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To study the activity of the sodium-lithium (Na+-Li + ) countertransport system in vivo in the erythrocytes of patients with untreated essential hypertension.Lithium substitutes for sodium efflux in the sodium-sodium (Na + -Na + ) countertransport system. In essential hypertension the efflux of lithium from cells in vitro has been used as a measure of the activity of the Na+—Na+ countertransporter and has been shown to be increased. We administered oral lithium and used its disposition in erythrocytes to measure Na + -I_i+ countertransporter activity in vivo.Ten men with essential hypertension who had never taken any antihypertensive treatment were matched with 10 male controls for age, weight, and plasma and erythrocyte sodium and potassium concentrations.Repeated measurements were made of plasma and intra-erythrocytic lithium concentrations during the 48 h after the oral administration of 16.2 mmol lithium carbonate. Data were analysed using standard pharmacokinetic techniques.The rate of lithium efflux from the erythrocytes was increased in all patients with hypertension and in none of the normotensive controls. Hill plots derived from in vivo activation curves for erythrocytic Na+ - L i + countertransport showed that the normotensive participants had a Hill slope of 1 (SD 0.1), whereas the hypertensives had a Hill slope of 3.2 (SD 1.0).The activity of the Na+-Li+ countertransport system is increased in untreated essential hypertension in vivo; this confirms in vitro findings. A new finding is that there is a change in either the stoichiometry or the co-operativity of lithium efflux via the Na + - L i + countertransport system, suggesting that the rate of sodium efflux may be greater than that of influx in the cells of people with hypertension.