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At least 19 recordsLinked to original sources
PubMed1991

Direct responses to selection for increased litter size, decreased age at puberty, or random selection following selection for ovulation rate in swine.

Nine generations of selection for high ovulation rate were followed by two generations of random selection and then eight generations of selection for increased litter size at birth, decreased age at puberty, or continued random selection in the high ovulation rate line. A control line was maintained with random selection. Line means were regressed on generation number and on cumulative selection differentials to estimate responses to selection and realized heritabilities. Genetic parameters also were estimated by mixed-model procedures, and genetic trends were estimated with an animal model. Response to selection for ovulation rate was about 3.7 eggs. Response in litter size to selection for ovulation rate was .089 +/- .058 pigs per generation. Average differences between the high ovulation rate and control lines over generations 10 to 20 were 2.86 corpora lutea and .74 pigs (P less than .05). The regression estimate of total response to selection for litter size was 1.06 pigs per litter (P less than .01), and the realized heritability was .15 +/- .05. When the animal model was used, the estimate of response was .48 pigs per litter. Total response in litter size to selection for ovulation rate and then litter size was estimated to be 1.8 and 1.4 pigs by the two methods. Total response to selection for decreased age at puberty was estimated to be -15.7 d (P less than .01) when data were analyzed by regression (realized heritability of .25 +/- .05) and -17.1 d using the animal model. No changes in litter size occurred in the line selected for decreased age at puberty. Analyses by regression methods and mixed-model procedures gave similar estimates of responses and very similar estimates of heritabilities.

Age Factors↗
PubMed1975

In vitro selection and extended culture of antigen-specific T lymphocytes. I. Description of selection culture procedure and initial characterization of selected cells.

Specific selection of antigen-responsive guinea pig peritoneal exudate lymphocytes (PELs) was achieved by a selection culture procedure. This procedure involved the addition of PELs from immune donors to monolayers of antigen-pulsed adherent peritoneal exudate cells from nonprimed syngeneic donors. PELs which failed to adhere were discarded at 24 and 48 h; after 1 wk of culture, lymphocytes were obtained which were highly responsive to the antigen for which they were selected but which demonstrated little or no response to other antigens to which the original donor of the lymphocyte was immune. These selected cells were largely T lymphocytes and could be maintained in culture for 2-5 wk in an antigen-responsive state and, in 20-30% of cases, for 8-10 wk in an antigen-independent state.

Albumins↗
PubMed1992

Twelve-year follow-up of a prospective, randomized trial of selective vagotomy with pyloroplasty and selective proximal vagotomy with and without pyloroplasty for the treatment of duodenal, pyloric, and prepyloric ulcers.

Between 1973 and 1981, 161 patients with prepyloric, pyloric, or duodenal ulcers were randomly allocated to selective vagotomy with pyloroplasty, selective proximal vagotomy with pyloroplasty, or selective proximal vagotomy alone. No significant differences in clinical results were found 3 years after surgery by Emås and Fernström (Am J Surg 1985; 149: 236-42). There was one postoperative death, and one patient lost to follow-up. Of 159 patients, 52 underwent selective vagotomy with pyloroplasty, 55 selective proximal vagotomy with pyloroplasty, and 52 selective proximal vagotomy alone. Fifteen patients did not undergo endoscopy, but they had no epigastric complaints. From 1 to 16 years after surgery, recurrent ulcer was detected in 13%, 18%, and 23%, respectively, after selective vagotomy with pyloroplasty, selective proximal vagotomy with pyloroplasty, or selective proximal vagotomy without pyloroplasty. Twenty-eight percent of the patients with recurrent ulcer had no symptoms and received no treatment. Sixteen patients died within 8 years after surgery of causes unrelated to the ulcer disease. At their final examination, 14 of the 16 patients had Visick I or II (modified Visick scale) results, and the disease that caused their deaths obscured evaluation in 2 patients. The remaining 143 patients were followed up for 8 to 16 years (average: 12 years). Epigastric pain with or without ulcer was recorded more often (significant) after selective proximal vagotomy alone (40%) than after selective vagotomy with pyloroplasty (17%) or selective proximal vagotomy with pyloroplasty (14%). Bowel habits were unchanged in 96% of patients who underwent selective vagotomy with pyloroplasty or selective proximal vagotomy with pyloroplasty and 100% of patients who had selective proximal vagotomy alone. Mild dumping tended to be more common after vagotomy with pyloroplasty but was a minor nuisance in only a few patients. Very good or good results (Visick I or II) were recorded in 75% of the patients after selective vagotomy with pyloroplasty or selective proximal vagotomy with pyloroplasty or selective proximal vagotomy with pyloroplasty and in 54% after selective proximal vagotomy alone (significant difference). Seventeen patients underwent reoperation with antrectomy and gastrojejunostomy Roux-en-Y (13 patients) or gastroduodenostomy (4 patients) with no mortality. The results of the reoperations were graded as Visick I or II results in all but one patient. The final grading, including the reoperations, were Visick I or II in 85% of patients after selective vagotomy with pyloroplasty and selective proximal vagotomy with pyloroplasty and in 55% after selective proximal vagotomy alone (significant difference).(ABSTRACT TRUNCATED AT 400 WORDS)

Duodenal Ulcer↗
PubMed1989

[Effect of selective and non-selective adrenergic beta receptor blockaders on selected electrophysiologic properties of the human heart].

Beta-2 adrenergic receptors were found in a human heart and their role in regulation of inotropic properties during last year was proved. The aim of our study was comparison of effects of selective (metoprolol) and nonselective (propranolol) beta-receptors blockade on cardiac electrophysiological properties. The study was carried out in 20 patients in the majority without organic heart injury and clinical symptoms of the sinus node dysfunction as well as atroioventricular conduction disorders. Method of the transoesophageal left atrial stimulation was utilized. Examinations were performed after drugs administrations in the same persons, during following days. Propranolol and metoprolol were intravenously administrated in a dose of 0.2 mg/kg b.w. Both drugs statistically significant lengthened sinus rhythm cycle time, sinus node recovery time, sinus node and a-v node effective refraction and lowered Wenckebach's point. They did not significantly effect on sinoatrial conduction and the atrial effective refraction. There were no significant differences between examined beta-blockers. Obtained results allowed us to conclude that: 1) eletrophysiologic properties of propranolol and metoprolol are similar, 2) it seems that in physiological conditions the effects of the adrenergic nervous system on electrophysiologic properties of sinus node, atrio-ventricular node and atrium is mainly realized by beta-1 adrenergic receptors.

Action Potentials↗
PubMed1975

Determination of the environmental sensitivity of selection lines by the selection environment.

The parents chosen to continue 10 independent selection lines of Schizophyllum commune over eight successive generations of selection, along with unselected controls, have been retrospectively examined for their response to growth at 15 degrees, 20 degrees, 25 degrees, 30 degrees and 35 degrees C. The regression of rate of growth on temperature was essentially linear over the range 15 degrees to 30 degrees C for all lines in all generations as was also the regression of rate of growth on various biological assessments of the environments over the whole temperature range. Either regression, therefore, provided linear regression coefficients which adequately accounted for the relative sensitivities of the lines to temperature in each generation of selection. These measures of environmental sensitivity confirmed our earlier report that selection for high mean performance in a good environment or for low mean performance in a poor environment leads to selections that are more sensitive to environmental variation than selections for high mean performance in a poor environment or for low mean performance in a good environment. These differences in sensitivity emerge as correlated responses during selection and the magnitude of these correlated responses is higher in the good environment than in the poor environment irrespective of the direction of selection. The environmental sensitivity of selection lines can be modified in either direction as required by either selecting for sensitivity simultaneously with the selection for mean performance or by selecting for mean performance in an above or below average environment. The quality of environments in which artificial selection is usually carried out is likely to have led to high selections with maximum environmental sensitivity and low selections with minimum sensitivity.

Environment↗
PubMed1986

The selection limit due to the conflict between truncation and stabilizing selection with mutation.

Long-term selection response could slow down from a decline in genetic variance or in selection differential or both. A model of conflict between truncation and stabilizing selection in infinite population size is analysed in terms of the reduction in selection differential. Under the assumption of a normal phenotypic distribution, the limit to selection is found to be a function of kappa, the intensity of truncation selection, omega 2, a measure of the intensity of stabilizing selection, and sigma 2, the phenotypic variance of the character. The maintenance of genetic variation at this limit is also analyzed in terms of mutation-selection balance by the use of the "House-of-cards" approximation. It is found that truncation selection can substantially reduce the equilibrium genetic variance below that when only stabilizing selection is acting, and the proportional reduction in variance is greatest when the selection is very weak. When truncation selection is strong, any further increase in the strength of selection has little further influence on the variance. It appears that this mutation-selection balance is insufficient to account for the high levels of genetic variation observed in many long-term selection experiments.

Alleles↗
PubMed1986

Genetic divergence under uniform selection. II. Different responses to selection for knockdown resistance to ethanol among Drosophila melanogaster populations and their replicate lines.

We have tested the hypothesis that genetic differences among conspecific populations may result in diverse responses to selection, using natural populations of Drosophila melanogaster. Selection for ethanol tolerance in a tube measuring knockdown resistance was imposed on five West Coast populations. In 24 generations the selected lines increased their mean knockdown times, on average, by a factor of 2.7. An initially weak latitudinal cline was steepened by selection. The two southernmost populations showed the same increases in the selected character, but differed consistently in their correlated responses in characters related to ethanol tolerance. This result indicates that the populations responded to selection by different genetic changes. Selection decreased female body weight and increased resistance to acetone, suggesting components of the response unrelated to ethanol metabolism. The Adhs allele was favored by selection in all populations at the onset, but increased in frequency only in the selected lines of the southernmost population. There was a correlation between latitude and Adh frequency changes, suggesting that fitnesses of the Adh alleles were dependent on the genetic background. Genetic background also had a large effect on the loss of fitness due to selection. Genetic drift between replicate lines caused more variation in selection response than initial genetic differences between populations. This result demonstrates the importance of genetic drift in divergence among natural populations undergoing uniform selection, since the effective population sizes approached those of small natural populations. Drift caused greater divergence between selected replicates than control replicates. Implications of this result for the genetic model of selection response are discussed.

Alcohol Dehydrogenase↗
PubMed2025

Evaluating selection at intermediate scales within genes provides robust identification of genes under positive selection in M. tuberculosis clinical isolates.

Multiple studies have reported genes in the M. tuberculosis (Mtb) genome that are under diversifying selection, based on genetic variants among Mtb clinical isolates. These might reflect adaptions to selection pressures associated with modern clinical treatment of TB. Many, but not all, of these genes under selection are related to drug resistance. Most of these studies have evaluated selection at the gene-level. However, positive selection can be evaluated on different scales, including individual sites (codons) and local regions within an ORF. In this paper, we use GenomegaMap, a Bayesian method for calculating selection, to evaluate selection of genes in the Mtb genome at all three levels. We present evidence that the intermediate analysis (windows of codons) yields the most credible list of candidate genes under selection (excluding PPE and PE_PGRS genes, which are predicted less reliably due to frequent sequencing errors). A further advantage of this approach is that it identifies specific regions within proteins that are under selective pressure, which is useful for structural and functional interpretation. In an analysis of two separate collections of Mtb clinical isolates (from Moldova; and a globally-representative set), we observed 53 and 173 significant genes under selection, with 36% overlap. The lists of genes under selection include many drug-resistance genes, as well as other genes that have previously been reported to be under selection (resR, phoR). The specific regions under selection identified within drug-resistance genes are shown to correspond to protein structural features known to be involved in resistance, supporting accuracy of the method. Positive selection in several ESX-1-related genes was also observed, suggesting adaptation to immune pressure.

adaptation↗
PubMed1989

Quantitative genetic variability maintained by mutation-stabilizing selection balance: sampling variation and response to subsequent directional selection.

A model of genetic variation of a quantitative character subject to the simultaneous effects of mutation, selection and drift is investigated. Predictions are obtained for the variance of the genetic variance among independent lines at equilibrium with stabilizing selection. These indicate that the coefficient of variation of the genetic variance among lines is relatively insensitive to the strength of stabilizing selection on the character. The effects on the genetic variance of a change of mode of selection from stabilizing to directional selection are investigated. This is intended to model directional selection of a character in a sample of individuals from a natural or long-established cage population. The pattern of change of variance from directional selection is strongly influenced by the strengths of selection at individual loci in relation to effective population size before and after the change of regime. Patterns of change of variance and selection responses from Monte Carlo simulation are compared to selection responses observed in experiments. These indicate that changes in variance with directional selection are not very different from those due to drift alone in the experiments, and do not necessarily give information on the presence of stabilizing selection or its strength.

Gene Frequency↗
PubMed1975

Hybridization and selection for increased penicillin titre in wild-type isolates of Aspergillus nidulans.

Repeated hybridization and selection among wild-type isolates produced strains of Aspergillus nidulans with increased penicillin titre. Four independent selection lines were established, each originating from a sexual cross between two different heterokaryon-incompatible wild-type isolates. In each generation, two selected high-titre sister strains were crossed to produce the next generation. An initial increase in titre was obtained in each line, but after four or five generations of selection the genetic variation was considerably reduced and the rate of response to selection had decreased. From a base population of wild-type isolates with a mean titre of 8-6 units/ml the progeny mean titre was raised to between 16 and 20 units/ml in each line. The gradual nature of the response suggests that a number of genes determine penicillin titre in the wild-type isolates used. The gene action throughout the selection programme was predominantly additive.

Aspergillus nidulans↗
PubMed1986

Selection in Hereford cattle. I. Selection intensity, generation interval and indexes in retrospect.

Selection intensity and generation interval were evaluated in a Hereford cattle herd made up of 14 inbred lines and 14 linecross groups corresponding to the lines of inbred sires at the Suan Juan Basin Research Center, Hesperus, Colorado. Selection indexes practiced were calculated in retrospect. Analyses of the records collected from 1946 through 1973 involved weaning weight (WW) and postweaning traits in males and females. Analyses by line were performed for the inbreds, while pooled analyses were done on the inbred and linecross populations. From records of 1,239 calves weaned, age of sire averaged 3.75 yr compared with 4.52 yr for age of dam, showing faster generation turnover for sires than for dams. Generation interval determined as actual age of midparent was 4.13 yr. Selection applied for WW, evaluated as annual selection differentials within inbred lines and then pooled over all lines, averaged .55 standard deviations (sigma)/generation for sires. For females, selection was much less intense. Midparent selection differential amounted to .33 sigma/generation. For sires, pooled standardized selection differentials per generation over all lines during the postweaning gain period were .49 sigma, .46 sigma, .40 sigma, -.20 sigma, -.10 sigma and .69 sigma, respectively, for initial weight, final weight, feed consumed, feed efficiency (FE, unadjusted and adjusted) and average daily gain (ADG). Selection of females for postweaning traits was not intense. Selection index actually practiced in retrospect for sires was: IS = .4461 (WW) - .0092 (FE) + .6126 (ADG). The indexes for dams included WW, 12-mo weight (12W), 18-mo weight (18W), mature spring weight (SPW) and mature fall weight (FAW) and were: for inbred dams, ID = .1824 (WW) - .0284 (12W) + .0736 (18W) - .1097 (SPW) - .1097 (FAW); for linecross dams, ID = .2693 (WW) - .2960 (12W) + .0147 (18W) + .1185 (SPW) - .0354 (FAW). The corresponding index selection differentials were .818, .203 and .209. Sire index selection differentials represent about 79% of the total selection differentials.

Animals↗
PubMed1975

In vitro selection and extended culture of antigen-specific T lymphocytes. II. Mechanisms of selection.

Functional selection of antigen-specific T lymphocytes can be achieved by culturing thymus-dependent (T) lymphocytes from immunized guinea pigs on "monolayers" of antigen-pulsed adherent peritoneal exudate cells (PEC) from nonimmune syngeneic donors. Several aspects of the in vitro selection of T lymphocyte-rich peritoneal exudate lymphocytes (PEL) were studied. It was shown that irradiated adherent PEC were equivalent to nonirradiated adherent PEC in supporting selection cultures, indicating that the lymphocytes harvested at the end of the selection culture derive from the immune donors of the PEL and not from the nonimmune donor of the adherent PEC. The relative importance of specific adherence and specific proliferation for achieving selection was determined by comparing the degree of selection obtained when nonadherent cells were discarded at 24 hr with that noted when the discard step was omitted. It was found that omitting the discard step markedly diminished the degree of selection. On the other hand, blocking proliferation with specific alloantisera after the discard step did not diminish the degree of selection, although it did diminish the cell yield. Thus, specific adherence to antigen-pulsed PEC appeared to be critical in the selection culture procedure. An estimate of the degree of enrichment obtained by the selection culture procedure was obtained by culturing selected cells in an excess of nonprimed PEL, so that auxiliary cells would not be limiting. Under these conditions, it appeared that selected cells were enrichied from 4- to 10-fold in antigen-responsive cells with respect to the initial cell population.

Animals↗
PubMed2026

Transition from Conventional to Genomic Selection (ssGBLUP) led to improve in accuracy gains and selection decisions in Sahiwal Cattle.

By using genome-wide markers to predict an individual's genetic potential, the introduction of Genomic Selection (GS) has transformed animal breeding. This greatly accelerated selection for complex traits by lowering reliance on drawn-out field trials, allowing for faster genetic gains in livestock. However, there is little research on the effects of genomic selection on Sahiwal cattle in India, and comparing it to the current culling or selection process is even more uncommon, particularly in nations with fewer genotyped animals. This study is an initial effort to address the aforementioned gaps in knowledge. Genomic selection was implemented in Sahiwal cattle for the 305 days milk yield using univariate animal model and the single-step Genomic Best Linear Unbiased Prediction (ssGBLUP) method. The Effective Population size (Ne) of the Sahiwal herd was calculated using genomic data and was reported for the previous generation to be 71.927. The heritability of 305 days milk yield was estimated as 0.177 ± 0.068. Genomic estimated breeding values (GEBVs) were predicted for each individual using ssGBLUP, yielding a mean prediction accuracy of 43.11%, compared with 40.88% obtained using conventional pedigree-based BLUP. Cross-validation further demonstrated superior predictive performance of ssGBLUP, with accuracies of 76.82% and 70.50% for ssGBLUP and PBLUP, respectively. To further check the effectiveness of the genomic selection methodology, we also compared the GEBVs obtained and compared it with the Expected Progeny Difference (EPD) which is being applied in our farm for culling decisions. It was seen that GEBVs obtained from ssGBLUP methodology were also in line with the conventionally used method of EPD. The use of genomic selection enables genetic studies with limited pedigree information. Additionally, the ssGBLUP methodology allows to check for pedigree errors, where family relationships are incorrectly recorded. The EPD and GEBVs were consistent with one another, indicating that genomic selection may also be utilised to support culling and selection decisions in a farm. Thus, in a conventional animal breeding program with constraint resources and an incomplete pedigree, we recommend employing the ssGBLUP model for regular genomic assessment and identification of suitable candidates to effectively carry out a genomic selection program.

Animals↗
PubMed2025

Positive selection and relaxed purifying selection contribute to rapid evolution of sex-biased genes in green seaweed Ulva.

BACKGROUND: The evolution of differences in gamete size and number between sexes is a cornerstone of sexual selection theories. The green macroalga Ulva, with incipient anisogamy and parthenogenetic gametes, provides a unique system to investigate theoretical predictions regarding the evolutionary pressures that drive the transition from isogamy to anisogamy, particularly in relation to gamete size differentiation and sexual selection. Its minimal gamete dimorphism and facultative parthenogenesis enable a rare window into early evolutionary steps toward anisogamy. RESULTS: By analyzing the expression profiles of sex-biased genes (SBGs) during gametogenesis, we found that SBGs evolve faster than unbiased genes, driven by higher rates of non-synonymous substitution (dN), indicating that SBGs are under stronger selective pressures. Mating type minus-biased genes (mt-BGs) exhibit higher dN/dS values than mating type plus-biased genes (mt+BGs), suggesting stronger selective pressures on mt-BGs, although this difference was not statistically significant (P = 0.08). Using branch-site and RELAX models, we found positive selection and relaxed purifying selection acting on a significant proportion of SBGs, particularly those associated with flagella function. CONCLUSIONS: This study highlights the selective pressures shaping anisogamy and provides insights into the molecular mechanisms underlying its evolution. The faster evolution of SBGs, particularly mt-BGs, and the positive selection on genes associated with motility, such as those related to flagella function, suggest the importance of enhanced gamete motility in the transition to anisogamy. These findings contribute to our understanding of sexual selection and the evolutionary forces that drive the differentiation of gamete size and number between sexes.

Selection, Genetic↗
PubMed1990

Transposable element-induced response to artificial selection in Drosophila melanogaster: molecular analysis of selection lines.

Artificial selection lines for abdominal bristle score of Drosophila melanogaster established from P-M hybrid dysgenic crosses showed increases in selection response, heritability and phenotypic variance compared to similar lines started from nondysgenic crosses. To determine whether this increased genetic variance could be due to enhanced transposition of P elements following the dysgenic cross, the cytological locations (sites) of P elements were determined by in situ hybridization for the whole genome of samples of 20 individuals from the parental P strain, 20 individuals from each of the eight dysgenic selection lines, and ten individuals from each of the eight nondysgenic selection lines. Variation among and within the selection lines and the parental P strain in P element insertion sites was exceptionally high. A total of 601 sites were identified, but there was no difference in total number of sites per line, mean number of sites per individual, mean copy number per individual, or site frequency between dysgenic and nondysgenic selection lines, or between lines selected for high and low bristle score. Transposition following nondysgenic crosses may explain additional observations of accelerated selection responses in nondysgenic selection lines. It was not possible to deduce which, if any, of the several hundred insertions in the dysgenic selection lines were responsible for their extreme bristle phenotypes.

Animals↗
PubMed1975

Population size and selection intensity effects on long-term selection response in mice.

Long-term response to within full-sib family selection for increased postweaning gain was evaluated in lines having different effective population sized (Ne) and selection intensities (i). Line designations were I4(4), I8(2), I16(2), M4(4), M8(2) and M16(2), where I and M indicate selection of the top 50% and 25%, respectively; 4, 8 and 16 represent the number of parental pairs per replicate and number of replicates is given in parentheses. Realized within full-sib family heritabilities (hR-2) in the first phase of selection (0-14 generations) were larger in 16-pair lines than in 4- and 8-pair lines. In the second phase of selection (greater than 14 generations), hR-2 declined significantly (P smaller than .01) in all lines, and only the I16 and M16 lines had hR-2 values significantly (P smaller than .01) greater than zero. Realized genetic correlations involving number born, 12-day litter weight, weaning weight and six-week weight tended to decline in the second phase of selection. The I16, M16 and control (C16) replicates were crossed in all combinations at generation 14. Crosses were then selected within litters for high postweaning gain. The hR-2 values in the crossbred lines were all larger than those in the second selection phase for M16-1. M16-2 and I16-1, but not for I16-2. Within each Ne level, total response was significantly (P smaller than .01) less for I lines compared with M lines. Total response increased as Ne increased, within each level of i. Relatively small differences in realized i values among Ne lines could not account for this result. The difference in total response among the Ne lines at a given selection intensity may be due to inbreeding depression and a combination of interactions involving "drift" and selection. By crossing replicates of the M lines with the C16 control, the effects of inbreeding depression were removed. Inbreeding depression and genetic drift, as defined herein, were equally important in accounting for differences among Ne lines in total response.

Animals↗
PubMed1985

Selection for weaning weight and postweaning gain in Hereford cattle. I. Population structure and selection applied.

Single trait selection was practiced in three lines of Hereford cattle derived from a common base population. Selection was practiced on males only within sire families for increased weaning weight (WW) in the WW line (WWL), for postweaning gain (PG) in the PG line (PGL) and at random in the control line (CTL). Females were culled on the basis of age or reproductive failure. Progeny of selected bulls were produced in two herds from 1970 through 1981. The data consisted of records on 2,467 progeny of 125 sires and 922 dams. Generations of selection to produce the 1981 calf crop were 1.96, 1.85 and 1.80 for WWL, PGL and CTL, respectively. For calves born in 1981, mean cumulative selection differentials (CSD) were 54.5 kg in WWL and 37.8 kg in PGL. Corresponding values in standard deviation units (SDU) were 2.31 and 1.68, respectively. Secondary selection differentials were 25 to 40% as large as selection differentials for the primary traits. Unintentional selection in the CTL in 1981 was 16.2 kg or .68 SDU for WW and .2 kg or .01 SDU for PG, respectively. Regressions of CSD on year were 4.1 kg or .17 SDU in WWL and 3.2 kg or .14 SDU in PGL. Realized selection differentials were approximately 88% of the potential selection differentials in both lines. Inbreeding coefficients of dam and calves in 1981 were 2.0 and 3.5% in WWL, 2.1 and 3.5% in PGL and 2.9 and 5.8% in CTL.

Animals↗
PubMed1987

The role of a low beta 1-adrenoceptor selectivity of [3H]CGP-12177 for resolving subtype-selectivity of competitive ligands.

On the basis of saturation binding studies on rat cardiac microsomes, which contained a mixed population of beta-adrenoceptor subtypes, [3H]CGP-12177 is presumed to be a non-selective beta-adrenergic radioligand. However, saturation binding studies carried out in the presence of subtype-saturating concentrations of the beta 2-selective antagonist ICI 118,551 and the beta 1-selective antagonist ICI 89,406, respectively, revealed a KD for beta 1-adrenoceptors of 0.33 +/- 0.02 nmol/l and a KD for beta 2-adrenoceptors of 0.90 +/- 0.14 nmol/l. Competition experiments with the highly selective antagonists revealed greatly different competition binding curves in the presence of either [3H]CGP-12177 or (-)[125I]iodocyanopindolol (ICYP), a beta-adrenergic radioligand considered to be as non-selective as [3H]CGP-12177. The following results are further suggestive for a selectivity of [3H]CGP-12177 for beta 1-adrenoceptors: (1) Using non-linear regression analysis, a significantly lower selectivity (expressed as the ratio of the IC50 for beta 2-adrenoceptors to the IC50 for beta 1-adrenoceptors) as well as a larger proportion of beta 1-adrenoceptors were calculated by competition of the beta 1-selective antagonist ICI 89,406 with [3H]CGP-12177 binding than by competition of ICI 89,406 with ICYP binding; (2) reducing the [3H]CGP-12177 concentration from 2 to 0.4 nmol/l, competition experiments with ICI 89,406 led to an increase in the estimated selectivity of the competitor and in the estimated proportion of beta 1-adrenoceptors; (3) reverse findings were obtained with ICI 118,551, a beta 2-selective antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗