20-HETE and circulating insulin in essential hypertension with obesity

Analogous to observations in Dahl salt-sensitive (SS) rats, we have shown that 20-hydroxyeicosatetraenoic acid (20-HETE) is involved in the pathogenesis of SS essential hypertension. A strong negative correlation between urine 20-HETE and body mass index (BMI) remains unexplained. We measured BP, urine sodium (UNaV), and 20-HETE in obese hypertensive subjects during a 24-hour salt load (160 mmol NaCl diet+2 L intravenous saline). We classified them into insulin-resistant (IR) (n=14) and insulin-sensitive (IS) (n=12), with the average insulin sensitivity index (SI=22.5x[fasting glucose x insulin](-1)) of 3 days (cutoff for IR, SI <0.161 mL x L/microU x mmol). IR were older (50+/-1 versus 44+/-2, P<0.03), more obese (BMI 38.2+/-1.4 versus 32.0+/-1.5 kg/m2, P<0.01), and had higher insulin (39.2+/-2.3 versus 22.0+/-1.1 microU/mL, P<0.0001) and lower SI (0.084+/-0.009 versus 0.222+/-0.013, P<0.0001) than IS. Blood pressure, UNaV, and sodium balance did not differ between groups. SI correlated negatively with age (r=-0.39, P<0.05) and BMI (r=-0.53, P<0.01). Urine 20-HETE was less in IR than in IS when normalized by serum insulin (0.91+/-0.25 versus 2.24+/-0.46 microg. 24 hours(-1)/microU x mL(-1), P<0.02), but not if uncorrected. Urinary 20-HETE excretion correlated negatively with insulin (r=-0.40, P<0.04), whereas the relationship between 20-HETE and SI was not statistically significant. Our data suggest that increased circulating insulin, not the state of insulin resistance, suppresses urine 20-HETE excretion in obese hypertensive subjects. Findings in experimental models suggest that an inhibitory effect of insulin on cytochrome P4504A, rather than effects of insulin on membrane-bound arachidonic acid or on its release to the cytosol, may explain our observation.