This paper describes experiments showing that one of the pathways of sodium transport across the red-cell membrane, sodium-lithium countertransport, is faster in patients with essential hypertension than in control subjects. This transport system accepts only sodium or lithium and is not inhibited by ouabain. The maximum rate of transport shows inherited differences. The mean maximum rate of sodium-lithium countertransport was found to be 0.55 +/- 0.02 (mean +/- S.E.M.) mmol (liter of red cells X hour)(-1) in a group of 36 patients with essential hypertension and 0.24 +/- 0.02 in 26 control subjects (P less than 0.001). The first-degree relatives of eight patients with essential hypertension and 10 control subjects had mean maximum rates of sodium-lithium countertransport of 0.54 +/- 0.05 and 0.23 +/- 0.02, respectively. Five patients with secondary hypertension had normal mean maximum rates of sodium-lithium countertransport. The relation between heritability of red-cell sodium-lithium countertransport and essential hypertension should be investigated further.

Only one third of patients with juvenile-onset insulin-dependent diabetes seem to be susceptible to diabetic nephropathy. To test whether this susceptibility is related to a predisposition to hypertension, we investigated the association of nephropathy with markers of risk for hypertension. We randomly selected 89 patients with insulin-dependent diabetes from a roster of children and adolescents who were seen between 1968 and 1972 at about the time the diagnosis was made. These 89 patients were recalled for examination, as young adults, in 1986 and 1987. Patients with nephropathy (cases, n = 33) were compared with controls without nephropathy (n = 56). Having a parent with hypertension tripled the risk of nephropathy (odds ratio, 3.7; 95 percent confidence interval, 1.4 to 10.1). Moreover, cases had significantly higher values for maximal velocity of lithium-sodium countertransport in red cells than controls (mean maximal velocity +/- SE, 0.51 +/- 0.04 vs. 0.38 +/- 0.02 mmol per liter of cells per hour; P less than 0.05). The excess risk associated with both these indicators of a predisposition to hypertension was evident principally in patients with poor glycemic control during their first decade of diabetes; the odds ratios were 4.5 (95 percent confidence interval, 1.1 to 18.7) for patients with a parental history of hypertension and 7.7 (95 percent confidence interval, 1.8 to 33.8) for patients with a maximal velocity of lithium-sodium countertransport greater than or equal to 0.35 mmol per liter of cells per hour. We conclude that the risk of renal disease in patients with juvenile-onset insulin-dependent diabetes is associated with a genetic predisposition to hypertension. Predisposition to hypertension appears to increase susceptibility for renal disease principally in patients with poor glycemic control.

The cellular mechanisms responsible for abnormalities in spontaneously hypertensive rat (SHR) vascular smooth muscle cell (VSMC) growth and vasoreactivity are not defined. Because Na+/H' exchange, which we have previously demonstrated in cultured VSMC, plays an essential role in mediating growth factor responses, we hypothesized that abnormalities in SHR growth regulation might be reflected in the activity of this transporter. To test this hypothesis, we studied DNA synthesis and Na+/H' exchange (measured as the rate of amiloride-sensitive intracellular alkalinization or Na' influx) in early subcultures (< 6) of aortic VSMC from 12-wk-old SHR and Wistar Kyoto (WKY) animals. Serum-deprived SHR VSMC grew more rapidly in response to 10% serum with an increase in [3Hjthymidine incorporation of 439% compared with 191% in WKY controls. Basal intracellular pH (pHj) values determined by fluorescent pH measurements were 7.37±0.04 and 7.27±0.03 (P < 0.05) in early passage SHR and WKY, respectively. Acid recovery (initial pH1 = 6.8) by SHR VSMC was faster than by WKY VSMC as measured by alkalinization (1.8±0.6 vs. 0.8±0.2 mmol Hf/liter * min, P < 0.05) or by amiloride-sensitive 22Na' influx (14.5±1.2 vs. 4.0±0.5 nmol Na+/mg protein * min, P < 0.05). In comparison to WKY cells early passage SHR VSMC exhibited 2.5-fold greater alkalinization and amiloride-sensitive 22Na' influx in response to 100 nM angiotensin II. During serial passage, WKY cells acquired enhanced Na+/H' exchange and growth rates so that by passage 6, these differences were no longer present. These findings in early cultures of SHR VSMC, removed from the in vivo neurohumoral milieu, suggest that increased Na+/H' exchange in SHR may reflect alterations in Na' homeostasis that might contribute to altered SHR VSMC function such as enhanced growth and vasoreactivity.

We report here that a Cl(-)-dependent K+ (K:Cl) efflux, which is stimulated by N-ethylmaleimide (NEM) and by increased red cell volume, exists in young red cells of individuals with normal hemoglobin A (AA) and in those homozygous for hemoglobin S (SS). We have investigated this K:Cl efflux in several density-defined red cell fractions obtained from Percoll-Stractan continuous density gradients. We found high activity of the NEM-stimulated K:Cl transport in reticulocytes and young red cells from nine sickle cell (SS) patients (43 +/- 27 mean +/- SD mmol K+/liter of cells/hr = flux units (FU)) and in the young cell fraction of three AA individuals with high reticulocytosis recuperating from nutritional anemias (41.7 +/- 10 FU). In addition, we observed significant interindividual variation of this K:Cl efflux in the discocyte fraction of SS blood. Cell swelling markedly stimulated the K:Cl efflux, in SS whole blood (9.8 +/- 7.4 FU, in SS young cells (13 +/- 13 FU), and in AA young cells (21.4 +/- 11 FU). The activity of the Na-K-Cl cotransport, as estimated by the bumetanide sensitive K+ efflux was not found to be cell-age dependent in either AA or SS cells. Measurements of red cell density by isopycnic gradients indicated that 27% of the young cells reduce their volume by a Cl(-)-dependent process in hypotonic or low pH-induced swelling. The large volume-stimulated K:Cl efflux in AA young cells raises the possibility that these fluxes may be involved in the maturation of erythropoietic precursors.(ABSTRACT TRUNCATED AT 250 WORDS)