Abstract
Low dietary sodium (LS) increases the effect of angiotensin-converting enzyme (ACE) inhibitor therapy in patients and experimental models, but mechanisms underlying this enhanced efficacy are largely unknown. Because the benefits of ACE inhibition are mediated to a considerable extent by their effect on the vasculature, we studied whether low sodium alters the vascular effects of ACE inhibition. Baseline functional and morphological characteristics, and endothelium-dependent and -independent dilatory responses were studied in isolated perfused small intrarenal and mesenteric arteries obtained from control rats (CON), rats on LS, lisinopril-treated rats (CON-LIS), or rats treated with lisinopril during LS (LS-LIS). We found, first, that LS-LIS compared with CON-LIS enhances blood pressure reduction. Second, interlobar renal arteries had increased lumen diameter and reduced adrenergic contractility in CON-LIS compared with CON, without additional effects of LS. In contrast, mesenteric arteries were not altered in CON-LIS compared with CON, but became triggered for increased myogenic and adrenergic constriction in LS-LIS. Third, LS-LIS decreased acetylcholine (ACh)-induced vasodilation in both mesenteric and renal arteries compared with CON-LIS. During the latter condition, opposite prostaglandins are involved in the endothelial function of the two different vascular beds, i.e., increased involvement of contractile prostaglandins in ACh-induced vasodilatation in renal arteries, versus dilatory prostaglandins in mesenteric arteries. Whether cause or consequence of the enhanced blood pressure response, our data demonstrate a modifying effect of dietary sodium on vascular effects of ACE inhibition. These findings provide a rationale for further studies addressing the mechanism-of-actions of our therapies to find additional strategies to improve therapy response.
Footnotes
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S.G. is a recipient of an Ubbo Emmius Grant from the Groningen University Institute of Drug Exploration.
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doi:10.1124/jpet.104.067272.
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ABBREVIATIONS: RAS, renin-angiotensin system; ACE, angiotensin-converting enzyme; LIS, lisinopril; LS, low dietary sodium; CON, control group; CON-LIS, lisinopril-treated group; LS, vehicle-treated group during low dietary sodium; LS-LIS, lisinopril-treated group during low dietary sodium; PE, phenylephrine; ACh, acetylcholine; PG, prostaglandin; COX, cyclooxygenase; SNP, sodium nitroprusside; AUC, area under the curve; ANOVA, analysis of variance; ACEi, angiotensin-converting enzyme inhibitor; TXA2, thromboxane A2.
- Received February 19, 2004.
- Accepted June 2, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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