Abstract 413: Renal Cyclooxygenase-2 Expression And Hemodynamic Role During Angiotensin II-dependent Hypertension

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Intrarenal cyclooxygenase-2 (COX-2) activity is increased during activation of the renin-angiotensin-system (RAS) increasing synthesis of prostaglandin E2 (PGE2) and buffering the vasoconstrictor and antinatriuretic effects of angiotensin II (AngII). While AngII upregulates intrarenal COX-2 expression, it remains unclear if this occurs in a time-dependent manner, thereby impacting renal hemodynamics differently during the early and late phases of the development of high blood pressure in AngII-induced hypertension. Male Sprague-Dawley rats were infused with AngII (0.4 μg/min/kg). Systolic blood pressure (SBP), COX-2 expression and PGE2 tissue content and urinary excretion were evaluated at day 3, 7 and 14 of the AngII infusions. In acute studies we evaluated the effects of COX-2 inhibition at day 5-7 and day 14 on renal hemodynamic parameters. Chronic AngII infusions increased SBP from day 7 through 14: 162 ± 5 mmHg; and 198 ± 15 mmHg versus controls: 114 ± 10 mmHg; P<0.05. COX-2 mRNA and protein levels were high in kidney cortex only at day 3 (mRNA: 241 ± 56%, protein: 160 ± 21%, P<0.05 versus controls). Medullary COX-2 mRNA and protein were increased on days 3 (mRNA: 176 ± 20%, protein: 185 ± 32%, P<0.05 versus controls), 7 (mRNA: 189 ± 23%, protein: 158 ± 15%, P<0.05 versus controls) and 14 (mRNA: 148 ± 15%, protein: 135 ± 13%, P<0.05 versus controls). Urinary and medullary PGE2 increased by day 3 and remained elevated during days 7 and 14. COX-2 inhibition decreased GFR and renal blood flow in AngII infused rats during both the early and late phases. Interestingly, COX-2 inhibition decreased mean arterial blood pressure at day 14 of AngII-infusion (COX-2 inhibition: 124 ± 9 versus 140 ± 7 mmHg, P<0.05) but not during the early normotensive phase (COX-2 inhibition: 110 ± 4 versus 115± 4 mmHg, P=NS). These results indicate that enhanced medullary COX-2 expression and PGE2 production during both the early and late phases attenuates the effects of AngII on renal hemodynamics. However COX-2 inhibition at day 14 reduced blood pressure, suggesting that a vasoconstrictor COX-2 metabolite contributes to the hypertension during the late phase.

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