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Biomedical subjects

P Robberecht

Publications and source records attributed to P Robberecht.

At least 199 records · Page 11Linked to original sources
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

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

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

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↗
PubMed1981

Presence of vasoactive intestinal peptide receptors coupled to adenylate cyclase in rat lung membranes.

(1) The binding of 125I-labelled vasoactive intestinal peptide (VIP) to a particulate fraction from rat lung was rapid, temperature dependent, saturable and specific. This process was also reversible and 125I-labelled VIP dissociation was accelerated by guanine triphosphate nucleotides. The curves describing the inhibition of tracer binding by peptides of the VIP-secretin family suggested the presence of at least two classes of VIP receptor: a "high-affinity' type with decreasing affinity for VIP in the order: VIP = [Val5]secretin greater than [Ala4, Val5]secretin; and a "low-affinity type' with decreasing affinity for VIP in the order: VIP greater than [Val5]secretin greater than [Ala4, Val5]secretin = secretin greater than [Ala4]secretin. (2) VIP and related peptides stimulated the adenylate cyclase activity of the same lung membrane preparation more efficiently than beta-adrenergic agonists and prostaglandins E1 and E2. The dose-effect curves of stimulation of adenylate cyclase by VIP and parent peptides were also compatible with the existence of two classes of VIP receptor, the relative peptide potencies being identical with their ability to compete with 125I-labelled VIP for binding.

Adenylyl Cyclases↗
PubMed1981

Binding of vasoactive intestinal peptide and its stimulation of adenylate cyclase through two classes of receptors in rat liver membranes. Effects of 12 secretin analogues and 2 secretin fragments.

1. Vasoactive intestinal peptide (VIP) receptors were identified in crude rat hepatic membranes by 125I-labelled VIP binding and by the ability of VIP to stimulate adenylate cyclase activity. The specificity of these receptors was evaluated by the capacity of secretin, synthetic secretin analogues, and secretin fragments to inhibit 125I-labelled VIP binding and to stimulate adenylate cyclase. 2. The results were compatible with the existence of two classes of VIP binding sites that could be distinguished according to their affinity for VIP and their specificity. High-affinity sites were more specific for VIP as secretin was 175 times less potent than VIP for recognition of these sites while being only 33 times less potent than VIP for recognition of low-affinity sites. 3. Secretin analogues, monosubstituted in position 2, 3, 4 or 6 were less potent than secretin for adenylate cyclase stimulation as well as for the recognition of the two classes of receptors. [Val5]secretin was more potent than secretin and appeared definitely more VIP-like than secretin; [Ala4, Val5] and [D-Ala4,Val5]secretin were equipotent to secretin. 4. The fragment secretin (7-27) was unable to recognize VIP receptors and to stimulate adenylate cyclase. The substituted fragment [Gln9,Asn15]secretin (5-27) recognized these receptors with weak potency but could not activate the enzyme.

Adenylyl Cyclases↗
PubMed1981

Comparative effects of alpha-methyldopa, propranolol and hydralazine therapy on cardiac adenylate cyclase activity in normal and spontaneously hypertensive rats.

Normotensive (WKY) and spontaneously hypertensive (SHR) male rats were treated orally, one week after weaning and for 9 weeks, with alpha-methyldopa (100 mg/kg per day), propranolol (30 mg/kg per day) or hydralazine (10 mg/kg per day). Untreated WKY and SHR rats served as controls. The development of hypertension in SHR rats were attenuated by treatment but none of the drugs was able to restore the impairment in isoproterenol, secretin and glucagon responsiveness of cardiac adenylate cyclase activity which is characteristic of these animals. In heart membranes from both WKY and SHR rats, alpha-methyldopa treatment increased the number of beta-adrenoceptors by 20-32% and the maximal response of adenylate cyclase activity to isoproterenol and glucagon by 20-34%. By contrast, the beta-blocker propranolol was ineffective on these parameters. The results obtained are consistent with the hypothesis that the change in adenylate cyclase seen in SHR rats is genetic in origin and is not a consequence of hypertension.

Adenylyl Cyclases↗