THE ROLE OF 20-HYDROXYEICOSATETRAENOIC ACID IN PREVENTING SALT INDUCED HYPERTENSION
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While there is a definite, positive correlation between salt intake and blood pressure, most animals and humans do not become hypertensive when exposed to high salt. Some however are "salt-sensitive". Sprague-Dawley (S-D) rats are generally considered to be salt-resistant, but when young may be more salt-sensitive. 20-hydroxyeicosatetraenoic acid (20-HETE), am- hydroxylated metabolite of arachidonic acid which is formed by the action of cytochrome 450 4A (CYP 4A) enzymes may be important in excreting a sodium load. Clofibrate, a lipid lowering agent and a peroxisome proliferator activated receptor a agonist induces CYP 4A and increases the renal synthesis of 20-HETE, and prevents hypertension in Dahl salt-sensitive rats. Based on the above, we hypothesized that when given a high salt intake, adult (52weeks of age) S-D rats would increase renal 20-HETE synthesis, and excrete the sodium load. In contrast, the young (5weeks of age) S-D rats would be unable to increase renal 20-HETE production, and therefore retain sodium and develop hypertension. Clofibrate should increase CYP 4A expression and 20-RETE synthesis in young animals. Groups of young rats were randomly assigned to receive either vehicle (20 mM Na2C03) or 0.9010 NaCI (saline) and half the number of animals in each group received clofibrate (80 mg/d) for three weeks. Adult rats were given either vehicle or saline to drink. Most parameters were measured after three weeks of treatment. Saline, but not vehicle induced a modest increase in blood pressure only in young rats (134± 2vs. 115± 2 mmHg, p<O.OOI). Clofibrate did not affect blood pressure in the vehicle treated group. Interestingly, clofibrate not only prevented the increase in blood pressure in saline treated rats but demonstrated a hypotensive effect: blood pressure was lower than that seen in controls (102± 2 mmHg). A high salt intake increased CYP 4A mRNA expression in the renal cortex in the adult rats and increased 20-HETE excretion. Younger animals showed decreased CYP 4A message and decreased urinary 20-HETE excretion. Clofibrate induced CYP 4A expression in the renal cortex of the saline treated young rats, and increased urinary 20-HETE levels. High salt intake also led to increased sodium retention, proteinuria and vascular super oxideanion production and decreased plasma total nitrite/nitrate levels in the young but not in the adult rats, all of which were prevented by clofibrate. Thus failure to increase renal synthesis of 20-HETE in the saline treated young rats led to sodium retention and hypertension which was prevented by clofibrate treatment. The adult rats increased renal 20-HETE synthesis on a high salt intake which aided in the excretion of sodium and prevented hypertension. We conclude that renal 20-HETE synthesis is important in excreting a sodium load. Failure to increase 20-HETE production may lead to salt-induced hypertension.