European Journal of Clinical Investigation (1981) 11, 337-339

EDITORIAL

Hypertension as a membrane disease

Hypertension results essentially from an increased peripheral resistance which is related to some func- tional alteration of the vascular smooth muscle cells and to structural changes reducing the arterial lumen.

The functional changes, comprising an increase in tone and in reactivity to vasoactive agents, precede the structural modifications, suggesting that hypertension could originate in some primary change of contractile cells.

On the other hand, one must take into account the hypertensive effect of Na+ excess which is firmly established by a series of clinical, epidemiological and experimental observations [ 13.

The analysis of the mechanism of hypertension therefore implies elucidation of the molecular changes of the blood vessel musculature as well as the interac- tion of Na+ ions at this level.

Role of the intracellular sodium. The absence of any significant alteration of extracellular volume in essen- tial hypertensives is an additional argument suggesting that investigations should be conducted at the intracel- lular level.

Twenty years ago, Losse and his colleagues recorded the first observation of an alteration of cell Na+ handling. Na+ concentration was found to be in- creased in red cells of hypertensive patients and in some of their offspring [2]. This observation was confirmed and extended to white blood cells, particu- larly to lymphocytes.

A Na+,Ca2+-exchange mechanism operates in the membrane of many cells, particularly in excitable cells [3]. An increased intracellular Na+ content therefore determines in turn an elevation of the intracellular free Ca2+ level. In contractile tissues this is the ultimate molecular event triggering the shortening of contrac- tile proteins.

The overall result of increased intracellular Na+ and the subsequently increased intracellular Ca2+ is there- fore an elevation of blood pressure.

In the present editorial we would like to propose that hypertension stems from some abnormality in the primary membrane mechanisms affecting intracellular Na+ homeostasis. The various alterations hitherto described at the membrane level will be analysed first and a hypothesis will be proposed as to their role in the pathogenesis of hypertension.

The concentration of extracellular Na+ is 14G145

0014-2972/8 1 / 10OO-0337$02.00 0 1981 Blackwell Scientific Publications

mmol/l whereas that of intracellular Na+ ranges between 7 and 10 mmol/l. The passive downhill movement of Na+, leading to its entry into the cells, is permanently corrected by active mechanisms extrud- ing Na+ against the concentration gradient.

A Na+ pump extruding three ions of intracellular Na+ in exchange for two ions of extracellular K+ has been described in membranes of all tissues investigated so far. Its energy is provided by the hydrolysis of ATP secondary to the activity of an enzyme, the Na+,K+- ATPase. Ouabain is a selective inhibitor of the Na+ Pump.

Another pathway has recently been described, con- sisting of an outward Na+,K +-cotransport which derives its energy from the transmembrane K + gra- dient. For this reason, the system is called a dissipator. Its stoichiometry is such that one Na+ ion is coupled to one K + ion. This system is inhibited by the diuretics furosemide and bumetanide.

The respective functional importance of the Na+ pump and the Na+,K+-cotransport is not fully under- stood. However, the number of Na+ ions extruded at V,,, is 8-10 times higher with the Na+ pump than with the cotransport, suggesting that the pump is the main physiological regulator and that the cotransport oper- ates mainly in the case of a Na+ load [4].

I t is clear that an increased intracellular Na+ content can be secondary to one or several of the following abnormalities: (i) a membrane leak increas- ing passive Na+ influx, (ii) a reduction in the activity of the Na+,K+-pump, (iii) a reduction of the outward Na + ,K+-cotransport.

An increased passive permeability has been observed in red blood cells of spontaneous hyperten- sive rats (SHR) and in the hypertension-prone sub- strain of Sabra rats, but not in erythrocytes of hypertensive patients. A decreased activity of the Na+,K+-pump has been described in erythrocytes [5] and leucocytes [6], but other investigators using differ- ent techniques could not confirm these findings. On the contrary, the V,,, of the pump appeared to be increased in some cases [7]. Several groups of workers have shown that at low intracellular Na+ concentra- tions, the activity of the outward Na+,K+-cotransport is reduced in a large number of essential hypertensives as compared to normotensive controls devoid of any family history of hypertension (Table I).

The following results were obtained in our labora- tory: (i) the Na+,K+-cotransport is reduced in 80% of essential hypertensives as compared to normotensive controls; (ii) the familial distribution of the Na+,K+-

337

338 EDITORIAL

Table 1. Outward Na+,K+-cotransport in essential hypertension

Investigator Normotensive controls Essential hypertensives

Dagher & Garay (Paris, 1980) 206 f I07 (34) Cusi et al. (Milan, 1981) 453+ 145 (24) 292 I57 (45) Ghione et at. (Pisa, 1981) 276 f 162 (9) Davidson (Capetown, 1981) 432f182(1l) 198f 150 (9) Brunois (Reims, 1981) 584+ 196 (24) 234 f 85 (27) Herubel (Rouen, 1981) 580f200 (18) 194+ I14 (7) Meckler & Ben-Ishay (Jerusalem, 1981) 416f 170 (12) Garay el al. (Paris, 1981) 496+ 125 (71)

472 f 1 I2 (22)

394f201 (9)

351 +224 (24) 200 f 1 10 (80)

Values are mean f S D of the N a + component of outward Na+,K+-cotransport and are expressed in prnoles x I cells-' x h- ' .

These results were reported at the Symposium 'Genetic Markers in Essential Hyperten- sion', a satellite meeting of the 8th Scientific Meeting of the International Society of Hypertension, held in Hbpital Necker, Paris, 25-27 May 1981. The proceedings are published in a special issue of Clinical and Experimenfal Hypertension (1981).

cotransport reduction follows the pattern of a genetic dominant and autosomic trait; (iii) the Na+,K+- cotransport reduction appears to be specific for hyper- tension [8,9]. Different results were obtained at higher intracellular Na+ concentrations [lo]. This discre- pancy can be explained by kinetic analysis indicating that the abnormality found in essential hypertension lies in a reduction of the apparent affinity for intracel- lular Na'..

A reduced Na + ,K + -cotransport has also been observed in the erythrocytes of SHR rats [ l l ] . This finding underlines clearly the linkage between the membrane abnormality and primary hypertension.

The increase in intracellular Na+ following an acute or chronic Na+ load is much more marked in erythro- cytes of SHR rats than in the WKY controls. and the most likely explanation is that this effect results partially at least from the reduction in cotransport activity [ 121.

Sodium hundling in tissues other than blood cells. As explained above, a membrane dysfunction similar to that described in erythrocytes, leading to a poor tolerance to a Na+ load, could induce changes in vascular smooth muscle leading to hypertension. Some evidence that Na+ handling is impaired in arteries of SHR has already been obtained [13], and a recent investigation performed on cultured myocytes has shown a reduction in the Na+-cotransport activity in cells derived from genetically hypertensive rats [ 141.

The results of these experiments require confirma- tion. However, several observations indicate the pre- sence in various tissues of membrane alterations similar to those described in erythrocytes, such as a reduction in Ca2+ binding on the inner side of the plasma membrane, changes in phosphoinositides, and variations in membrane viscosity. All appear to be specific for primary hypertension and transmitted genetically.

Hypothesis. Our hypothesis is that the primary defect in hypertension could consist of a genetically

transmitted membrane change impairing the intracel- lular Na+ homeostatic mechanisms which normally compensate a Na+ load. In excitable cells, an increase in intracellular Na+ concentration via the Na+,K +

exchange could be responsible for the rise in blood pressure according to the mechanism discussed above occurring in the myocardium, the peripheral arteries and possibly the sympathetic nervous system.

This hypothesis is compatible both with the heredi- tary nature of hypertension and with the hypertenso- genic effect of excess salt intake. Without the environ- mental factor (Na+ excess), the genetic factor (mem- brane defect) remains silent; without the predisposing genetic factor, Na+ excess does not cause a rise in blood pressure. Detection of the membrane change in accessible cells such as erythrocytes may thus be of use in organizing a selective prevention based upon the detection of a marker of a genetic predisposition to develop hypertension.

The mono- (or oligo-) genic transmission of the membrane defect may, at first, appear to be in contradiction with the continuum of the blood pres- sure distribution curves. It must be emphasized again that the membrane alteration is only a permissive factor. The shape of the curve may reflect the complex- ity of the interaction between genes and environment. In addition, despite what is generally believed, the curve of blood pressure distribution does not have the aspect of a normal Gaussian curve.

The pathogenic role of the kidney has been demon- strated in various cross-transplantation experiments performed between genetically hypertensive rats and their corresponding normotensive controls. It has been suggested that a natriuretic factor elaborated by the kidney may be involved in the pathogenesis of hyper- tension, as this factor appears to inhibit the Na+ pump and accordingly to enrich the intracellular content in Na+ [15]. However, no significant reduction of Na+,K+-ATPase has been observed in any tissue of spontaneously hypertensive rats.

Conversely, one may suggest that the kidney partici-

EDITORIAL 339

pates in the mechanism of the disease via a membrane dysfunction which is similar to that reported in other tissues.

The actual knowledge of the renal Na+,K+-cotrans- port is poor, and the effect of its reduction in tubular cells is not predictable. However, in renal arterioles, this reduction could be responsible for the increase in tone which is characteristic of primary hypertension.

PHILIPPE MEYER RICARDO P. GARAY

INSERM U7ICNRS LA 318 Dhpurtement de Nhphrologie, H6pitul Necker, 161 rue de SPvres, 75015 Puris, France

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