Studies of plasma membrane function in human hypertension.

Considerable evidence has emerged in recent years to suggest that the cell plasma membrane handles univalent and divalent cations abnormally in patients with untreated essential hypertension. Many of the phenomena originally discovered in patients with the established disease have now been found to occur in the genetically hypertension-prone offspring of hypertensive patients when their blood pressure is normal. The studies described in this thesis were designed to investigate the mechanisms which might explain these disturbances of membrane function. The first experiments were performed to investigate whether a circulating blood-borne factor might be present in excess in hypertensive patients and their relatives and by exposing cells from subjects with normal blood pressure and no family history to serum from patients and their offspring, the object was to try and reproduce the findings in hypertension. These studies were negative. Because of many reports of an overactive sympathetic nervous system in hypertension leucocytes were exposed to noradrenaline and this was found to influence sodium transport in cells from control subjects suggesting that at least some of the phenomena described in hypertension might be related to autonomic dysfunction. An alternative hypothesis to explain these abnormalities is that there is a genetically predetermined disturbance of the physicochemical structure of the plasma membrane which alters its function. The abnormality might well lie within the lipid fraction of the cell membrane. Attempts to alter this were undertaken using changes in dietary fat intake. These lowered blood pressure slightly and indeed altered sodium influx. The final series of experiments involved detailed examination of one fraction of plasma membrane phospholipids which is highly metabolically active, namely the phosphoinositides, and indeed using red cells it was possible to demonstrate that these lipids are overactive in the early stages of hypertension. These findings suggest that the plasma membrane is structurally abnormal in hypertension, the abnormality may reside in the phospho- inositide lipids and may possibly be susceptible to dietary manipulation.