have reported previously on the first spontaneously immortalized, nonmalignant human breast epithelial cell line, HMT-3522, which is entirely dependent on exogenous epidermal growth factor (EGF). In passage 118, cells were adapted to grow in medium without EGF and a new growth-transformed subline, HMT-3522/gt-1, was generated and propagated at high growth rate without exogenous EGF (Madsen et al., Cancer Res., 52: 1210-1217, 1992). Here we have used this subline and the continuum of the parent line, HMT-3522/wt, to pose the question whether a relevant change in a physiological parameter of the microenvironment will induce malignant transformation. The two cell lines were cultured under identical conditions with the only exception that EGF was omitted in the medium for gt-1. Initially, wt and gt-1 were identical in terms of karyotype as well as morphology, growth rate, and protein expression as revealed by two-dimensional gel electrophoresis. A highly dramatic shift to phenotype was observed in passage 238 when the gt-1 line became tumorigenic in nude mice. After two mouse-culture passages, the resulting malignantly transformed cell line (HMT-3522/mt-1) was refractory to the growth-modulating effect of EGF and presented an extra copy of a chromosome marker, 7q-, as the only cytogenetic difference from the gt-1. Our results suggest that microenvironmental cues are powerful factors in the induction of malignancy. A major role of EGF receptor in the malignant transformation is emphasized by loss of EGF sensitivity and acquisition of an extra chromosome 7p harboring the EGF receptor gene. We hypothesize that during premalignant hyperplasia, a population of EGF/transforming growth factor alpha autonomous epithelial cells in situ may develop as a consequence of local transforming growth factor alpha deprivation, a condition reflected in the culture model as autonomy after EGF withdrawal.

Animals↗
PubMed1997

Features of macrophage differentiation induced by p19INK4d, a specific inhibitor of cyclin D-dependent kinases.

The mitogen-dependent induction of cyclin D-dependent kinase activity is required for cells to enter the DNA synthetic (S) phase of their division cycle. Immature 32Dcl3 myeloid cells (32D) proliferating in the presence of interleukin-3 (IL-3) normally express cyclins D2 and D3, which assemble into binary holoenzyme complexes with their catalytic subunits, CDK4 and CDK6. When 32D cells are switched to medium containing granulocyte colony-stimulating factor (G-CSF) instead of IL-3, D-type cyclins are degraded and, in the absence of their associated kinase activity, the cells arrest in the first gap phase (G1) of the cell cycle and differentiate to neutrophils. We derived 32D cells in which the expression of p19INK4d, a specific polypeptide inhibitor of CDK4 and CDK6, is regulated by the heavy metal-inducible sheep metallothionein promoter. Induction of p19INK4d in response to zinc prolonged cell survival in the absence of growth factor treatment. When maintained in medium containing both IL-3 and zinc, these cells lost cyclin D-dependent kinase activity, underwent G1 phase arrest, and acquired certain morphologic, antigenic, and functional properties of mononuclear phagocytes. Cells induced to express p19INK4d did not synthesize receptors for macrophage colony-stimulating factor (M-CSF/CSF-1) and reverted to an immature myeloid phenotype when shifted back into medium containing IL-3 alone. These cells exhibited accelerated differentiation to neutrophils in response to G-CSF but also gave rise to macrophage-like cells when maintained in medium containing both G-CSF and zinc. Therefore, the acquisition of macrophage properties in response to zinc treatment neither depended upon IL-3 nor upon G1 phase arrest per se and instead reflects some ability of p19INK4d, and presumably cyclin D-dependent kinases, to affect myeloid differentiation.

Carrier Proteins↗
PubMed1987

Shifts in macrophage (M phi) surface phenotypes during tumor growth: association of Mac-2+ and Mac-3+ M phi with immunosuppressive activity.

Rat anti-mouse monoclonal antibodies (mAb), anti-Mac-1, -2, and -3, directed against macrophage (M phi) glycoprotein surface antigens, were used to demonstrate a tumor-induced shift in peritoneal M phi subpopulations. This study of the tumor-induced shift was approached in two steps. First, to show that separate phenotypic M phi subpopulations existed and second, to show that a shift in these populations was involved in immunosuppression of the host during tumor growth. Endogenous peroxidase activity was examined among normal and tumor-bearing host (TBH) M phi. A significant increase in the number of peroxidase-positive M phi occurred during tumor growth. Indirect immunofluorescence showed a decrease in Mac-2+ cells and an increase in Mac-3+ cells in TBH M phi populations. When the mAb, anti-Mac-1,-2, and -3 were used in the presence of complement (C), they were cytotoxic for M phi and showed differential depletion of normal and TBH M phi. Peroxidase-positive TBH M phi were susceptible to C-mediated lysis by anti-Mac-1 and -3 but not by anti-Mac-2, whereas no direct relationship was observed among normal host M phi. To demonstrate differences between normal and TBH M phi subpopulations, soluble inhibitory factors were examined from mAb plus C-modified M phi populations. Anti-Mac plus C-treated normal and TBH M phi produced supernatants with different regulatory capabilities as assessed in the mixed-lymphocyte reaction (MLR). Anti-Mac-2 plus C treatment significantly reduced the ability of TBH M phi to produce a soluble suppressor(s) but did not alter normal host M phi-derived suppressor production. In contrast, anti-Mac-1 and -3 plus C treatment of normal host M phi significantly reduced suppressor production. In the TBH, however, anti-Mac-1 plus C had no effect, while anti-Mac-3 plus C had only a limited reduction as compared to the normal host. Determination of levels of prostaglandin E2 (PGE2) in M phi supernatants showed that normal host Mac-1+ M phi were involved in down regulation of PGE2 production. This control was missing in the TBH M phi. Mac-2+ M phi were the apparent producers of PGE2 which accounts for the factor-mediated MLR suppression attributed to TBH Mac-2+ M phi. Collectively, these data suggest that tumor-induced aberrations in immunoregulation can in part be attributed to differences in anti-Mac mAb-defined M phi subpopulations.

Animals↗
PubMedDate not supplied

Differentiation hotspots: the deterioration of hierarchy and stochasm.

The conception of the present-day model of hematopoiesis was begun by the work of Professor Ernst Neumann in the 19th century when he established that immature blood cells in the bone marrow migrate out into the blood vessels. Here was the birth of the hierarchical model of hematopoiesis. Jumping 135 years into the present day, recent data suggests that the stem cell regulation is not based on the classic hierarchical model, but instead more on a functional continuum. Presumptively, chromatin remodeling with cycle transit underlies changes in gene expression. This implies that the differentiative potential of primitive stem cells should also shift with cycle transit. This model proposes a less rigid system, at least in the early stem cell and progenitor compartments in which the functional characteristics of stem cells change as they go through cycle transit. We have shown that hematopoietic stem cells reversibly shift their engraftment phenotype with cytokine induced cell cycle transit. Other shifts include adhesion protein expression, cytokine receptor expression, gene expression, and progenitor phenotype. We have also found differentiation "hotspots", culture times (reflective of cell cycle state) at which stem cell differentiation was directed toward a specific lineage. This data inaugurates the end of a pure stochastic model. This work complements existing scientific work without discounting it and adds an additional dimension of complexity (or simplicity) to the process of hematopoiesis.

Animals↗
PubMed2006

Regulation of bladder muscarinic receptor subtypes by experimental pathologies.

1 The M3 muscarinic receptor subtype is widely accepted as the receptor on smooth muscle cells that mediates cholinergic contraction of the normal urinary bladder and other smooth muscle tissues, however, we have found that the M2 receptor participates in contraction under certain abnormal conditions. The aim of this study was to determine the effects of various experimental pathologies on the muscarinic receptor subtype mediating urinary bladder contraction. 2 Experimental pathologies resulting in bladder hypertrophy (denervation and outlet obstruction) result in an up-regulation of bladder M2 receptors and a change in the receptor subtype mediating contraction from M3 towards M2. Preventing the denervation-induced bladder hypertrophy by urinary diversion prevents this shift in contractile phenotype indicating that hypertrophy is responsible as opposed to denervation per se. 3 The hypertrophy-induced increase in M2 receptor density and contractile response is accompanied by an increase in the tissue concentrations of mRNA coding for the M2 receptor subtype, however, M3 receptor protein density does not correlate with changes in M3 receptor tissue mRNA concentrations across different experimental pathologies. 4 This shift in contractile phenotype from M3 towards M2 subtype is also observed in aged male Sprague-Dawley rats but not females or either sex of the Fisher344 strain of rats. 5 Four repeated, sequential agonist concentration response curves also cause this shift in contractile phenotype in normal rat bladder strips in vitro, as evidenced by a decrease in the affinity of the M3 selective antagonist p-fluoro-hexahydro-sila-diphenidol (p-F-HHSiD). 6 A similar decrease in the contractile affinity of M3 selective antagonists (darifenacin and p-F-HHSiD) is also observed in bladder specimens from patients with neurogenic bladder as well as certain organ transplant donors. 7 It is concluded that although the M3 receptor subtype predominantly mediates contraction under normal circumstances, the M2 receptor subtype can take over a contractile role when the M3 subtype becomes inactivated by, for example, repeated agonist exposures or bladder hypertrophy. This finding has substantial implications for the clinical treatment of abnormal bladder contractions.

Age Factors↗