20-HETE REQUIRES INCREASED VASCULAR TONE TO CONSTRICT RABBIT AFFERENTARTERIOLES

Renal production of 20-hydroxyeicosatetraenoic acid (20-HETE), a cytoc hrome P-450-dependent arachidonate metabolite, increases during develo pment of hypertension in spontaneously hypertensive rats, and inhibiti on of its production prevents hypertension. Since 20-HETE is a potent vasoconstrictor, these findings suggest that 20-HETE may contribute to the development of hypertension by elevating renal vascular resistanc e. In this study we examined the direct action of 20-HETE on the affer ent arteriole, a vascular segment crucial to the control of renal vasc ular resistance. Rabbit afferent arterioles were microperfused at 60 m m Hg in vitro, and 20-HETE was added to the lumen. Although 20-HETE (1 0(-10) to 10(-6) mol/L) had no effect on the diameter of nontreated af ferent arterioles (n=6), it caused dose-dependent constriction when va scular tone was increased with norepinephrine (0.3 mu mol/L); 20-HETE at 10(-6) mol/L decreased diameter by 43+/-4% (n=6, P<.001). This cons triction was abolished by disrupting the endothelium (n=5). Moreover, pretreatment with the cyclooxygenase inhibitor indomethacin (50 mu mol /L) or the thromboxane/endoperoxide receptor antagonist SQ29548 (1 mu mol/L) significantly (P<.03) attenuated 20-HETE-induced constriction: 20-HETE at 10(-6) mol/L constricted norepinephrine-treated afferent ar terioles by 28+/-3% (n=6) and 25+/-4% (n=5), respectively. These resul ts demonstrate that an increase in afferent arteriolar tone is require d for the vasoconstrictor action of 20-HETE, which is partly mediated by the endothelial cyclooxygenase pathway. Thus, increased production of 20-HETE in the kidney and increase in afferent arteriolar tone, bot h of which often precede the development of hypertension, may synergis tically contribute to the development of hypertension by elevating ren al vascular resistance.