Cyclooxygenase-2 inhibition decreases renin content and lowers blood pressure in a model of renovascular hypertension

It has been proposed that the macula densa participates in the regulation o f increased renin expression in renovascular hypertension (RVH) and that pr ostaglandins may be among the mediators of macula densa function. We have p reviously shown that in renal cortex, cyclooxygenase-2 (COX-2) expression i s localized to the macula densa and surrounding cortical thick ascending li mb and increases in high-renin states, such as salt restriction and angiote nsin-converting enzyme inhibition. In the present studies, we examined the effect of the selective COX-2 inhibitor SC58236 on plasma renin activity (P RA) and renal renin expression in: RVH in rats. The aorta was coarcted betw een-right and left renal arteries, and animals received either SC58236 or v ehicle for 1 week. At day 8, vehicle-treated coarcted rats were hypertensiv e (mean carotid arterial blood pressure: 138+/-3 versus 87+/-2 mm Hg in sha m-operated controls, n=9 to II; P<0.001) and exhibited a disparity of kidne y size (ratio left/right kidney: 0.78+/-0.04 versus 1.02+/-0.02; n=9 to 10; P<0.001). PRA increased significantly (84.6+/-6.5 versus 9.0+/-1.4 ng angi otensin I [Ang I] per milliliter per hour; n=8 to 9; P<0.01). In the coarct ed rats, neither renin mRNA expression nor renin activity of the right kidn ey was altered (renin/GAPDH mRNA: 1.12+/-0.05-fold levels in control rats; n=6; P=NS; renin activity: 23.4+/-1.8 versus 27.1+/-3.4 ng Ang I per hour p er milligram protein; n=8 to 9; P=NS). However, the renin mRNA of the left kidney increased to 3.0+/-0.6-fold of control (n=6), and the renin activity increased to 189.0+/-28.6 ng Ang I per hour per milligram protein (n=8; P< 0.01). Expression of COX-2 mRNA and immunoreactive protein increased in the affected left kidney but was not different from control in the unaffected right kidney. SC58236 treatment to coarcted rats did not affect kidney size (ratio left/right kidney: 0.79+/-0.06; n=9). However, PRA was significantl y decreased compared with the vehicle-treated coarcted rats (19.8+/-2.8 ng Ang I per milliliter per hour; n=9; P<0.01). The left kidney renin mRNA and renin content were also decreased (1.7+/-0.3-fold control; n=6; P<0.05; an d 45.7+/-7.6 ng Ang I per hour per milligram protein; n=9; P<0.01, respecti vely), while renin mRNA and renin content of the right kidney were not alte red: SC58236 lowered mean arterial blood pressure (122+/-5 mm Hg; n=14; P<0 .05 compared with vehicle). A significant correlation was observed between PRA. and mean blood pressure (r=0.75; P<0.01). In summary, these studies in dicate that the selective COX-2 inhibitor SC58236 decreases renin productio n and release in RVH and suggest an important role for COX-2 regulation of the renin-angiotensin system.