Enhanced renal microvascular reactivity to angiotensin II in hypertension is ameliorated by the sulfonimide analog of 11,12-epoxyeicosatrienoic acid

Objectives Epoxygenase metabolites produced by the kidney affect renal bloo d flow and tubular transport function and 11,12-epoxyeicosatrienoic acid (1 1,12-EET) has been putatively identified as an endothelium-derived hyperpol arizing factor. The current studies were performed to determine the influen ce of 11,12-EET on the regulation of afferent arteriolar diameter in angiot ensin Ii-infused hypertensive rats. Materials and methods Male Sprague-Dawley rats received angiotensin II (60 ng/min) or vehicle via an osmotic minipump, Angiotensin II-infused hyperten sive and vehicle-infused normotensive rats were studied for 2 weeks followi ng implantation of the minipump, Renal microvascular responses to the sulfo nimide analog of 11,12-EET (11,12-EET-SI) and angiotensin II were observed utilizing the in-vitro juxtamedullary nephron preparation. Renal cortical e poxygenase enzyme protein levels were quantified by Western blot analysis, Renal microvessels were also isolated and epoxygenase metabolite levels mea sured by negative ion chemical ionization (NICl)/gas chromatography-mass sp ectroscopy. Results Systolic blood pressure averaged 118 +/- 2 mmHg prior to pump impla ntation and increased to 185 +/- 7 mmHg in rats infused with angiotensin II for 2 weeks. Afferent arteriolar diameters of P-week normotensive animals averaged 22 +/- 1 mum. Diameters of the afferent arterioles were 17% smalle r in hypertensive rats (P < 0.05); however, arterioles from both groups res ponded to 11,12-EET-SI (100 nmol) with similar 15-17% increases in diameter . As we previously demonstrated, the afferent arteriolar reactivity to angi otensin II was enhanced in angiotensin II-infused animals. Interestingly, e levation of 11,12-EET-SI levels to 100 nmol reversed the enhanced vascular reactivity to angiotensin II associated with angiotensin II hypertension. R enal microvascular EET levels were not different between groups and average d 81 <plus/minus> 9 and 87 +/- 13 pg/mg per 30 min in normotensive and hype rtensive animals, respectively. Renal cortical microsomal levels of the epo xygenase CYP2C23 and CYPSC11 proteins were also similar in normotensive and angiotensin II hypertensive rats. Conclusions Taken together, these data support the concept that renal micro vascular 11,IP-EET activity and levels may not properly offset the enhanced angiotensin II renal vasoconstriction during angiotensin II hypertension. J Hypertens 19:983-992 (C) 2001 Lippincott Williams & Wilkins.