RESUMEN
To assess the role of metabolic shifts in pathogenesis of excretory renal dysfunction arising in chronic glomerulonephritis (CGN), two groups of patients were considered. Fourteen patients of group 1 had CGN in a preazotemia stage, thirteen patients of group 2 died of CGN-induced uremia. Cortical nephrobiopsies obtained intravitally (group 1) and renal tissue specimens obtained at autopsies during postmortal hours 0-2 (group 2) were investigated. Apical epithelium of proximal canaliculi in group 1 showed higher levels of acid phosphatase (AP), though much lower of succinate dehydrogenase (SDH) and lactate dehydrogenase (LDH) compared to group 2. In basal proximal nephrothelium of group 1 the activity of LDH and AP was inhibited against these values in group 2. The activity of NADPN2-dehydrogenase, SDH and AP in group 1 surpassed that in group 2 in endothelium of renal cortex peritubular capillaries. These structures LDH and AP proved more active in group 1. The authors observed a series of significant multidirectional correlations between the activity of the enzymes studied and renal excretion. The growing activity of NADN2-dehydrogenase and AP was associated with diminution of electrolyte and water excretion, while enhancing LDH activity exhibited the opposite effect. It is concluded that progression of cortical disorders in the kidneys of CGN patients entails serious metabolic derangement reflected by imbalance in aerobic and anaerobic metabolism. These biochemical shifts result in ambiguous functional sequelae and may contribute both to renal retention of fluid, electrolytes and their excretion. The latter is likely a compensatory mechanism involved in maintenance of water-salt homeostasis in relevant patients.
Asunto(s)
Endotelio Vascular/enzimología , Glomerulonefritis Membranoproliferativa/enzimología , Túbulos Renales/enzimología , Riñón/fisiopatología , Nefronas/enzimología , Adolescente , Adulto , Capilares/enzimología , Enfermedad Crónica , Epitelio/enzimología , Femenino , Glomerulonefritis Membranoproliferativa/fisiopatología , Histocitoquímica , Humanos , Riñón/enzimología , Fallo Renal Crónico/enzimología , Fallo Renal Crónico/fisiopatología , Túbulos Renales/irrigación sanguínea , Masculino , Persona de Mediana EdadRESUMEN
[D-Arg2,Leu5]enkephalin and its analogues, shortened from the C-terminus, were studied in a rat brain membrane fraction with the aid of radioreceptor analysis. The interaction between these compounds and the peripheral opiate receptors of isolated organs (guinea pig ileum and mouse vas deferens) was also investigated. The ethyl ester of the [D-Arg2]tripeptide retains approximately 10% of the mu-receptor activity of leucine-enkephalin. This implies that for interaction with the mu-subclass of opiate receptors there is no requirement for a second aromatic ring in addition to the tyramine group in the minimal active moiety of the enkephalin molecule.
Asunto(s)
Encefalina Leucina/análogos & derivados , Receptores Opioides/metabolismo , Secuencia de Aminoácidos , Animales , Corteza Cerebral/metabolismo , Encefalina Leucina/metabolismo , Cobayas , Íleon/metabolismo , Masculino , Ratones , Datos de Secuencia Molecular , Unión Proteica , Ratas , Receptores Opioides delta , Receptores Opioides mu , Relación Estructura-Actividad , Conducto Deferente/metabolismoRESUMEN
The sterically acceptable structures of cyclo(2 delta----5)[D-Orn2, Pro5]- and cyclo(2 delta----5)[D-Orn2, Leu5]enkephalin (CE1 and CE2) consistent with NMR data including coupling constants, temperature dependencies of chemical shifts for amide protons and NOE values have been found by use of energy calculations in terms of rigid valence geometry and refined by the MM2 procedure. It has been shown that the major trans-isomer (with respect to Phe4-Pro5 bond) of CE1 in solution corresponds only to the FD*F*AA type of peptide backbone, and the minor cis-isomer of CE1 corresponds only to the FE*D*DF type. The less conformationally rigid CE2 analogue apparently exists in solution in the dynamic conformational equilibrium with preference of FD*C*AA type of the backbone structure. The obtained data on CE1 and CE2 space structures have been used for interpretating results of their biological testing.
Asunto(s)
Encefalinas , Péptidos Cíclicos , Secuencia de Aminoácidos , Animales , Encefalina Leucina/análogos & derivados , Encefalina Leucina/farmacología , Encefalinas/farmacología , Cobayas , Íleon/efectos de los fármacos , Técnicas In Vitro , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Datos de Secuencia Molecular , Péptidos Cíclicos/farmacología , Conformación Proteica , Túbulos Seminíferos/efectos de los fármacosRESUMEN
[D-Arg2,Leu5]Enkephalin and two series of its N-terminal short-chain analogues with a free and modified C-terminal carboxylic group, viz. amides and ethyl esters of tri- and tetrapeptides, were synthesized in solution and by solid-phase method. Their analgesic activity, assayed by the "tail pinch" method following intracisternal and intravenous administration to mice, was compared with activity of enkephalins and morphine. To study the space structure of the synthesized compounds, conformational calculations and fluorescence spectroscopy were applied to measure distance between aromatic nuclei of tyrosine and phenylalanine residues in the two tetrapeptides. Ethyl esters of the tri- and tetrapeptides exceed in analgesic activity the corresponding carboxylic acids and amides. In contrast to the pentapeptide, the tetrapeptide analogues were active upon intravenous administration. Conformational aspects of this series of analogues are discussed in detail; the abrupt increase in activity upon transition from tri- to tetrapeptides does not appear to be related to conformational changes.
Asunto(s)
Analgésicos/síntesis química , Endorfinas/síntesis química , Encefalinas/síntesis química , Analgésicos/análisis , Dipéptidos/análisis , Dipéptidos/síntesis química , Endorfinas/análisis , Encefalinas/análisis , Conformación Proteica , Espectrometría de FluorescenciaRESUMEN
The cyclic analogue of [Leu5]enkephalin--cyclo (Lys-Tyr-Gly-Gly-Phe-Leu) and two corresponding linear hexapeptides with lysine residue attached to the N- or C-terminus of the molecule have been synthesized by classical methods of peptide chemistry. The addition of lysine residue to the N-terminus of cyclization of the molecule reduce the interaction of these analogues with both central and peripheral opiate receptors. The addition of lysine residue to the C-terminus of the molecule through the epsilon-amino group does not affect the interaction of the analogue with mu-receptors but reduces approximately tenfold its affinity for delta-receptors. All three analogues have analgesic potency similar to that of [Leu5]enkephalin as assayed after intracisternal administration to mice.
Asunto(s)
Encefalina Leucina/análogos & derivados , Péptidos Cíclicos/síntesis química , Animales , Fenómenos Químicos , Química , Encefalina Leucina/síntesis química , Encefalina Leucina/metabolismo , Encefalina Leucina/farmacología , Cobayas , Íleon/efectos de los fármacos , Técnicas In Vitro , Masculino , Ratones , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Péptidos Cíclicos/metabolismo , Péptidos Cíclicos/farmacología , Receptores Opioides/efectos de los fármacos , Receptores Opioides/metabolismo , Túbulos Seminíferos/efectos de los fármacosRESUMEN
The effect of substance P (SP) and of its fragments 5-11, 8-11, 9-11, 10-11 administered into the brain ventricles in doses of 5, 25 and 50 nM on the behavior and content of biogenic monoamines of the rat brain was studied. The analgetic properties of the substances under consideration and those of fragment SP 10-11 in doses of 5, 25, 50 and 100 nM were also subjected to examination. It was found that SP and fragment 5-11 stimulate and enhance the locomotor activity in rats, while fragments 8-11 and 9-11 provoke hypoactivity. The substances under study increase the serotonin and dopamine turnover, whereas SP and fragment 8-11 lower the serotonin content as well. After administration of SP and fragment 5-11 analgesia was seen to transform to hyperalgesia depending on the dose. Fragments 8-11 and 9-11 produce analgetic effect. It is suggested that both SP fragments and the whole SP molecule can influence the neurochemical process that regulate behavior and pain perception.