The Li+-Na+ exchange and Na+-K+-Cl- cotransport systems in essential hypertension.

Abstract

SUMMARY This review examines the physiological functions of the Li + -Na + exchanger and Na + -K+-CI" cotransport system in human red blood cells. Both transporters are family aggregated and determined mainly by genetic factors; they are present in kidney and vascular cells, where they are regulated by vasoactive substances. To assess the physiological function of these two transporters, we investigated their kinetic and equilibrium properties, and their modulation by vasoactive substances. Recent studies in red blood cells indicate that the Li + -Na + exchanger may be a mode of operation of the Na + -H + exchanger, which plays an important role in the regulation of cell pH, cell volume, and transtubular sodium transport. In vascular cells, Na + -H + exchanger is modulated by vasoconstrictors such as growth factors and angiotensin, while Na + -K + -Cl~ cotransport is modulated by vasodilators such as atrial natriuretic factor and bradykinin. Kinetic studies in red blood cells of hypertensive patients and their offspring indicate the presence of subsets with elevated V,,^ of Li + -Na + exchange or high K m for cell sodium for outward Na + -K + -Cl~ cotransport. The latter alteration is found most frequently in young blacks born of hypertensive parents, and it appears to be dependent on their level of sodium intake. The relationship between the alterations of the red blood cell sodium exchanger and Na + -K + -CI~ cotransport and risk factors for hypertension indicates that they can provide a tool to examine the interaction of genetic, hormonal, and environmental factors in human hypertension. 1. To define their physiological function and mechanism of regulation by studying their kinetic, equilibrium properties, and modes of operation. 2. To provide a tool for the study of genetic and environmental interactions in the etiology of human essentiaJ hypertension. 3. To assess whether alterations of these transporters in patients with essential hypertension may be due to a) differences in the number of transport sites; b) differences in the K m of the transport protein, which can alter their function; or c) differences in their modulation by vasoactive substances and/or growth factors.

Correlates of sodium-lithium countertransport. Findings from the Gubbio Epidemiological Study. The Gubbio Collaborative Study Group.

“…Volume and pH regulatory actions of the Na+-H exchange system in smooth muscle cells could influence vascular reactivity and therefore peripheral vascular resistance. 23 The Gubbio data confirm the previously reported independent association between plasma uric acid and countertransport in men24 and expand this finding to women. This association could be an indication of a direct relation between Na-Li CT in red blood cells and renal proximal tubular absorption of uric acid.…”

Mixture analysis of erythrocyte lithium-sodium countertransport and blood pressure.

“…We can offer no explanation for the cause of this correlation, as the mechanisms relating high RBC Li + -Na + countertransport and hypertension are still uncertain, but the finding of a significant inverse relation in the subgroup with higher MAP provides further support for the contention that Li + -Na + countertransport or an analog system is intimately linked to the pathophysiological basis of hypertension in some individuals. In this regard, the recent observations reported by Canessa et al 27 that RBC Li + -Na + countertransport may be a mode of Na + -H + exchange and by Livne et al 28 that platelet Na + -H + exchange is increased in essential hypertension suggest that abnormalities of the ubiquitous transmembrane Na + -H + exchange may be a fruitful area for future research into the cellular mechanism causing human hypertension.…”

Red blood cell lithium-sodium countertransport in the tecumseh blood pressure study.

“…Yap 34 it seems that the regulatory defect causing an increased \ mtI for Li + r Na + 0 countertransport in essential hypertension is intracellular, and it has been suggested that measurements of Li + influx and efflux may not be congruent. 37 In addition, our patients were younger, had milder hypertension and presumably had less severe left ventricular hypertrophy, since we used echocardiographic measurements while Yap et al 35 applied electrocardiographic criteria. Thus, the two studies may not be strictly comparable, and although it appears that in our study, in patients at the earliest stage of hypertension, an elevated V^ for RBC Li + -Na + countertransport is not associated with left ventricular hypertrophy, it remains possible that as blood pressure rises, the course of progression of hypertrophy may be different.…”