Opposite COX‐2 effects on blood pressure and renal hemodynamics during early and late Angiotensin II‐infused hypertension

COX‐2, unlike COX‐1, opposes angiotensin II (AngII) actions on renal hemodynamics and blood pressure (BP). It remains unclear if an altered balanced between the COX isoforms promotes AngII‐dependent hypertension. Therefore, we explored the COX‐2 renoprotective and anti‐hypertensive roles in the pre‐hypertensive and hypertensive phases of AngII‐infusion. Clearance experiments were performed in anesthetized rats after 3–5 days (pre‐hypertensive; n=10) or 13–14 days (hypertensive; n=8) of AngII‐infusion (80 ng/kg/min). In the pre‐hypertensive phase COX‐2 inhibition with nimesulide (NMS) decreased GFR (1.08±0.09 to 0.77±0.09 ml/min/g) and RBF (6.29±0.71 to 5.37±0.49 ml/min/g) but not BP (115.0±4.2 to 110.3±3.6 mmHg). Subsequent COX‐1 inhibition with SC‐560 decreased BP (94.4±4.4 mmHg) but not GFR or RBF. In the hypertensive phase, NMS lowered BP (140.4±7.4 to 124.9±8.6 mmHg), GFR (0.93±0.09 to 0.65±0.07 ml/min/g) and RBF (7.65±0.71 to 6.10±0.56 ml/min/g) and raised renal vascular resistance. Subsequent SC‐560 lowered BP (114.5±10.2 mmHg) but not GFR and RBF. SC‐560 decreased pre‐hypertensive phase BP more than NMS (−14.5±2.7% vs. −2.3±0.9), but the isoforms similarly affected hypertensive phase BP. NMS lowered RBF more during the hypertensive than pre‐hypertensive phase (−19.9±2.9% vs. −13.8±2.2%) and lowered cortical blood flow more than SC‐560 (−14.1±3.0% vs. −4.1±3.8%). These data indicate COX‐1 consistently elevates BP without affecting hemodynamics. In contrast AngII‐dependent hypertension involves augmented COX‐2 prohypertensive systemic effects despite increased renoprotective vasodilation opposing intrarenal AngII.