Biomedical subjects

N Fraeyman

Publications and source records attributed to N Fraeyman.

30 records · Page 2Linked to original sources

PubMed1992

Influence of age on the beta 1- and beta 2-adrenergic receptors in rat liver.

The influence of maturation and aging on beta receptors in rat liver was studied. Competition binding experiments with the nonselective beta-antagonist propranolol and the subtype selective antagonists ICI 118,551 (beta 2) ICI 89,406 (beta 1), and CGP 20,712A (beta 1) revealed the presence of a mixed beta 1 and beta 2 receptor population in crude plasma membrane preparations from livers of newborn, mature, and senescent rats. The percentage of beta 1 receptors was lowest in livers from newborn rats and was increased in livers from mature and senescent rats. This increase is caused by a decrease in beta 2 receptor density on maturation, although the beta 1 receptor density is nearly constant throughout the life span of the rat. Isoproterenol-stimulated adenylate cyclase activity was inhibited in livers from senescent rats by propranolol and ICI 118,551 and to a lesser extent by ICI 89,406 and CGP 20,712A. The isoproterenol-stimulated glucose output in hepatocytes from senescent rats was inhibited concentration dependently by propranolol, ICI 118,551, ICi 89,406, and CGP 20,712A. From these results we conclude that beta 1 and beta 2 receptors are present in livers from rats of the three age groups and that the beta 1 to beta 2 receptor ratio is increased in livers from mature and senescent rats compared with newborn rats. Both beta receptor subtypes are linked to the cAMP second messenger system in newborn and senescent rats; beta 1 and beta 2 receptors are equally involved in the regulation of glycogenolysis in hepatocytes from senescent rats.

Adenylyl Cyclases↗

PubMed1991

Receptor function in heart failure.

In patients with congestive heart failure, down-regulation of beta-adrenoceptors is present, probably as a result of sympathetic overstimulation. In end-stage dilated cardiomyopathy, beta 1-adrenoceptor density is markedly reduced, while beta 2-adrenoceptor density is normal. This latter finding does not necessarily imply normal sensitivity to beta 2-stimulation, due to possible alterations in the beta-adrenoceptor/adenylate cyclase complex beyond the receptor. In some disease states, such as ischemic cardiomyopathy and mitral valve disease, there seems to be a concomitant reduction of the beta 1- and beta 2-adrenoceptor density. The finding of beta-adrenoceptor down-regulation has stimulated the search for novel therapeutic approaches in heart failure patients. Beta-agonists could even further down-regulate beta receptors, and this perhaps explains why they seem not to be useful in long-term use. Agents that directly stimulate adenylate cyclase activity, such as forskolin, or that increase cyclic adenosine monophosphate degradation, such as the phosphodiesterase inhibitors, are being tested. Beta-adrenoceptor blocking agents were used in treatment of heart failure before beta-adrenoceptor down-regulation was recognized in these patients. It is tempting to speculate that the beneficial clinical and hemodynamic effects seen in these patients treated with metoprolol is indeed due to an antagonism of the beta-adrenoceptor down-regulation. Studies testing whether beta-adrenoceptor blocking agents can improve survival in congestive heart failure patients are on-going.

Down-Regulation↗

PubMed1991

Effect of age on the kinetics of the binding of iodocyanopindolol to a membrane preparation of rat lungs.

The association (k+1) and dissociation (k-1) rate constants, and the equilibrium thermodynamic binding parameters (delta G0, delta H0 and delta S0) of the beta-adrenergic ligand [125Iodo]cyanopindolol (ICYP) were studied in a crude lung membrane preparation of rats of different ages. There was no difference in k+1-values for the different age groups, while the k-1-values were in all cases difficult to measure: almost no dissociation of ICYP from its binding site occurs. The thermodynamic properties were not affected by age. It is concluded that, in these experimental conditions, age has no effect on the kinetic parameters of the binding of ICYP to the beta-adrenoceptors in rat lung.

Aging↗

PubMed1990

Characterization of the beta-adrenergic transduction system in spleen mononuclear leukocyte membranes of young and senescent rats.

The effect of aging on some of the properties of the beta-adrenergic transduction system was determined in a membrane fraction of spleen mononuclear leukocytes from young (2-3 months) and old (24-25 months) rats. Receptor density was unchanged and the percentage of receptors in the high affinity configuration for isoproterenol was reduced with increasing age. Adenylate cyclase activity, either unstimulated or stimulated with forskolin, GTP or isoproterenol was not affected by aging. This suggests the presence of compensatory mechanisms in the beta-adrenergic signal transduction system of rat spleen mononuclear cells in order to ensure equal cAMP production for equal agonist stimulation.

Adenylyl Cyclases↗

PubMed1990

The beta-adrenergic transduction system in kidneys from young and senescent rats.

beta-Adrenoceptor density, ligand affinity, high-affinity agonist binding, basal adenylate cyclase activity and cAMP synthesis upon stimulation with either forskolin, F-, guanine nucleotides (GTP or GppNHp) or isoproterenol in the presence of the nucleotides were studied in membranes prepared from kidneys of young (2-3 month) and old (24-25 month) male Wistar rats. There is a significant (P less than 0.01) 62% increase in beta-receptor density, a significant (P less than 0.05) 115% decrease in ligand affinity, a significant (P less than 0.05) 33% decrease of high-affinity binding sites for (-)-isoproterenol and a significant (P less than 0.01) 151% decrease of the affinity of the high-affinity agonist binding site. Basal adenylate cyclase activity and the activity after stimulation with guanine nucleotides and forskolin were significantly higher in old animals as compared to young (P less than 0.01). Stimulation of the system with isoproterenol in the presence of GTP was more effective in old animals, although the P less than 0.05 level of significance was barely reached. It is suggested that age-dependent changes of the beta-adrenoceptors in rat kidney are similar to those described for lungs: changes at the different levels of the beta-adrenergic transduction chain associated with age are compensatory so as to ensure equal cAMP synthesis for a given agonist stimulation.

Adenylyl Cyclase Inhibitors↗

PubMed1989

Effect of aging on properties and function of beta-adrenoceptors in rat lung.

beta-Adrenoceptor density and ligand affinity, basal adenylate cyclase activity and cAMP synthesis upon stimulation with forskolin, fluoride, guanine nucleotides (GTP or guanylyl imidodiphosphate (GppNHp) or isoproterenol in the presence of the nucleotides were studied in membranes prepared from lungs of young (aged 2-3 months) and of old (aged 24-25 months) male Wistar rats. There was a significant (P less than 0.05, 21%) increase in beta-receptor density and a significant (P less than 0.05, 38%) decrease in the percentage of high-affinity binding sites for isoproterenol. Both basal adenylate cyclase activity and that after stimulation with guanine nucleotides or isoproterenol in the presence of nucleotides were unaltered with age. Forskolin stimulation of cAMP synthesis was significantly reduced (by 24%, P less than 0.05) in tissues from older animals. It is suggested that the age-dependent changes in properties of beta-receptors in rat lungs are compensatory, in order to ensure equal cAMP production for equal agonist stimulation.

Adenylyl Cyclases↗

PubMed1989

Evaluation of a semiautomatic cell harvester filtration for the determination of beta-adrenoceptors in human mononuclear leukocytes.

The ligand affinity (Kd) and the number (Bmax) of beta-adrenoceptors in human mononuclear leukocytes was measured using a semiautomatic cell harvester method for the separation of bound and free ligand. The method was first evaluated in terms of contamination, nonspecific filter binding, and well-to-well reproducibility. A comparison was then made with the conventional manual filtration method. The Kd values for the binding of [125lodo]-cyanopindolol to mononuclear leukocyte membranes were independent of the method, whereas the Bmax values were systematically higher (around 30%) when determined with the cell harvester filtration method. A highly significant correlation was found between the Bmax values obtained with both methods.

Adult↗

PubMed1989

Effect of turpentine-induced inflammation on the disposition kinetics of propranolol, metoprolol, and antipyrine in the rat.

Plasma concentrations after oral administration of the high extraction drug propranolol are increased in patients and animals with inflammation. This could be due to increased serum propranolol binding, but also to decreased first-pass metabolism. We studied the pharmacokinetics of 3 drugs in control rats and in rats with turpentine-induced inflammation: propranolol, which is bound extensively to alpha 1-acid glycoprotein (alpha 1-AGP); metoprolol, another high extraction drug, but which is negligibly bound to alpha 1-AGP; and antipyrine, a low extraction drug, not bound to serum proteins. After IV administration of propranolol in rats with inflammation, systemic clearance, volume of distribution, and free fraction decreased, and the area under the curve (AUC) increased, whereas the half-life did not change. As the systemic clearance of a high extraction drug such as propranolol depends on hepatic blood flow only, a fall in hepatic blood flow or transition to a low extraction situation should be postulated. After oral administration of propranolol, the AUC was increased 20-fold in rats with inflammation; as the decrease in free fraction was only 4-fold, it can be concluded that a considerable decrease in hepatic intrinsic clearance was present. For metoprolol, in contrast to propranolol, after IV administration, no changes in pharmacokinetic parameters as a result of inflammation were observed. After oral administration, the AUC was increased about 4 times in rats with inflammation; as metoprolol is only negligibly bound to serum proteins, the increase in AUC can be attributed to a decrease in hepatic intrinsic clearance.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1987

Alpha 1-acid glycoprotein and serum binding of drugs in healthy and diseased dogs.

Inter-individual variation in drug serum protein binding was studied in healthy dogs and in dogs with inflammatory diseases for lidocaine, oxprenolol and propranolol, which bind mainly to alpha 1-acid glycoprotein (alpha 1-AGP), and for diazepam, digitoxin and phenytoin, which bind mainly to albumin. For the drugs mostly bound to alpha 1-AGP, in both groups of dogs binding varied considerably, and it was markedly higher in dogs with inflammatory disease. For the other drugs, the variation in binding was smaller and did not differ between the two groups of dogs. In both groups of dogs, the alpha 1-AGP concentration varied widely; it was higher in the serum of the dogs with inflammation, while the concentration of albumin was lower in these animals. There was a significant negative correlation between percentage free lidocaine, oxprenolol or propranolol and alpha 1-AGP concentration, suggesting that the inter-individual variation in binding of these drugs is due to the variation in alpha 1-AGP concentration. There was a marked intra-individual variation in lidocaine binding and in serum alpha 1-AGP concentration, studied over a period of 3 weeks in healthy dogs; a significant negative correlation between percentage free lidocaine and alpha 1-AGP concentration was obtained.

Animals↗

PubMed1985

Membrane resting potentials in cultured mouse neuroblastoma cells.

Membrane resting potentials (MRP) were measured systematically in cultured mouse N2A neuroblastoma cells: in the logarithmic growth phase; in subconfluent cultures; in confluent cultures; after dBcAMP had induced morphological differentiation. Neurite extension was accompanied by a significant increase in MRP as compared to the appropriate controls. No significant differences in MRP were observed with regard to the different growth phases.

Animals↗

PubMed1984

A method for the assay of alpha 1-acid glycoprotein in dog serum and its application to the plasma binding of propranolol and oxprenolol in animals receiving rifampicin.

A method for determination of alpha 1-acid glycoprotein (alpha 1-AGP) in dog serum was developed. Dog alpha 1-AGP was purified to homogeneity from pooled serum by DEAE and CM ion exchange chromatography. A monospecific antibody was obtained by injecting the antigen in rabbits. The antibody was used in a turbidimetric method that allowed detection at 10 micrograms/ml in serum. A linear correlation was found between the optical density and alpha 1-AGP concentration up to 20 micrograms alpha 1-AGP in the sample. The method has been used to demonstrate the effect of treatment with rifampicin on the alpha 1-AGP serum concentrations and its relation to the protein binding of oxprenolol and propranolol.

Animals↗

PubMedDate not supplied

Species and strain-related differences in the expression and functionality of beta-adrenoceptor subtypes in adipose tissue.

The beta-adrenoceptor subtypes which trigger lipolysis in white adipocytes vary markedly between calf and rats, and even between different rat strains. In calf adipocytes, CGP12177, a potent antagonist for beta 1- and beta 2-adrenoceptors (i.e., "classical beta-adrenoceptors") and a partial agonist for atypical beta-adrenoceptors, did not stimulate lipolysis, but inhibited with high affinity (IC50 = 0.66 nM) the lipolytic response to 10 nM isoproterenol. In adipocytes from both Wistar rats and Sprague-Dawley OFA rats, CGP12177 stimulated lipolysis to almost the same extent as isoproterenol. Low concentrations of CGP12177 (3 nM) inhibited part of the lipolytic response to 10 nM isoproterenol in the Sprague-Dawley OFA rat adipocytes, but not in Wistar rats at all ages tested (2-4 weeks, 2-4 months, 24-26 months). Hence, functional beta-adrenoceptors are only classical in calf adipocytes, only atypical in Wistar rat adipocytes and both classical and atypical in Sprague-Dawley OFA rat adipocytes. Binding experiments were performed with 150 pM [125I]CYP. On calf adipocyte membranes, competition binding curves with CGP12177 displayed one high affinity binding site (IC50 = 4.7 nM), whereas the curves for CGP20712 (beta 1-selective antagonist) and ICI118551 (beta 2-selective antagonist) were biphasic. In agreement with the functional data, these results indicate that only beta 1- and beta 2-adrenoceptors are present in calf adipose tissue. For both rat strains, only half of the displaceable [125I]CYP binding sites displayed high affinity for CGP12177 (IC50 = 6.8 to 7.5 nM), and competition binding studies with CGP20712 and ICI118551 indicated that they represent beta 1- and beta 2-adrenoceptors. The remaining [125I]CYP binding sites possessed an about 50 times lower affinity for CGP12177 (IC50 = 260 to 345 nM). They are likely to represent atypical beta-adrenoceptors. It is concluded that the presence and the physiological relevance of beta-adrenoceptor subtypes in adipose tissue may not only be species-related, but also strain-related.

Adipocytes↗