Endothelium-Derived Constricting Factor in Renovascular Hypertension

We have reported that in two-kidney, one clip hypertensive rats, renal perfusion is maintained by a balance between the vasodilator endothelium-derived nitric oxide and the vasoconstrictor angiotensin II. Others have suggested that endothelium-derived constricting factor, reported to be thromboxane A 2 and/or endoperoxide, contributes to increased blood pressure in angiotensin II–dependent hypertension. We hypothesized that in angiotensin II–dependent two-kidney, one clip hypertension, endothelium-derived constricting factor contributes to vasoconstriction of the clipped kidney following nitric oxide synthesis inhibition. Using radioactive microspheres, we studied renal blood flow to the stenotic kidney of two-kidney, one clip hypertensive rats 4 weeks after clipping. The influence of nitric oxide on systemic and renal hemodynamics was evaluated by determining the response to nitric oxide synthesis inhibition using 10 mg/kg N ω -nitro- l -arginine methyl ester in these rats, which were either not treated (n=8) or treated (n=8) with 4 mg/kg of the constricting factor receptor antagonist BMS 180,291. Mean basal blood pressure in rats was 167±9 mm Hg (mean±SEM). N ω -Nitro- l -arginine methyl ester increased blood pressure by 35±7 mm Hg ( P <.001). In the clipped kidney, N ω -nitro- l -arginine methyl ester decreased renal blood flow by 40% (from 4.5±0.9 to 2.7±0.6 mL · min −1 · g kidney −1 ; P <.01) and increased renal vascular resistance by 100% (from 51.9±9.6 to 105.0±19.2 mm Hg · mL −1 · min −1 · g kidney −1 ; P <.005). Pretreatment with BMS 180,291 had no effect on basal blood pressure (167±7 mm Hg) or blood flow to the clipped kidney. However, constricting factor blockade diminished the pressor response to N ω -nitro- l -arginine methyl ester by 63%, decreasing the response to only 13±4 mm Hg ( P <.02). In rats treated with BMS 180,291, N ω -nitro- l -arginine methyl ester decreased blood flow to the clipped kidney by only 12% (from 5.4±0.6 to 4.7±0.5 mL · min −1 · g kidney −1 ; P <.05), while renal vascular resistance increased by only 17% (from 36.7±7.1 to 43.0±7.2 mm Hg · mL −1 · min −1 · g kidney −1 ; P <.005). In conclusion, although blocking endothelium-derived constricting factor in hypertensive rats affected neither basal blood pressure nor renal blood flow, it dramatically blunted both the systemic pressor and renal constrictor responses to inhibition of endothelium-derived nitric oxide synthesis. These data suggest a significant regulatory interaction between endothelium-derived constricting factor and endothelium-derived nitric oxide in renovascular hypertension.