bq-123 and Pre-Eclampsia

To compare the effect of endothelin on isolated resistance arteries from different vascular beds in normal and preeclamptic women before and after pretreatment with the ETA receptor antagonist BQ-123.. Resistance arteries from myometrial and omental biopsies obtained at cesarean section of normal pregnant and preeclamptic women were dissected and mounted in organ baths for recording of isometric tension. The contractile response to endothelin-1 in presence and absence of BQ-123 was recorded.. Endothelin-1 induced similar concentration-dependent contractions in all arteries investigated. In women with preeclampsia the contractile response induced by endothelin-1 was significantly higher in omental as compared to myometrial vessels. Pretreatment with BQ-123 significantly shifted the concentration-response curve to the right but only reduced the maximum contractile response in omental vessels.. Endothelin-1 is a potent constrictor of resistance arteries from different vascular beds in normal pregnancy and preeclampsia. The contractile effect is at least in part mediated by ETA receptors, since it was significantly reduced after pretreatment with BQ-123. In preeclamptic but not in normal pregnant women the response to endothelin-1 was reduced in myometrial as compared to omental arteries, possibly secondary to receptor down regulation.

Topics: Adult; Arteries; Biopsy; Cesarean Section; Elective Surgical Procedures; Endothelins; Female; Humans; Informed Consent; Myometrium; Omentum; Peptides, Cyclic; Pre-Eclampsia; Pregnancy; Receptors, Endothelin

To compare the effect of endothelin on isolated resistance arteries from different vascular beds in normal and preeclamptic women before and after pretreatment with the ETA receptor antagonist BQ-123.. Resistance arteries from myometrial and omental biopsies obtained at cesarean section of normal pregnant and preeclamptic women were dissected and mounted in organ baths for recording of isometric tension. The contractile response to endothelin-1 in presence and absence of BQ-123 was recorded.. Endothelin-1 induced similar concentration-dependent contractions in all arteries investigated. In women with preeclampsia the contractile response induced by endothelin-1 was significantly higher in omental as compared to myometrial vessels. Pretreatment with BQ-123 significantly shifted the concentration-response curve to the right but only reduced the maximum contractile response in omental vessels.. Endothelin-1 is a potent constrictor of resistance arteries from different vascular beds in normal pregnancy and preeclampsia. The contractile effect is at least in part mediated by ETA receptors, since it was significantly reduced after pretreatment with BQ-123. In preeclamptic but not in normal pregnant women the response to endothelin-1 was reduced in myometrial as compared to omental arteries, possibly secondary to receptor down regulation.

Topics: Adult; Arteries; Biopsy; Cesarean Section; Elective Surgical Procedures; Endothelins; Female; Humans; Informed Consent; Myometrium; Omentum; Peptides, Cyclic; Pre-Eclampsia; Pregnancy; Receptors, Endothelin

Recent studies have shown that preeclampsia (PE) is associated with the presence of autoantibodies (AABs) that activate the angiotensin II AT1 receptor, which could contribute to many of the symptoms of PE.. To investigate the frequency and the targets of AABs in preeclamptic women (31 cases) and healthy pregnant normotensive women (29 cases) in Brazil, antibodies from serum samples were detected by a bioassay using spontaneously beating neonatal rat cardiomyocytes in culture. In the cardiomyocytes, the agonistic AABs induce a positive or negative chronotropic response, mimicking the corresponding receptor agonists. The specificity of the AAB response was identified by specific receptor antagonists.. Thirty preeclamptic patients (97%) presented AABs against the angiotensin II AT1 receptor. The agonistic effect of the AAB was blocked by irbesartan and neutralized by a peptide corresponding to the second extracellular loop of this receptor. Strikingly, we discovered that all sera from the severe preeclamptic patients (16 cases) contained a novel agonist-like AAB directed against the endothelin-1 ETA receptor in addition to the AABs against the angiotensin II AT1 receptor. This AAB was selectively blocked by the antagonist BQ-123, antagonized by the protein kinase C (PKC) inhibitor Calphostin C and neutralized by peptides corresponding to the second extracellular loop of the endothelin-1 ETA receptor subtype.. We described, for the first time, the presence of endothelin-1 ETA receptor AABs in PE. Our results suggest that the presence of both agonistic AABs may be involved in the pathogenesis of severe PE.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Animals; Autoantibodies; Biphenyl Compounds; Case-Control Studies; Endothelin Receptor Antagonists; Enzyme Inhibitors; Female; Gestational Age; Heart Rate; Humans; Irbesartan; Myocytes, Cardiac; Naphthalenes; Peptides, Cyclic; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Protein Kinase C; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Endothelin A; Severity of Illness Index; Tetrazoles; Young Adult

Preeclampsia is a life-threatening pregnancy disorder. However, its pathogenesis remains unclear. We tested the hypothesis that gestational hypoxia induces preeclampsia-like symptoms via heightened endothelin-1 (ET-1) signaling. Time-dated pregnant and nonpregnant rats were divided into normoxic and hypoxic (10.5% O2 from the gestational day 6-21) groups. Chronic hypoxia had no significant effect on blood pressure or proteinuria in nonpregnant rats but significantly increased blood pressure on day 12 (systolic blood pressure, 111.7 ± 6.1 versus 138.5 ± 3.5 mm Hg; P=0.004) and day 20 (systolic blood pressure, 103.4 ± 4.6 versus 125.1 ± 6.1 mm Hg; P=0.02) in pregnant rats and urine protein (μg/μL)/creatinine (nmol/μL) ratio on day 20 (0.10 ± 0.01 versus 0.20 ± 0.04; P=0.04), as compared with the normoxic control group. This was accompanied with asymmetrical fetal growth restriction. Hypoxia resulted in impaired trophoblast invasion and uteroplacental vascular remodeling. In addition, plasma ET-1 levels, as well as the abundance of prepro-ET-1 mRNA, ET-1 type A receptor and angiotensin II type 1 receptor protein in the kidney and placenta were significantly increased in the chronic hypoxic group, as compared with the control animals. Treatment with the ET-1 type A receptor antagonist, BQ123, during the course of hypoxia exposure significantly attenuated the hypoxia-induced hypertension and other preeclampsia-like features. The results demonstrate that chronic hypoxia during gestation induces preeclamptic symptoms in pregnant rats via heightened ET-1 and ET-1 type A receptor-mediated signaling, providing a molecular mechanism linking gestational hypoxia and increased risk of preeclampsia.

Topics: Animals; Blood Pressure; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Female; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney; Peptides, Cyclic; Placenta; Pre-Eclampsia; Pregnancy; Proteinuria; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Signal Transduction

We attempted to determine the role of endothelin in a previously characterized animal model of preeclampsia by studying the effect of a specific endothelin antagonist, BQ123, on blood pressure.. A preeclampsia-like condition was induced by infusing pregnant rats with the nitric oxide synthase inhibitor N(G)-nitro-L -arginine methyl ester. Osmotic minipumps were inserted subcutaneously into timed pregnant Harlan-Sprague-Dawley rats on day 17 of pregnancy (term, 22 days). The pumps were loaded to continuously deliver either vehicle (control group) or N(G)-nitro-L -arginine methyl ester 50 mg/d, either alone or with BQ123 at 0.5 mg/d. In a similar but separate experiment, the dose of BQ123 was increased to 1 mg/d. Blood pressure was measured with the tail-cuff method before pump insertion and then daily until postpartum day 2.. Except for a decrease on the day after pump insertion, BQ123 0.5 mg/d had no significant effect on the hypertension induced by N(G)-nitro-L -arginine methyl ester. At the higher dose, however, BQ123 significantly attenuated the increase in blood pressure induced by N(G)-nitro-L -arginine methyl ester during most of the study period.. The effect of nitric oxide inhibition can be successfully attenuated by the use of an endothelin antagonist, thereby supporting the role of endothelin in the hypertension described with the preeclampsialike condition seen in pregnant rats.

Topics: Animals; Blood Pressure; Disease Models, Animal; Endothelins; Enzyme Inhibitors; Female; Gestational Age; Hypertension; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Peptides, Cyclic; Pre-Eclampsia; Pregnancy; Rats; Rats, Sprague-Dawley