The elevation of Vmax of red cell Li/Na exchange in some hypertensives and in their normotensive offspring is mainly accounted for by genetic factors. In order to understand the pathophysiological meaning of this finding, we have studied if it is an operational mode of H/Na exchange, a transport system involved in the regulation of cell pH in vascular and kidney cells. To define the relationship of the Li/Na exchange to the H/Na exchange pathway, we have investigated the kinetic effects of internal and external H+ on H/Na, H/Li, and Li/Na exchange. These three exchange modes have highly asymmetric affinities for H+ much greater than Li+ greater than Na+, are activated by internal H+ (Hi) with a high "Hill coefficient" (n = 2.5), and competitively inhibited by external H+ (Ho). Moreover, cell Li activates H/Na exchange while being transported by Li/Na exchange at a lower rate than Hi. These observations support the conclusion that Li/Na exchange is a mode of operation of H/Na exchange. Li+ discriminates better than cell H+ between regulatory and transport sites in red cells of normotensive subjects. Kinetic studies of H/Na exchange in red cells of hypertensive subjects with high Li/Na exchange indicate that the Vmax of both pathways are not linearly related. Thus, Li/Na exchange does not measure the number of Na/H sites but assesses the occupancy of an internal site. We found that H/Na exchange in hypertensive subjects has a reduced Hill coefficient for the cell pH dependence of Na influx, which is interpreted as a defective Hi regulatory site.(ABSTRACT TRUNCATED AT 250 WORDS)