on December 22, 2003
Published online before print December 22, 2003, doi: 10.1161/01.HYP.0000111138.78714.1a
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Submitted on September 29, 2003
From the Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University School of Medicine, Sendai, Japan. * To whom correspondence should be addressed. E-mail: shuarima{at}mail.cc.tohoku.ac.jp.
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<0.01) constriction was observed from 5x10-9 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 (3x10-5 mol/L), which blocks inositol 1,4,5-triphosphate (IP3)-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 IP3 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.
Revised on November 5, 2003
Endothelium-Derived Nitric Oxide Modulates Vascular Action of Aldosterone in Renal Arteriole
Shuji Arima*;
Key words: aldosterone • endothelium • nitric oxide • arterioles • phospholipases • protein kinases • inositol
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