The physiological mechanisms through which COX-2 inhibitors increase blood pressure are gradually being elucidated. Experimental evidence from animal models suggests an important vasodilator role for endogenous COX-2–derived prostaglandins, reducing the systemic pressor effects of angiotensin II. 6 These findings underscore the importance of COX-2 activity in regulating the tone of peripheral resistance vessels. COX-2, but not COX-1, inhibition also reduces renal medullary blood flow and urine salt excretion, 6 which is in agreement with clinical studies in humans showing COX-2 inhibition impairs renal salt excretion. 7 As a consequence of COX-2 inhibition, the combined increase in peripheral activity of pressors (like angiotensin II) and reduced renal salt excretion likely conspire to predispose humans to hypertension.

The precise cellular sources of the COX-2–derived products promoting vascular dilator tone and renal salt excretion remain uncharacterized. In the kidney, COX-2 expression is restricted to 2 main cellular compartments: the macula densa with surrounding cortical thick ascending limb8 and renal medullary interstitial cells. 9, 10 In this issue of Hypertension, Zewde and Mattson provide evidence that focuses attention on the renal medulla as the important intrarenal site of endogenous COX-2 activity protecting against the development of systemic hypertension. 11 These investigators report that when animals were placed on a high-salt diet, selective intramedullary infusion of a COX-2 inhibitor or COX-2 antisense oligonucleotides caused animals to develop hypertension. Because renal medullary COX-2 is primarily expressed in medullary interstitial cells, 6, 9 the study by Zewde