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Biomedical subjects

J Christophe

Publications and source records attributed to J Christophe.

At least 181 records · Page 10Linked to original sources
PubMed1983

Inhibition of forskolin-stimulated cardiac adenylate cyclase activity by short-chain alcohols.

The diterpene forskolin stimulated rat cardiac adenylate cyclase activity at least 20-fold and potentiated the effect of NaF. The stimulatory effect of forskolin was reduced in the presence of Gpp(NH)p. Ethanol markedly reduced the stimulation of adenylate cyclase by forskolin while potentiating NaF and Gpp(NH)p stimulation. The inhibitory effect of ethanol on forskolin stimulation appeared to be of a mixed type with both a competitive and a non-competitive component. Three other short-chain linear alcohols (methanol, propanol, butanol) also inhibited forskolin-stimulation, this effect being proportional to the number of carbon atoms.

Adenylyl Cyclases↗
PubMed1983

Mechanism of 3-phenylpyruvate-induced insulin release. Metabolic aspects.

1. The metabolism and metabolic effects of 3-phenylpyruvate were examined in rat pancreatic islets. 2. Islet homogenates catalysed transamination reactions between 3-phenylpyruvate and L-glutamate, L-leucine, L-norleucine or L-valine. 3-Phenylpyruvate failed to activate glutamate dehydrogenase. 3. 3-Phenylpyruvate rapidly entered into islet cells, was extensively converted into phenylalanine but slowly oxidized. 4. The conversion of phenylpyruvate into phenylalanine coincided with a fall in the content of several amino acids (especially glutamate and aspartate) in the islets and incubation medium, the accumulation of 2-oxoglutarate and a modest fall in the NH4+ production rate. 5. 3-Phenylpyruvate failed to affect 14CO2 output from islets prelabelled with [U-14C]palmitate, but augmented 14CO2 output from islets prelabelled or incubated with L-[U-14C]glutamine. 6. In the presence of L-glutamine, 3-phenylpyruvate augmented the ATP/ADP ratio and NAD(P)H islet content, and caused a rapid and sustained decrease in the outflow of radioactivity from islets prelabelled with [2-3H]adenosine. 7. These data support the view that the insulin-releasing capacity of 3-phenylpyruvate coincides with an increase in the catabolism of endogenous amino acids acting as 'partners' in transamination reactions leading to the conversion of 3-phenylpyruvate into phenylalanine.

Adenine Nucleotides↗
PubMed1983

Topographical distribution of the secretin- and VIP-stimulated adenylate cyclase system in the heart of five animal species.

Adenylate cyclase stimulation by secretin and VIP was compared to the effect of glucagon, D,L-isoproterenol, Gpp[[NH]p, and NaF in atria and ventricles from rat, guinea pig, rabbit, dog and Cynomolgus monkey. In rat ventricular membranes, secretin was a better stimulant than VIP and was as active as D,L-isoproterenol. In rat auricular membranes both peptides were inactive. In guinea pig and rabbit heart membranes (ventricular and auricular) VIP and secretin were inactive. In dog and monkey atria, VIP stimulation of adenylate cyclase was comparable to that of D,L-isoproterenol, secretin being inactive. In dog ventricles, VIP was less efficient than D,L-isoproterenol, secretin being inactive. In monkey ventricles, by contrast, VIP was slightly more efficient than D,L-isoproterenol, secretin having a small effect only in left ventricles. The present results established a clear difference between animal species with respect to the efficacy of the peptides of the secretin/VIP family: the presence of "secretin-preferring" receptors in rat heart contrasted with the presence of "VIP-preferring" receptors in dog and monkey heart. Our results in dog and monkey hearts suggest that VIP might be a candidate for a physiological control of heart function.

Adenylyl Cyclases↗
PubMed1983

The cardiac inotropic response to secretin is lower in genetically obese (fa/fa) than in lean (fa/?) Zucker rats.

The efficacy and potency of secretin in rat heart was documented by comparing secretin and D,L-isoproterenol effects on: 1. the inotropic response of papillary muscles electrically stimulated in vitro, and 2. adenylate cyclase activity in a crude membrane preparation from heart ventricle. In male adult lean (FA/?) Zucker rats, the extent of the positive inotropic response and the stimulatory effect on adenylate cyclase were similar in magnitude for secretin and D,L-isoproterenol, the two corresponding EC50 values for inotropic effects being 5- to 10-fold lower than the EC50 values for adenylate cyclase stimulation. In male adult obese (fa/fa) Zucker rats, the stimulatory effects exerted by secretin on the inotropic response and adenylate cyclase activity were reduced by 73% and 70%, respectively, while the extent of similar D,L-isoproterenol responses were reduced, respectively, by 29% and 25% only. With D,L-isoproterenol, the EC50 value for the inotropic effect was 5-fold lower than the EC50 value for adenylate cyclase activation whereas both EC50 values were comparable when secretin was used as a stimulant.

Adenylyl Cyclases↗
PubMed1983

Thermodependence of basal and stimulated cardiac adenylate cyclase activity in normotensive and spontaneously hypertensive rats.

The cardiac adenylate cyclase activity from normotensive and spontaneously hypertensive (SHR) rats was studied as a function of temperature between 17 degrees and 37 degrees C. Arrhenius plots of adenylate cyclase activity displayed a break around 31 degrees C when tested under basal conditions or in the presence of GTP but were linearized after activation with p[NH]ppG, NaF, secretin, glucagon or isoproterenol. The energy of activation of adenylate cyclase activity in the presence of GTP (9.5 +/- 0.5 kcal/mol) was significantly lower than in the presence of p[NH]ppG (17.7 +/- 0.8 kcal/mol). A hormone was without effect on the energy of activation observed with either GTP or p[NH]ppG but the simultaneous presence of hormone and nucleotide increased markedly the activity of the enzyme. The energies of activation were analyzed in terms of variation of enthalpy and entropy and discussed in relation with the process of activation and coupling of the guanine nucleotide regulatory protein. These thermodynamic characteristics were similar in cardiac membranes from normotensive and spontaneously hypertensive rats, suggesting that the impairment of hormone-stimulated adenylate cyclase activity observed in the heart membranes of hypertensive rats was not a consequence of a defect in the activation process of the enzyme.

Adenylyl Cyclases↗
PubMed1983

Selective alteration of secretin-stimulated cardiac adenylate cyclase activity in streptozotocin-diabetic rats.

Secretin stimulation of adenylate cyclase activity in heart membranes was selectively altered in streptozotocin-diabetic adult male rats suffering from moderately severe diabetes, 40 days after i.v. streptozotocin administration (40 mg/kg body weight). The efficacy of secretin was reduced by 55% whilst its potency was unaffected. By contrast, the stimulation of adenylate cyclase by NaF, GTP, Gpp(NH)p, D,L-isoproterenol, and glucagon remained normal. The present data, together with the markedly reduced secretin response of cardiac adenylate cyclase in genetically obese (fa/fa) Zucker rats might indicate that hypoinsulinemia and insulin resistance both reduce the number of secretin receptors coupled to the adenylate cyclase system, an alteration whose contribution to diabetic cardiomyopathy remains to be determined.

Adenylyl Cyclases↗
PubMed1983

The human heart beta-adrenergic receptors. I. Heterogeneity of the binding sites: presence of 50% beta 1- and 50% beta 2-adrenergic receptors.

Beta-adrenergic receptors were characterized in a particulate fraction of human auricles obtained from patients operated upon for coronary insufficiency or valvular disease. [125I] Hydroxybenzylpindolol binding was evaluated in terms of kinetics; KD and Bmax values; and inhibition of binding in the presence of 10 microM GTP and of increasing concentrations of four nonselective agonists giving a Hill coefficient of 1 (isoproterenol, salbutamol, fenoterol, and epinephrine), of two nonselective antagonists giving a Hill coefficient of 1 (pindolol and propranolol), and of a series of selective drugs giving a Hill coefficient of 0.60-0.72 that included three beta 1-selective antagonists (practolol, metoprolol, and atenolol) and two beta 2- selective agonists (procaterol and zinterol). KD values for all drugs were compatible with the coexistence in membranes from human auricles of beta 1- and beta 2-adrenergic receptors, the relative proportions of receptors of each subclass being approximately the same.

Adrenergic beta-Agonists↗
PubMed1983

The human heart beta-adrenergic receptors. II. Coupling of beta 2-adrenergic receptors with the adenylate cyclase system.

The beta-adrenergic stimulation of adenylate cyclase in membranes from human auricles, ventricles, and fetal heart was compared with the binding properties of beta-adrenergic receptors in human auricles. In terms of adenylate cyclase activation, three full agonists (isoproterenol, epinephrine, and norepinephrine), four partial agonists (procaterol, salbutamol, fenoterol, and zinterol), and four antagonists (propranolol, metoprolol, atenolol, and practolol) were tested. The beta-adrenergic activation of adenylate cyclase in membranes from rat heart (with a majority of beta 1-adrenergic receptors), rat erythrocytes, and rat reticulocytes (with a homogeneous population of beta 2-adrenergic receptors) served as reference. The reactivity of human heart adenylate cyclase, estimated by the Kact or Ki values of 11 beta-adrenergic agents, indicated that the activation of this enzyme occurred through receptors of the beta 2-subtype only. Receptors of the beta 1-subtype (50% of the total population) were not coupled to the enzyme.

Adenylyl Cyclases↗
PubMed1982

Early decrease in secretin-, glucagon-, and isoproterenol-stimulated cardiac adenylate cyclase activity in rats treated with isoproterenol.

Male Wistar albino rats received three times daily for one to five days 0.25 to 5.0 mg/kg D,L-isoproterenol intraperitoneally. D.L-Isoproterenol injections provoked a time dependent- and dose-related cardiac hypertrophy. With moderate hypertrophy, a selective decrease in secretin-stimulated adenylate cyclase activity occurred. When heart hypertrophy was more pronounced, greater losses in secretin-, as well as in D,L-isoproterenol-, glucagon-, guanine nucleotide-, and fluoride-stimulated enzyme activity developed. Hormone stimulations of adenylate cyclase were more severely, curtailed (60 to 65%) than guanine nucleotide or fluoride stimulations (40 to 45%). The accompanying loss in beta-receptors (35%) was proportionately lower than the loss of D,L-isoproterenol sensitivity of adenylate cyclase. This complex pattern of adenylate cyclase desensitization in heart membranes from animals chronically treated with D,L-isoproterenol is reminiscent of that observed in heart membranes from spontaneously hypertensive rats.

Adenylyl Cyclases↗
PubMed1982

Specific photoaffinity crosslinking of [125I]cholecystokinin to pancreatic plasma membranes. Evidence for a disulfide-linked Mr 76 000 peptide in cholecystokinin receptors.

In rat pancreatic plasma membranes, preincubated with [125I]cholecystokinin-33 (CCK-33) and washed free of unbound tracer, the irradiation by UV light induced the irreversible binding of radioactivity to high molecular weight peptides as shown by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate (SDS) and autoradiography. This was not observed when the membranes were preincubated in the simultaneous presence of [125I]CCK-33 and of either an excess of unlabelled CCK-8 or of guanosine 5'-(beta, gamma-imido)-triphosphate. The radioactivity was mostly crosslinked with a Mr 96,000 peptide and peptide species of Mr greater than 200,000, after SDS solubilization in the absence of beta-mercaptoethanol. Peptide reduction with beta-mercaptoethanol converted the high molecular weight radioactive species into a Mr 76,000 peptide that contained as much as 65% of the radioactivity crosslinked. The Mr 76,000 peptide appears, therefore, to be a disulfide-linked constituent of rat pancreatic cholecystokinin receptors.

Animals↗
PubMed1982

Effects of PHI on vasoactive intestinal peptide receptors and adenylate cyclase activity in lung membranes. A comparison in man, rat, mouse and guinea pig.

The presence of receptors, recognized by vasoactive intestinal peptide (VIP) as well as by PHI (a peptide with N-terminal histidine and C-terminal isoleucine amide), was documented in lung membranes from rat, mouse, guinea pig and man by the ability of these receptors, once occupied, to stimulate adenylate cyclase. In lung membranes from rat, mouse and guinea pig, the capacity of VIP, PHI and secretin to stimulate the enzyme and the potency of the same peptides to compete with 125I-VIP for binding to VIP receptors were similar, the affinity decreasing in the order: VIP greater than PHI greater than secretin. In addition, dose-effect curves were compatible with the coexistence of high-affinity and low-affinity VIP receptors, in the four animal species considered. If PHI was able to recognize all VIP receptors it could not, however, discriminate the subclasses of VIP receptors.

Adenylyl Cyclases↗
PubMed1982

Evidence for the existence of actomyosin ATPase in the rat pancreas. Isolation and biochemical characterization.

In a crude extract of rat pancreas, myosin was associated with a protein having the same electrophoretic mobility as actin. This myosin was purified after dissociation of the actomyosin complex with KI-ATP. On sodium dodecylsulfate/acrylamide gel electrophoresis, the isolated pancreatic myosin showed a major component of approximately 200 kDa, and two smaller components with apparent molecular weight of 22 and 15 kDa, respectively. This purified myosin exhibited high ATPase activity in the presence of K+ + EDTA or Ca2+ and very little activity in the presence of Mg2+. (K+ + EDTA)-ATPase activity showed one pH optimum at 8.0, while Ca2+-ATPase activity showed two pH optima at 6.0 and 9.0, respectively. (K+ + EDTA)-stimulated enzyme activity was specific for ATP whereas Ca2+-stimulated activity showed low specificity for nucleoside triphosphates.

Actomyosin↗
PubMed1982

Characterization of secretin and vasoactive intestinal peptide receptors in rat pancreatic plasma membranes using the native peptides, secretin-(7-27) and five secretin analogues.

A comparison has been made of the ability of vasoactive intestinal peptide (VIP), secretin, secretin analogues, and secretin-(7-27) to stimulate adenylate cyclase in rat pancreatic plasma membranes. A parallel study of the capacity of peptides of the VIP-secretin family to compete with 125I-VIP for binding to the same plasma membranes was conducted. This allowed a classification of VIP-secretin receptors into three subtypes: (1) VIP-preferring receptors; (2) high-affinity secretin receptors, and (3) low-affinity secretin receptors. The properties of secretin at high-affinity secretin receptors were likely to reflect a contribution of membranes from centroacinar and duct cells.

Adenylyl Cyclases↗
PubMed1982

Rat cardiac muscarinic receptors. II. Influence of thyroid status and cardiac hypertrophy.

The effects of the thyroid state and of aortic stenosis on muscarinic cholinergic binding sites in heart membranes were compared (with proper controls) by simultaneously determining total and high-affinity binding sites and estimating low-affinity binding sites by difference. Hyper- and hypothyroidism induced decreased and increased concentration of high-affinity agonist binding sites, respectively, supporting the hypothesis that these sites were directly regulated by thyroid hormones. This was not the case for low-affinity binding sites, as they decreased in number in both hyper- and hypothyroidism. In hyperthyroid rats, this decreased number of low-affinity binding sites could be due to the rapidly developing cardiac hypertrophy. Indeed, cardiac hypertrophy provoked by aortic stenosis led also to a decreased concentration of low-affinity binding sites without affecting the concentration of high-affinity binding sites.

Animals↗
PubMed1982

Hormonal and metabolic changes induced by an isocaloric isoproteinic ketogenic diet in healthy subjects.

The effects of a 4-day isocaloric isoprotenic dietary replacement of carbohydrate by fats were studied in six healthy subjects, the experimental diet being preceded and followed by a 3-day period of balanced diet. During the ketogenic regimen, the concentrations of fat derived substrates (free fatty acids, glycerol and 3-hydroxybutyrate) rose significantly and glucose levels decreased by 16.5 +/- 3.2% (mean +/- SEM). The hormonal pattern switched towards a catabolic mode with a fall in insulin levels (-44.0 +/- 6.3%) and a rise in glucagon concentration (+39.0 +/- 10.4%). A significant fall in triiodothyronine and rise in reverse triiodothyronine were observed, while thyroxine levels remained unchanged. The average levels of the most important gluconeogenic amino acids (alanine, glutamine, glycine, serine and threonine) were reduced by 8-34% while those of the branched chain amino acids increased by more than 50%. Since these changes reproduce those observed after a few days of total fasting, we suggest that it is the carbohydrate restriction itself which is responsible for the metabolic and hormonal adaptations of brief fasting.

Adult↗
PubMed1982

Rat cardiac muscarinic receptors. I. Effects of guanine nucleotides on high- and low-affinity binding sites.

The binding properties of muscarinic cholinergic binding sites were investigated in rat cardiac membranes, using the labeled agonist [3H] oxotremorine-M ([3H]Oxo-M) and the labeled antagonist L-[benzilic-4,4'-3H]quinuclidinyl benzilate (L-[3H]QNB). The binding of both tracers was inhibited stereospecifically by dexetimide and levitimide. [3H]Oxo-M labeled only high-affinity agonist binding sites, whereas L-[3H]QNB bound to high- and low-affinity agonist binding sites with equal affinity. Agonists were unable to induce "negative cooperativity" interactions by increasing the dissociation of labeled agonist or antagonist. Guanine nucleotides decreased markedly the affinity of high- and low-affinity binding sites for agonists, without affecting their affinity for antagonists. In the presence of a maximally effective concentration of GTP, all muscarinic receptors showed the same low affinity for agonists. Among these agonists, carbamylcholine and oxotremorine (but not pilocarpine) displayed a lower affinity for both classes of binding sites in the presence of GTP.

Animals↗