Maureen O'Hara

Sphingosine-1-Phosphate Acts via Rho-Associated Kinase and Nitric Oxide to Regulate Human Placental Vascular Tone

Abstract Sphingosine-1-phosphate (S1P), a bioactive lipid released from activated platelets, has been demonstrated in animal models to regulate vascular tone through receptor-mediated activation of Rho-associated kinase 1 and nitric oxide synthase 3. The role of S1P in regulation of human vascular tone (particularly during pregnancy, with its unique vascular adaptations and localized platelet activation) is unknown. We hypothesized that S1P would constrict small placental arteries through activation of Rho-associated kinases with modulation by nitric oxide. Reverse transcription-polymerase chain reaction of chorionic plate artery preparations detected mRNAs encoding all five receptors for S1P, and S1P induced dose-dependent vasoconstriction of both chorionic plate and stem villous isobarically mounted arteries, which at 10 μmol/L was 32.9% ± 3.86% (mean ± SEM) and 34.6% ± 7.01%, respectively. In stem villous arteries, S1P-induced vasoconstriction was enhanced significantly following inhibition of nitric oxide synthases with NG-nitro-L-arginine methyl ester (100 μmol/L, 52.6% ± 6.28%, P < 0.05). The S1P-induced vasoconstriction was reversed by Y27632, an inhibitor of Rho-associated kinases (10 μmol/L) in both chorionic plate (to 14.9% ± 4.95%) and stem villous arteries (to 2.71% ± 6.13%). The S1P added to alpha-toxin-permeabilized, isometrically mounted chorionic plate arteries bathed in submaximal Ca2+-activating solution induced Ca2+-sensitization of constriction, which was 47.7% ± 10.0% of that occurring to maximal Ca2+-activating solution. This was reduced by Y27632 to 18.4% ± 18.4%. Interestingly, S1P-induced vasoconstriction occurred in all isobarically mounted arteries but was inconsistent in isometrically mounted chorionic plate arteries. In summary, S1P-induced vasoconstriction in human placental arteries is mediated by increased Ca2+-sensitization through activation of Rho-associated kinases, and this vasoconstriction also is modulated by nitric oxide. Identification of these actions of S1P in the placental vasculature is important for understanding both normal and potentially abnormal vascular adaptations with pregnancy.

Cutaneous absorption of trivalent chromium: tissue levels and treatment by exchange transfusion.

ABSTRACT A man was accidentally immersed in hot acidic trivalent chromium sulphate solution but none was swallowed. The clinical course was dominated by burns, intravascular haemolysis, and acute renal failure. Blood concentrations of chromium were measured during treatment and tissue concentrations were measured at death. Exchange transfusion reduced blood chromium concentrations by two-thirds. The total quantities of chromium absorbed and removed by various routes were calculated. In-vitro studies showed that the chromium solution did not directly cause haemolysis.

Modulation of Human Arterial Tone During Pregnancy: The Effect of the Bioactive Metabolite Sphingosine-1-Phosphate

Abstract Sphingosine-1-phosphate (S1P) is a potent bioactive lipid that has been implicated in cardiovascular disease. The objective of the present study was to determine the vasoactive effects and underlying mechanisms of S1P on adult human maternal arteries. The isometric tensions of the omental and myometrial arteries isolated from normal pregnant women at term were assessed in response to incremental doses of S1P in the presence or absence of the nitric oxide (NO) synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). The putative involvement of Rho-associated kinases (ROCKs) in intact arteries and in those permeabilized with α-toxin, to study agonist-dependent calcium-sensitization, was assessed with the inhibitor Y27632. Real-time RT-PCR established the presence of mRNA encoding the S1P receptors (S1P1 to 3), previously known as endothelial differentiation gene receptors (EDG1, 3 and 5), in both artery types. S1P induced a dose-dependent increase in the isometric tension of all the arteries. Y27632 reduced constriction due to S1P in intact arteries and reduced S1P-induced sensitization of contraction to submaximal activating Ca2+ in permeabilized arteries. L-NAME also modulated S1P vasoactive responses in a tissue-specific manner. Two subgroups of omental arteries were identified, one of which utilizes the NO pathway. In myometrial arteries, S1P evoked oscillatory constrictions, whereas pretreatment with L-NAME resulted in only tonic constrictions of unaltered peak magnitude. The prominent vasoactive actions of S1P in the maternal arteries of pregnant women are modulated by inhibitors of ROCKs and NO bioavailability. The subtle tissue-specific functional differences in the modulation of S1P actions by NO have important implications for vascular tone regulation by this bioactive circulatory metabolite during pregnancy.