cyclic-gmp and Diabetes--Gestational

The adverse environment in early life can modulate adult phenotype, including blood pressure. Our previous study shows, in a rat streptozotocin (STZ)-induced maternal diabetes model, fetal exposure to maternal diabetes is characterized by established hypertension in the offspring. However, the exact mechanisms are not known. Our present study found, as compared with male control mother offspring (CMO), male diabetic mother offspring (DMO) had higher blood pressure with arterial dysfunction, i.e., decreased acetylcholine (Ach)-induced vasodilation. But there is no difference in blood pressure between female CMO and DMO. The decreased Ach-induced vasodilation was related to decreased nitric oxide (NO) production in the endothelium, not NO sensitivity in vascular smooth muscle because sodium nitroprusside (SNP)-mediated vasodilation was preserved; there was decreased NO production and lower eNOS phosphorylation in male DMO. The reactive oxygen species (ROS) level was increased in male DMO than CMO; normalized ROS levels with tempol increased NO production, normalized Ach-mediated vasodilation, and lowered blood pressure in male DMO rats. It indicates that diabetic programming hypertension is related to arterial dysfunction; normalizing ROS might be a potential strategy for the prevention of hypertension in the offspring.

Topics: Age Factors; Animals; Arterial Pressure; Blood Glucose; Cyclic GMP; Diabetes Mellitus, Experimental; Diabetes, Gestational; Endothelium, Vascular; Female; Hypertension; Male; Mesenteric Artery, Superior; Nitric Oxide; Oxidative Stress; Pregnancy; Prenatal Exposure Delayed Effects; Rats, Sprague-Dawley; Reactive Oxygen Species; Sex Factors; Vasodilation

Pregnancy complicated by diabetes is associated with increased risk of unfavorable obstetric outcomes. A common abnormality in diabetes is endothelial dysfunction resulting in an altered pattern of vasoactive substance production by the endothelial cells. The aim of study was to assess serum endothelin-1 (ET-1) and cyclic guanosine monophosphate (cGMP) in pregnant women with pregravid (PGDM) or gestational diabetes (GDM).. At the time of delivery, serum ET-1, cGMP, glycated hemoglobin (A1c), fructosamine and non-fasting glucose were measured in 19 PGDM, 23 GDM and 18 controls.. ET-1 and cGMP were similar in all groups. In GDM there was a positive association between A1c and ET-1 (r = 0.437; p < 0.05) and cGMP (r = 0.542; p < 0.02). In the controls, but not in PGDM and GDM, we found a positive correlation between ET-1 and cGMP (r = 0.634; p < 0.005). In women with diabetes, an optimal (A1c <6%) or inadequate (A1c >6%) metabolic control of diabetes did not influence ET-1 or cGMP levels.. In women with PGDM and GDM, serum ET-1 and cGMP were similar to the levels observed in healthy pregnant women. However, the physiological balance between vasoconstrictor and vasodilator substances might be defective in pregnancies complicated by diabetes.

Topics: Blood Glucose; Cyclic GMP; Diabetes, Gestational; Endothelin-1; Female; Fructosamine; Glycated Hemoglobin; Humans; Pregnancy; Pregnancy in Diabetics; Statistics, Nonparametric

The aim of the study was to assess the relationship between maternal and umbilical cord plasma concentrations of endothelin 1 (ET-1) and cyclic guanosine monophosphate (cGMP) in women with diabetes mellitus (DM).. The study was performed on 19 neonates of women with pregestational DM, 23 neonates of women with gestational diabetes (GDM), and 18 neonates of healthy uncomplicated pregnancies.. We found that umbilical and maternal ET-1 and cGMP concentrations in pregestational DM or GDM women were not changed in comparison with the controls. In women without DM, positive correlations between maternal (r=0.64; p<0.005) and umbilical cord plasma (r=0.60; p<0.009) ET-1 and cGMP concentrations were found. However in pregnancies complicated by pregestational DM or GDM such associations were not observed.. Umbilical and maternal plasma concentrations of ET-1 and cGMP in pregnant women with pregestational diabetes as well as gestational diabetes were not changed in comparison with the non-diabetic women. In women without DM maternal and umbilical cord plasma ET-1 and cGMP concentrations showed positive correlations. In pregnancies complicated by pregestational DM or GDM maternal and umbilical cord plasma ET-1 and cGMP concentrations were not interdependent.

Topics: Adult; Cyclic GMP; Diabetes, Gestational; Endothelin-1; Female; Fetal Blood; Humans; Pregnancy; Pregnancy in Diabetics; Risk Factors; Young Adult

Adenosine transport was characterized in human umbilical artery smooth muscle cells isolated from non-diabetic and diabetic pregnant subjects. Transport of adenosine was mediated by a Na+-independent transport system inhibited by nanomolar concentrations of nitrobenzylthioinosine (NBMPR) in both cell types. Diabetes increased adenosine transport, an effect that was associated with a higher maximal velocity (Vmax) for NBMPR-sensitive (es) saturable nucleoside transport (18 +/- 2 vs. 61 +/- 3 pmol (microgram protein)-1 min-1, P < 0.05) and the maximal number of binding sites (Bmax) for specific [3H]NBMPR binding (74 +/- 4 vs. 156 +/- 10 pmol (microgram protein)-1, P < 0.05), with no significant changes in the Michaelis-Menten (Km) and dissociation (Kd) constants, respectively. Adenosine transport was unaltered by inhibition of nitric oxide (NO) synthase (with 100 microM NG-nitro-L-arginine methyl ester, L-NAME) or protein synthesis (with 1 microM cycloheximide), but was increased by inhibition of adenylyl cyclase activity (with 100 microM, SQ-22536) in non-diabetic cells. Diabetes-induced adenosine transport was blocked by L-NAME and associated with an increase in L-[3H]citrulline formation from L-[3H]arginine and intracellular cGMP, but with a decrease in intracellular cAMP compared with non-diabetic cells. Expression of inducible NO synthase (iNOS) was unaltered by diabetes. Dibutyryl cGMP (dbcGMP) increased, but dibutyryl cAMP (dbcAMP) decreased, adenosine transport in non-diabetic cells. dbcGMP or the NO donor S-nitrosoacetylpenicillamine (SNAP, 100 microM) did not alter the diabetes-elevated adenosine transport. However, activation of adenylyl cyclase with forskolin (1 microM), directly or after incubation of cells with dbcAMP, inhibited adenosine transport in both cell types. Our findings provide the first evidence that adenosine transport in human umbilical artery smooth muscle cells is mediated by the NBMPR-sensitive transport system es, and that its activity is upregulated by gestational diabetes.

Topics: Adenosine; Biological Transport; Cells, Cultured; Cyclic AMP; Cyclic GMP; Diabetes, Gestational; Female; Humans; Intracellular Membranes; Kinetics; Muscle, Smooth, Vascular; Nitric Oxide; Nucleotides, Cyclic; Pregnancy; Reference Values; Thioinosine; Umbilical Arteries

This study has used an in vitro perfusion method to investigate the mechanism by which CRH causes vasodilatation in the human fetal-placental circulation. In normal term placentas, vasodilatory responses to human CRH (24-7000 pmol/L) were examined during submaximal vasoconstriction (100-120 mm Hg) of the fetal-placental vasculature induced by prostaglandin F2 alpha (0.7-2 mumol/L), KCl (50-100 mmol/L), or the thromboxane A2 mimetic, U46619 (0.05-0.5 mumol/L). Infusion of CRH caused a concentration-dependent vasodilatation that was similar in the presence of each constrictor agent (P > 0.05). The CRH antagonist, alpha-helical CRH-(9-41) (200 pmol/L), and a polyclonal CRH antiserum significantly inhibited CRH-induced vasodilatation during constriction with prostaglandin F2 alpha (P < 0.05). Vasodilatory responses to CRH were attenuated by the nitric oxide synthase inhibitor, N omega-nitro-L-arginine (100 mumol/L; P < 0.05), and the guanylate cyclase inhibitor, LY 83583 (1 mumol/L; P < 0.05), but not by the cyclooxygenase inhibitor, indomethacin (3 mumol/L; P > 0.05). In placentas of women with increased fetal vascular resistance, as demonstrated by Doppler ultrasound waveforms in vivo, CRH-induced vasodilatation was significantly reduced (P < 0.05). These results indicate that in the human fetal-placental circulation, CRH causes a vasodilatory response via a nitric oxide-/cGMP-dependent pathway. CRH may play a role in the control of vascular resistance to blood flow in the normal human placenta, and there may be a deficiency in the CRH signaling pathway of placentas with increased fetal vascular resistance.

Topics: Adult; Birth Weight; Corticotropin-Releasing Hormone; Cyclic GMP; Diabetes, Gestational; Dinoprost; Dose-Response Relationship, Drug; Female; Fetal Growth Retardation; Fetus; Humans; In Vitro Techniques; Infant, Newborn; Maternal-Fetal Exchange; Muscle, Smooth, Vascular; Nitric Oxide; Placenta; Potassium Chloride; Pregnancy; Pregnancy Complications; Reference Values; Regression Analysis; Signal Transduction; Vascular Resistance; Vasoconstriction; Vasodilation