Effects of antenatal betamethasone on preterm human and mouse ductus arteriosus: comparison with baboon data.

BackgroundAlthough studies involving preterm infants ≤34 weeks gestation report a decreased incidence of patent ductus arteriosus after antenatal betamethasone, studies involving younger gestation infants report conflicting results.MethodsWe used preterm baboons, mice, and humans (≤276/7 weeks gestation) to examine betamethasone's effects on ductus gene expression and constriction both in vitro and in vivo.ResultsIn mice, betamethasone increased the sensitivity of the premature ductus to the contractile effects of oxygen without altering the effects of other contractile or vasodilatory stimuli. Betamethasone's effects on oxygen sensitivity could be eliminated by inhibiting endogenous prostaglandin/nitric oxide signaling. In mice and baboons, betamethasone increased the expression of several developmentally regulated genes that mediate oxygen-induced constriction (K+ channels) and inhibit vasodilator signaling (phosphodiesterases). In human infants, betamethasone increased the rate of ductus constriction at all gestational ages. However, in infants born ≤256/7 weeks gestation, betamethasone's contractile effects were only apparent when prostaglandin signaling was inhibited, whereas at 26-27 weeks gestation, betamethasone's contractile effects were apparent even in the absence of prostaglandin inhibitors.ConclusionsWe speculate that betamethasone's contractile effects may be mediated through genes that are developmentally regulated. This could explain why betamethasone's effects vary according to the infant's developmental age at birth

Role of extracellular calcium and calcium channels in the response of human placental venous smooth muscle to endothelin-1

Objective: Our purpose was to evaluate the role of calcium and calcium channels in endothelin-1-induced contraction of the smooth muscle of human placental veins. Study design: Placentas were collected after vaginal delivery at term. After their removal from the chorionic plate, placental veins were divided into rings that were suspended in organ chambers and stretched to optimal tension. In the first part of the study, vessels from six women were initially suspended in calcium-poor modified Krebs-Ringer solution. They were then treated with either EGTA [ethylene glycol-bis(β-aminoethyl ether)N,N,N',N'-tetraacetic acid; calcium chelator, 0.5 mmol/L] or calcium chloride 2.5 mmol/L (control). Endothelin-1 was then added cumulatively (10-10 to 10-7 mol/L), and the resulting changes in isometric tensions were recorded. In the second part of the study vessels from six other women were treated with either (1) normal modified Krebs-Ringers solution (control), (2) calcium-poor modified Krebs-Ringers solution, or (3) nicardipine (dihydropyridine calcium channel inhibitor, 10-7 mol/L) in separate organ chambers. Endothelin-1 was then added cumulatively. Results: Endothelin-1 produced concentration-dependent contractions in placental veins, with maximal tension reached at 10-7 mol/L. Substitution of calcium-poor for standard Krebs-Ringers solution in the organ chamber abolished contractions to low endothelin-1 concentrations (≤ 10-9 mol/L, p < 0.001) but did not affect the contractile response to higher concentrations. EGTA abolished contractions to all concentrations tested (p < 0.02). Nicardipine significantly, but incompletely, inhibited the contractile responses to all endothelin-1 concentrations tested (p < 0.05). Conclusions: Endothelin-1 induces contraction of the smooth muscle of human placental veins, which requires the influx of extracellular calcium. Dihydropyridine-sensitive calcium channels represent a major route of entry, but other pathways participate. The fetal effects of nifedipine and other calcium-channel blockers deserve specific evaluation in intrauterine growth retardation and other pregnancies complicated by elevated fetal levels of endothelin-1.link_to_subscribed_fulltex

Contractile effect of endothelin in human placental veins: Role of endothelium prostaglandins and thromboxane

Objective: The aim was to study the effects of endothelin-1 on human placental veins and the role of cyclooxygenase products as mediators of these effects. Study design: Rings of placental veins with and without endothelium were suspended in organ chambers filled with physiologic salt solution. After a period of stabilization at optimal basal tension, isometric tensions in the control group were recorded at increasing concentrations of endothelin-1 (10-10 to 10-7 mol/L). Rings in the experimental groups were treated with either indomethacin (cyclooxygenase inhibitor, 10-5 mol/L), dazoxiben (thromboxane synthetase inhibitor, 10-4 mol/L), or SQ29548 (thromboxane receptor antagonist 10-6 mol/L) before addition of endothelin-1. To demonstrate the presence of functional thromboxane receptors in the rings, contractile responses to U-46619 (10-9 to 10-6 mol/L), a thromboxane A2 analog were measured. The effectiveness of SQ29548 blockade was tested in rings treated with SQ29548 (10-6 mol/L) before addition of U-46619. The concentration-response curves of the treated and control groups were compared with the Student paired t test. Results: Endothelin-1 in doses of 10-10 to 10-7 mol/L caused concentration-dependent contraction of placental veins. Indomethacin significantly reduced the response of veins with endothelium to low endothelin-1 concentrations (10-9.5 to 10-9 mol/L), (p < 0.05). However, it had no effect at higher endothelin-1 concentrations or in vessels without endothelium. The presence of functional thromboxane A2 receptors was confirmed by the vasoconstrictor effect of U-46619 and its blockade by treatment with SQ29548. Neither SQ29548 nor the thromboxane A2 synthesis inhibitor dazoxiben significantly influenced the response to endothelin-1. Conclusions: These results demonstrated that endothelin-1 is a potent vasoconstrictor in the human placental vein. Although functional thromboxane A2 receptors exist in this vessel, endothelin-1 is action is independent of thromboxane A2. Prostaglandins may mediate part of the endothelin-1-induced placental vasoconstriction. However, endothelin-1 acts primarily by a direct effect on vascular smooth muscle cells.link_to_subscribed_fulltex

Endothelins 1 and 3 and big endothelin-1 contract isolated human placental veins

Experiments were designed to investigate the reactivity of vascular smooth muscle to endothelins (ETs) in veins taken from human placentas immediately after delivery. The placental veins were cut into rings and suspended between two stirrups in conventional organ chambers (filled with aerated, modified Krebs-Ringer bicarbonate solution) for isometric recording of tension. ET-1 and ET-3 caused concentration-dependent contractions of the isolated human placental veins. The responses induced by ET-1 were greater than those evoked by ET-3 and were not significantly affected by BQ-123, a selective inhibitor of ET(A) receptors. Contractions to big ET-1 were obtained in rings both with and without endothelium; they were inhibited by phosphoramidon, an inhibitor of endothelin-converting enzyme. These findings indicate that the conversion of the precursor of ET-1 can occur in human placental veins. The receptors mediating the contraction of human placental veins to endothelins do not belong to the ET(A) subtype; the response to the peptides is probably mediated in part by an uncharacterized ET-receptor subtype and in part by ET(B) receptors. The output of big ET-1 in the vascular wall or from surrounding tissues in the placenta could be involved in the regulation of venous tone in this organ.link_to_subscribed_fulltex

Ability of sickle cells to scavenge endothelium-derived nitric oxide is reduced

AIM: To assess the ability of sickle cells to interfere with the release or transfer of endothelium-derived relaxing factor (EDRF) in comparison to normal erythrocytes. METHODS: A perfusion-superfusion bioassay system was used a canine carotid artery with endothelium (donor of EDRF) and a ring of the same vessel without endothelium (detector) were separated by tubing resulting in a five second interval for transfer of EDRF from donor to detector. Changes in isometric tension were monitored in both the donor and the detector preparations. Release of EDRF, as determined by sustained relaxations during the contractions to phenylephrine, was induced by infusing acetylcholine through the donor artery. RESULTS: Superfusion with normal and sickle erythrocytes caused impairment of the endothelium-dependent relaxations in both detector and donor tissues. When infused through the transfer line, sickle cells were less potent than normal erythrocytes in inhibiting relaxation in the detector tissues. In contrast, infusion of either normal erythrocytes or sickle cell through the donor artery caused similar degrees of inhibition in donor and detector arteries. Hemolysates from both types of erythrocytes were equieffective at either site of infusion. CONCLUSION: These results indicate that sickle cells are intrinsically less potent scavengers of EDRF than normal erythrocytes. However, exposure to the endothelium enhances the ability of sickle cells to inhibit lumenal release of endothelium-derived relaxing factor.link_to_subscribed_fulltex