Endothelium-Derived Nitric Oxide Modulates Vascular Action of Aldosterone in Renal Arteriole

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Abstract
We have recently demonstrated that aldosterone causes nongenomic vasoconstriction by activating phospholipase C (PLC) in the preglomerular afferent arteriole (Af-Art). In the present study, we tested the hypothesis that endothelium modulates this vasoconstrictor action by releasing nitric oxide (NO). In addition, to study the post-PLC mechanism, we examined possible contributions of phosphoinositol hydrolysis products. Rabbit Af-Arts were microperfused at 60 mm Hg in vitro, and increasing doses of aldosterone (10 −10 to 10 −8 mol/L) were added to the bath and lumen. Aldosterone caused dose-dependent vasoconstriction (within 10 minutes); significant ( P −9 mol/L, and at 10 −8 mol/L, intraluminal diameter decreased by 29%±3% (n=9). Disrupting the endothelium augmented vasoconstriction; significant constriction was observed from 10 −10 mol/L, and at 10 −8 mol/L, the diameter decreased by 38%±2% (n=6). NO synthesis inhibition reproduced this augmentation (n=7). Pretreatment with chelerythrine (10 −6 mol/L), a protein kinase C (PKC) inhibitor, slightly attenuated the constriction; aldosterone at 10 −8 mol/L now decreased the diameter by 18%±3% (n=7). However, in Af-Arts treated with thapsigargin (10 −6 mol/L) or dantrolene (3×10 −5 mol/L), which blocks inositol 1,4,5-triphosphate (IP 3 )-induced intracellular calcium release, aldosterone at 10 −8 mol/L decreased the diameter by only 9%±1% (n=6) or 9%±2% (n=5), respectively. These results demonstrate that in the Af-Art endothelium-derived NO modulates vasoconstrictor actions of aldosterone that are mediated by the activation of both IP 3 and PKC pathways. Such vasoconstrictor actions of aldosterone may contribute to the development or aggravation of hypertension by elevating renal vascular resistance in cardiovascular diseases associated with endothelium dysfunction.