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1 Tulane Hypertension and Renal Center of Excellence, and Department of Physiology, Tulane University Health Sciences Center, New Orleans, LA, USA
2 Departments of Medicine and Pharmacology, Michael E. DeBakey VA Medical Center, and Baylor College of Medicine, Houston, TX, USA
* To whom correspondence should be addressed. E-mail: Fruzsi123{at}aol.com.
Vascular tissues express heme oxygenase (HO) that metabolizes heme to form carbon monoxide (CO). Heme-derived CO inhibits nitric oxide synthase and promotes endothelium-dependent vasoconstriction. After 4 weeks of high-salt diet, Dahl salt-sensitive (Dahl-S) rats display hypertension, increased vascular HO-1 expression, and attenuated vasodilator responses to acetylcholine (ACh) that can be completely restored by acute treatment with an inhibitor of HO. The purpose of this study is to examine the temporal development of HO-mediated endothelial dysfunction in isolated pressurized first-order gracilis muscle arterioles, identify the HO product responsible, and study the blood pressure effects of HO inhibition in Dahl-S rats on a high-salt diet. Male Dahl-S rats (5-6 weeks) were placed on high-salt (8% NaCl) or low-salt (0.3% NaCl) diets for 0-4 weeks. Blood pressure increased gradually and responses to an endotheliumdependent vasodilator, ACh, decreased gradually with the length of high-salt diet. Flow-induced dilation was abolished in hypertensive Dahl-S rats. Acute in vitro pretreatment with an inhibitor of HO, chromium mesoporphyrin (CrMP), restored endothelium-dependent vasodilation and abolished the differences between groups. The HO product CO prevented the restoration of endothelium-dependent dilation by CrMP. Furthermore, administration of a HO inhibitor lowered blood pressure in Dahl-S rats with salt-induced hypertension, but not in low-salt controls. These results suggest that hypertension and HO-mediated endothelial dysfunction develop gradually and simultaneously in Dahl-S rats on high-salt diets. They also suggest that HO-derived CO underlies the impaired endothelial dysfunction and contributes to hypertension in Dahl-S rats on high-salt diets.
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