15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Anemia--Sickle-Cell

Sickle cell disease (SCD), the most common inherited hematologic disorder in the United States and the most common single gene disorder in the world, causes substantial morbidity and mortality. The major pathobiologic processes that underlie SCD include vaso-occlusion, inflammation, procoagulant processes, hemolysis, and altered vascular reactivity. The present study examined the vasoactive response to a-adrenergic activation in a murine model of SCD. Isolated aortas from sickle mice as compared with wild-type mice exhibit heightened contractions to norepinephrine and phenylephrine; such responses were completely blocked by an a1-receptor antagonist, prazosin. Aortas from either group exhibited comparable contractile responses to potassium chloride and the thromboxane agonist U46619 and no contractile response to an a2-adrenergic receptor agonist, UK14304. We conclude that there is an exaggerated vasoconstrictive response to a1-receptor agonists in SCD. Because sickle crisis is induced by diverse forms of stress, the latter attended by increased adrenergic activity, our findings may be relevant to the occurrence of sickle crisis. We also suggest that such heightened reactivity may contribute to vaso-occlusive processes that underlie ischemic injury in SCD. Finally, our findings urge caution in the use of phenylephrine in patients with SCD.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Anemia, Sickle Cell; Animals; Aorta; Female; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Receptors, Adrenergic, alpha-1; Up-Regulation; Vasoconstriction

Patients with sickle cell disease have been described to have decreased platelet aggregation. The cause of this decrease is believed to be the refractory state of platelets from continual in vivo activation. In this study, plasma 6-keto PGF1 alpha (stable metabolite of vessel wall-derived prostaglandin, prostacyclin) levels were measured to study the mechanism of decreased platelet aggregation. Plasma 6-keto PGF1 alpha levels were measured by radioimmunoassay in ten patients with sickle cell disease and in ten control subjects. Plasma 6-keto PGF1 alpha levels in normal subjects ranged from 0 to 100 pg/ml (mean 40 +/- 14 pg/ml), but were significantly higher in patients with sickle cell disease (range 170 to 880 ng/ml, mean 446 +/- 89 pg/ml, P less than .002). Platelet aggregation in response to an endoperoxide analog in these patients was lower compared with that of the control subjects. This study suggests that prostacyclin activity is increased in subjects with sickle cell disease. This increased activity is probably due to persistent stress to the endothelium from hemolysis and continual platelet activation. Decreased platelet aggregation seen in these patients may be due to elevated prostacyclin activity.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Anemia, Sickle Cell; Child; Child, Preschool; Female; Humans; Infant; Male; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic