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Androgen-induced activation of 20-HETE production may contribute to gender differences in blood pressure regulation

Physiology and Pharmacology, University of Southern Denmark, DK-5000 Odense, Denmark

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GENDER-SPECIFIC DIFFERENCES in blood pressure and susceptibility to cardiovascular morbidity have led to a search for possible effects of sex hormones on cardiovascular function. As an example, blood pressure in male spontaneously hypertensive rats (SHR) is higher than that of females. Early castration or blockade of androgen receptors attenuates the development of hypertension, and, conversely, testosterone treatment increases blood pressure in ovariectomized females and castrated males (8, and references therein). Ovariectomy of female SHR does not result in altered blood pressure. Androgens therefore seem to be a significant risk factor. The same picture has emerged in humans, where blood pressure is higher in age-matched men than in women and where estrogens do not reduce blood pressure or protect against cardiovascular morbidity, whereas conditions with elevated androgen production in women are associated with increased risk (8).

Arachidonic acid is metabolized by cyclooxygenases into prostaglandins, prostacyclin, and thromboxane A₂ and by lipoxygenases into leukotrienes. Capdevila et al. (1) opened what has been called a Pandora's box (5) by showing that arachidonic acid also is metabolized by enzymes of the cytochrome P-450 family. This led to identification of a large number of biologically active molecules [see extensive review by Roman (9)]. The most abundant metabolites are 20-HETE, which is generated by CYP enzymes with -hydroxylase activity, and epoxyeicosatrienoic acids (EETs), generated by CYPs acting as epoxygenases. In the renal, coronary, and cerebral vasculature, cytochrome P-450-induced EET acts as an endothelium-derived hyperpolarizing factor. It diffuses into the smooth muscle cells, where it activates calcium-activated potassium channels (K_Ca), leading to hyperpolarization and relaxation (9). Conversely, stretch causes the vascular smooth muscle cells to metabolize arachidonic acid by the -hydroxylase CYP 4A pathway into 20-HETE, which inhibits K_Ca, thereby causing depolarization and contraction, e.g., in renal arterioles (9, 12). The ability of 20-HETE to cause vasoconstriction is likely to be prohypertensive, but in the kidney 20-HETE also has antihypertensive properties because it promotes salt excretion through inhibition of the Na-K-ATPase and NaK-2Cl cotransporter. In certain conditions, 20-HETE promotes vasodilation, probably after conversion by cyclooxygenase to vasodilatory prostaglandins (2, 9). The effect of 20-HETE on blood pressure may therefore vary and be dependent on the conditions studied.

On the basis of the observations that 20-HETE caused vasoconstriction, that the expression of CYP4A -hydroxylases correlated to development of hypertension in the SHR, and that inhibitors of -hydroxylases reduced blood pressure in the SHR (10, 11), it has been suggested that an increase in -hydroxylase activity plays a role in the pathophysiology of hypertension in this rat model (5). In the DOCA-salt hypertensive model the picture is less clear, because 20-HETE has been suggested to be associated with either aggravation (7) or prevention of development of hypertension (4).

In a recent study, gene targeting was used to delete the mouse CYP 4A14 enzyme (3). This CYP isoform is closely related to the rat CYP4A2 and CYP4A3 -hydroxylases, but the mouse CYP 4A14 enzyme catalyzes lauric acid oxidation, and it is not involved in arachidonic acid metabolism. The intriguing observation was that, in male mice, the plasma androgen concentration doubled, the CYP 4A12 enzyme was induced and caused -hydroxylation of arachidonic acid and formation of 20-HETE, and the animals became hypertensive. Castration prevented the blood pressure increase and enzyme induction, and androgen replacement restored the hypertension and CYP 4A12 enzyme activity. Although the link between CYP4A14 deletion and stimulation of androgen production is unknown, the observation provides a hitherto unknown link between sex hormones, P-450 -hydroxylases, and blood pressure.

In the present issue of American Journal of Physiology, Regulatory, Integrative and Comparative Physiology, Nakagawa et al. (6) expand these observations to the rat. They show that treatment of Sprague-Dawley rats with 5-dihydrotestosterone (DHT) increases the activity of the renal arachidonate -hydroxylases and the biosynthesis of 20-HETE both in kidney microsomes and in microdissected preglomerular blood vessels, whereas there is a marked reduction in renal epoxygenase activity. Treatment for 2 wk increases systolic blood pressure in male and female rats by 46 and 57 mmHg, respectively. Treatment with DHT had only minimal effects on the overall rates of arachidonic acid metabolism by male or female kidney microsomes, but the treatments were associated with an increase in the expression of the -hydroxylase CYP4A8 mRNA and a decrease in the expression of CYP4A1, which had epoxygenase activity. These results are clearly consistent with the hypothesis that androgen-induced activation of 20-HETE production may lead to increased blood pressure.

Taken together, these studies have identified a new link between androgens and blood pressure regulation, which may contribute to the association between gender, sex hormones, and hypertension, suggested both by animal studies and epidemiological studies in humans.

	FOOTNOTES

Address for reprint requests and other correspondence: O. Skøtt, Physiology and Pharmacology, Univ. Southern Denmark, Winsløwparken 21, DK-5000 Odense, Denmark (E-mail: oskott{at}health.sdu.dk).

10.1152/ajpregu.00768.2002

	REFERENCES

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