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P Chidiac

Publications and source records attributed to P Chidiac.

25 records · Page 2Linked to original sources
PubMed1992

Effects of adenyl nucleotides and carbachol on cooperative interactions among G proteins.

Muscarinic agonists and adenyl nucleotides are noncompetitive modulators of sites labeled by [35S]GTP gamma S in washed cardiac membranes from Syrian golden hamsters. Specific binding of the radioligand and its inhibition by either GTP gamma S or GDP reveals three states of affinity for guanyl nucleotides. In the absence of adenyl nucleotide, carbachol promotes an apparent interconversion of sites from higher to lower affinity for GDP; the effect recalls that of guanyl nucleotides on the binding of agonists to muscarinic receptors. In the presence of 0.1 mM ATP gamma S, the binding of [35S]GTP gamma S is increased at concentrations up to about 50 nM and decreased at higher concentrations. At a radioligand concentration of 160 pM, binding exhibits a bell-shaped dependence on the concentration of both ATP gamma S and AMP-PNP; with ADP and ATP, there is a second increase in bound [35S]GTP gamma S at the highest concentrations of adenyl nucleotide. ATP gamma S and AMP-PNP also modulate the effect of GDP, which itself emerges as a cooperative process: that is, binding of the radioligand in the presence of AMP-PNP exhibits a bell-shaped dependence on the concentration of GDP; moreover, the GDP-dependent increase in bound [35S]GTP gamma S is enhanced by carbachol. The interactions among GDP, GTP gamma S, and carbachol can be rationalized quantitatively in terms of a cooperative model involving two sites tentatively identified as G proteins. Both GTP gamma S and GDP exhibit negative homotropic cooperativity; carbachol enhances the homotropic cooperativity of GDP and induces or enhances positive heterotropic cooperativity between GDP and [35S]GTP gamma S. An analogous mechanism may underlie the guanyl nucleotide-dependent binding of agonists to muscarinic receptors. The data suggest that the binding properties of G proteins and their associated receptors reflect cooperative effects within heterooligomeric arrays; agonist-induced changes in cooperativity may facilitate the exchange of GTP for bound GDP and thereby constitute the mechanism of G protein activation in vivo.

Adenine Nucleotides↗
PubMed1991

Inefficient muscarinic transduction in cardiomyopathic Syrian hamsters.

Regulation of cyclic AMP (cAMP) production and muscarinic binding were studied in highly washed left ventricular membranes from spontaneously cardiomyopathic Syrian hamsters (TO strain). Basal production of cAMP was decreased relative to that in random-bred (RB) controls, with proportionally similar decreases in stimulated production elicited by 7 beta-deacetyl-7 beta-(gamma-N-methylpiperazino)-butyryl forskolin and by the beta-adrenergic agonist isoproterenol. GTP-stimulated production of cAMP was inhibited fully by the muscarinic agonist carbachol in tissue from controls, but only partially in tissue from TO hamsters. Total muscarinic binding, as revealed by N-[3H]methylscopolamine, was similar in the two strains. Competition between carbachol and the radioligand revealed at least three classes of sites for the agonist, the apparent affinities of which were insensitive to the disease. Upon the addition of guanylyl imidodiphosphate (GMP-PNP, 0.1 mM), there was a disease-dependent redistribution such that the sites appeared to be predominantly of low affinity for the agonist in RB tissue and predominantly of medium affinity in TO tissue. The potency of GMP-PNP in mediating the change in carbachol binding apparently was unaffected by the disease. The loss of muscarinic regulation of cAMP production in TO left ventricular tissue appears to reflect a disease-related change in the coupling of muscarinic receptors to inhibitory GTP-binding proteins.

Adenylyl Cyclases↗
PubMed1987

Lack of induction of nuclear aberrations by captan in mouse duodenum.

The fungicide, captan, is known to induce point mutations in vitro. In extremely high doses, technical grade captan leads to duodenal tumors in mice. In short-term in vivo assays for genotoxicity, equivocal results have been obtained with captan. In this study, the genotoxicity of captan was studied in vivo in the proximal small intestine of the mouse, the site of its oncogenicity. Orally administered captan up to 4,000 mg/kg body weight failed to induce a response in the small intestine nuclear aberration assay in a wide range of doses under a variety of experimental conditions, including pretreatment of animals with L-buthionine-S, R-sulfoximine (an inhibitor of glutathione biosynthesis). 1,2,3,6-Tetrahydrophthalimide and bis (trichloromethyl)disulfide, two compounds that have been identified as impurities in technical grade captan, also failed to produce positive results in this assay.

Animals↗
PubMed1986

An in vivo assay for small intestine genotoxicity.

The induction of nuclear aberrations (NA) (apoptotic bodies and micronuclei) in duodenal crypts in a dose-dependent manner was associated with administration of agents known to induce tumours in the small intestine. These included X-irradiation, N-methyl-N-nitrosourea (MNU), benzo[a]pyrene (B[a]P), and 1,2-dimethylhydrazine (DMH), which were found to induce NA in cells in the proliferative region of crypts 24 h after they were given to mice. Methylurea (MU) and benzo[e]pyrene (B[e]P), which are non-carcinogenic structural analogues of MNU and B[a]P, respectively, did not induce NA under similar conditions. Based on these results, the ability of an agent to induce NA in the small intestine appears to reflect of its oncogenic potential in that organ.

Alkylating Agents↗
PubMed1978

Radionuclide quantitation of left-to-right cardiac shunts in children.

In order to evaluate the clinical usefulness of radionuclide methods measuring the magnitude of left-to-right cardiac shunts, a comparison has been made of the results obtained using these procedures with those estimated by cardiac catheterization. Seventy children in whom the presence or absence of a shunt had been established, were studied. Two methods for radionuclide shunt quantitation, the pulmonary to systemic blood flow ratio (Qp/Qs) of Maltz and Treves and their modified C2/C1, were evaluated. The former was found to be superior and showed a high correlation of shunt size with the catheter results. With attention to the performance of the investigation and in the data analysis, good discrimination can be achieved between normal patients and those with shunts. Because of the atraumatic nature of the investigation, it is concluded that the procedure is of value in the diagnosis of a cardiac murmur, the assessment of postoperative patients and the follow-up of patients known to have a small shunt.

Adolescent↗