No abstract

Two sons of a previously reported Ghanaian homozygote for the hereditary persistence of fetal hemoglobin (HPFH) (Ringelhann et al., 1970) also are HPFH homozygotes. In addition, another unrelated adult Ghanaian homozygote has been detected. All of these Ghanaian homozygotes as well as three American Black HPFH homozygotes have the G gamma A gamma type of HPFH with a G gamma to A gamma ratio of about 3:2, in contrast to an Asiatic Indian homozygote who has the G gamma type. Globin chain synthesis in HPFH homozygotes is unbalanced, with a gamma/alpha ratio of 0.6 or less, whereas it is balanced in heterozygotes according to most reports.

No abstract

The sickling of homozygous sickle cells upon deoxygenation is inhibited in the presence of 3 mM L-phenylalanine benzyl ester (Phe-OBzl) or benzyl esters of other aromatic or hydrophobic amino acids. Phe-OBzl was found to permeate into erythrocytes rapidly, and the deoxygenated cells maintained considerable flexibility as measured by their ability to pass through 3-,um pores. The osmotic fragility of the cells was unchanged and the oxygen dissociation curve was shifted slightly from a 50% saturation value of28.5mm Hg to 31.0mm

The calcium channel antagonist, bepridil, beta-(2-methylpropoxy)methyl-N-phenyl-N-(phenylmethyl)-1-pyrrol idineethanamine monochloride monohydrate, inhibits the sickling of deoxygenated sickle (SS) erythrocytes, as determined by light microscopy. The anti-sickling effect was seen only in dilute suspensions of red cells. In concentrated erythrocyte suspensions, sickling was not inhibited and measurements of hematocrit and cell density were unchanged by bepridil. The determination of cell volume in dilute suspensions was complicated by bepridil's tendency to aggregate, but rapid measurements by electronic sizing also indicated no increase in cell volume, up to a bepridil concentration of 200 microM. Ektacytometry of dilute sickle cell suspensions suggested an explanation for the anti-sickling action of bepridil. Osmotic scan ektacytometry disclosed that bepridil initially increased the surface area of the red cell, as shown by a shift in the low osmolality minimum. This change was complete in 10 sec, the shortest time that could be measured. Subsequently, at concentrations that were observed to inhibit the sickling of deoxygenated sickle cells (100 microM or greater), red cells underwent a loss in surface area that was complete in 1 min. There was a concomitant loss of cell deformability. Light and scanning electron microscopy has previously shown that bepridil is a stomatocytic agent. Using transmission electron microscopy, we verified that the loss of surface area was a consequence of endocytosis, presumably as the end stage of the stomatocytic transformation induced by bepridil. Bepridil did not inhibit intracellular hemoglobin S polymerization even at 200 microM, as shown by oxygen scan ektacytometry. Bepridil thus appears to inhibit the sickling of deoxygenated SS cells by inducing endocytosis and lowering cell deformability. This mechanism may explain the anti-sickling effect of other basic amphiphiles, such as chlorpromazine.