RESUMO
Insufficient invasion of the spiral arteries by trophoblast cells is associated with the etiology of pre-eclampsia, the syndrome of hemolysis, elevated liver enzymes and low platelet counts (HELLP) and pre-eclampsia-associated intrauterine growth restriction (IUGR). Mannose-binding lectin (MBL) is a component of the innate immune system. MBL-mediated activation of the complement cascade is an important event in the destruction of invading trophoblasts. The gene coding for MBL is polymorphic, and variant alleles result in greatly reduced circulating MBL levels. The aim of this study was to test the association between an MBL polymorphism and pre-eclampsia, HELLP syndrome and IUGR. DNA was extracted from buccal swabs of 51 women with pre-eclampsia, 81 women with HELLP syndrome and 184 healthy pregnant controls. Aliquots were tested for a single nucleotide MBL gene polymorphism at codon 54 by PCR and endonuclease digestion. Homozygosity for the wild-type allele was more frequent in patients with pre-eclampsia (P = 0.04) and HELLP syndrome (P = 0.02) when compared with controls. The presence of the variant allele was more prevalent among controls than in women with pre-eclampsia (P = 0.02) or HELLP syndrome (P = 0.028). Twenty-two (55%) patients with pre-eclampsia and 43 (53%) women with HELLP syndrome delivered an IUGR neonate. MBL-54 heterozygosity was more frequent in controls (27.2%) than in pre-eclamptic women (4.5%, P = 0.025) and those with HELLP syndrome (11.7%, P = 0.05) who delivered an IUGR neonate. Genotype frequencies of neonates born to mothers in all study groups were similar. Carriage of the MBL codon 54 polymorphism protects against pre-eclampsia, HELLP syndrome and IUGR and implies that an MBL-mediated event might be involved in the pathogenesis of these disorders.
Assuntos
Retardo do Crescimento Fetal/genética , Síndrome HELLP/genética , Lectina de Ligação a Manose/genética , Polimorfismo de Nucleotídeo Único , Pré-Eclâmpsia/genética , Adulto , Estudos de Casos e Controles , Códon , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Heterozigoto , Homozigoto , Humanos , Razão de Chances , Gravidez , Medição de Risco , Fatores de RiscoRESUMO
Original quinolinone derivatives structurally related to diazoxide were synthesized and their effects on insulin secretion from rat pancreatic islets and the contractile activity of rat aortic rings determined. A concentration-dependent decrease of insulin release was induced by 6-chloro-2-methylquinolin-4(1H)-one (HEI 713). The average IC(50) values were 16.9+/-0.8 microM for HEI 713 and 18.4+/-2.2 microM for diazoxide. HEI 713 increased the rate of (86)Rb outflow from perifused pancreatic islets. This effect persisted in the absence of external Ca(2+) but was inhibited by glibenclamide, a K(ATP) channel blocker. Inside-out patch-clamp experiments revealed that HEI 713 increased K(ATP) channel openings. HEI 713 decreased (45)Ca outflow, insulin output and cytosolic free Ca(2+) concentration in pancreatic islets and islet cells incubated in the presence of 16.7 or 20 mM glucose and extracellular Ca(2+). The drug did not affect the K(+)(50 mM)-induced increase in (45)Ca outflow. In aortic rings, the vasorelaxant effects of HEI 713, less potent than diazoxide, were sensitive to glibenclamide and to the extracellular K(+) concentration. The drug elicited a glibenclamide-sensitive increase in (86)Rb outflow from perifused rat aortic rings. Our data describe an original compound which inhibits insulin release with a similar potency to diazoxide but which has fewer vasorelaxant effects. Our results suggest that, in both aortic rings and islet tissue, the biological effects of HEI 713 mainly result from activation of K(ATP) channels ultimately leading to a decrease in Ca(2+) inflow.
Assuntos
Ilhotas Pancreáticas/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Canais de Potássio/efeitos dos fármacos , Quinolonas/farmacologia , Trifosfato de Adenosina/fisiologia , Animais , Aorta/efeitos dos fármacos , Aorta/fisiologia , Cálcio/metabolismo , Cálcio/farmacologia , Radioisótopos de Cálcio/metabolismo , Diazóxido/química , Diazóxido/farmacologia , Relação Dose-Resposta a Droga , Glucose/farmacologia , Glibureto/farmacologia , Técnicas In Vitro , Insulina/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/metabolismo , Lipídeos/química , Músculo Liso Vascular/fisiologia , Canais de Potássio/fisiologia , Quinolonas/síntese química , Quinolonas/química , Ratos , Ratos Wistar , Radioisótopos de Rubídio/metabolismo , Fatores de Tempo , Vasoconstrição/efeitos dos fármacosRESUMO
A series of 6-substituted 2-alkylaminoquinazolin-4(3H)-ones structurally related to 3-alkylamino-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides were synthesized and tested as putative K(ATP) channel openers on isolated pancreatic endocrine tissue as well as on isolated vascular, intestinal, and uterine smooth muscle. Most of the 6-halogeno-2-alkylaminoquinazolin-4(3H)-ones were found to inhibit insulin release from pancreatic B-cells and to exhibit vasorelaxant properties. In contrast to their pyridothiadiazine dioxide isosteres previously described as more active on the endocrine than on the smooth muscle tissue, quinazolinones cannot be considered as tissue selective compounds. Biological investigations, including measurements of (86)Rb, (45)Ca efflux from pancreatic islet cells and measurements of vasodilator potency in rat aortic rings exposed to 30 or 80 mM KCl in the presence or the absence of glibenclamide, were carried out with 6-chloro- and 6-iodo-3-isopropylaminoquinazolin-4(3H)-ones. Such experiments showed that, depending on the tissue, these new compounds did not always express the pharmacological profile of pure K(ATP) channel openers. Analyzed by X-ray crystallography, one example of quinazolinones appeared to adopt a double conformation. This only suggests a partial analogy between the 2-alkylaminoquinazolin-4(3H)-ones and the 3-alkylamino-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides. In conclusion, the newly synthesized quinazolinones interfere with insulin secretion and smooth muscle contractile activity. Most of the compounds lack tissue selectivity, and further investigations are required to fully elucidate their mechanism(s) of action.