Renal Medullary Infusion of CoPP Prevents Angiotensin‐II Dependent Hypertension in Mice

Several studies have established systemic induction of Heme Oxygenase‐1 (HO‐1) as a viable means of attenuating the development of hypertension in several experimental models. However, the precise mechanism behind the anti‐hypertensive actions of HO‐1 induction is still unclear. In this study, we tested the hypothesis that kidney specific induction of HO‐1 can prevent the development of Ang‐II dependent hypertension. To test this hypothesis, renal medullary interstitial catheters were implanted into the left kidney of uninephrectomized mice. Infusion of a known inducer of HO‐1, cobalt protoporphyrin (CoPP; 250 μg/ml; at 50 μl/hr for 48hrs), resulted in significant induction of HO‐1 mainly in the renal medulla when examined 2 weeks after the infusion with no induction observed in other organs such as the brain, heart, and liver. Next, we examined the effect of this approach of inducing of HO‐1 on the development of Ang II dependent hypertension. CoPP or Vehicle (0.1 M NaOH, pH 8.3) was infused as indicated above 2 days prior to implantation of an osmotic minipump which delivered Ang II at a rate of 1 μg/kg/min. Mean arterial pressure (MAP) was measured in conscious, unrestrained mice for 3 consecutive days starting 7 days after the implantation of the Ang II minipumps. MAP averaged 112 ± 4, 121 ± 4, 162 ± 2 and 126 ± 6 mmHg in Vehicle + Vehicle, CoPP + Vehicle, Vehicle + Ang II and CoPP + Ang II treated mice respectively (n=6). These results suggest that renal medullary infusion of CoPP to induce HO‐1 specifically in the kidneys can prevent the development of Ang II dependent hypertension in mice. Induction of HO‐1 in the renal medulla may be the mechanism by which systemic delivery of CoPP lowers blood pressure in Ang‐II dependent hypertension.