Heme oxygenase-derived carbon monoxide promotes arteriolar endothelial dysfunction and contributes to salt-induced hypertension in Dahl salt-sensitive rats

Am J Physiol Regul Integr Comp Physiol. 2005 Mar;288(3):R615-22. doi: 10.1152/ajpregu.00123.2004. Epub 2004 Nov 4.


Vascular tissues express heme oxygenase (HO), which metabolizes heme to form carbon monoxide (CO). Heme-derived CO inhibits nitric oxide synthase and promotes endothelium-dependent vasoconstriction. After 4 wk of high-salt diet, Dahl salt-sensitive (Dahl-S) rats display hypertension, increased vascular HO-1 expression, and attenuated vasodilator responses to ACh that can be completely restored by acute treatment with an inhibitor of HO. In this study, we examined the temporal development of HO-mediated endothelial dysfunction in isolated pressurized first-order gracilis muscle arterioles, identified the HO product responsible, and studied the blood pressure effects of HO inhibition in Dahl-S rats on a high-salt diet. Male Dahl-S rats (5-6 wk) were placed on high-salt (8% NaCl) or low-salt (0.3% NaCl) diets for 0-4 wk. Blood pressure increased gradually, and responses to an endothelium-dependent 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 an HO inhibitor lowered blood pressure in Dahl-S rats with salt-induced hypertension but did not do so in low-salt control rats. 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylcholine / pharmacology
  • Animals
  • Arterioles / drug effects
  • Arterioles / enzymology
  • Arterioles / physiopathology*
  • Blood Pressure / drug effects
  • Carbon Monoxide / metabolism*
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / enzymology
  • Endothelium, Vascular / physiopathology*
  • Enzyme Inhibitors / pharmacology
  • Heme Oxygenase (Decyclizing) / antagonists & inhibitors
  • Heme Oxygenase (Decyclizing) / metabolism*
  • Hypertension / chemically induced
  • Hypertension / enzymology
  • Hypertension / physiopathology*
  • In Vitro Techniques
  • Male
  • Mesoporphyrins / pharmacology
  • Muscle, Skeletal / blood supply
  • Rats
  • Rats, Inbred Dahl
  • Regional Blood Flow
  • Sodium Chloride, Dietary / administration & dosage
  • Time Factors
  • Vasodilation / drug effects
  • Vasodilator Agents / pharmacology


  • Enzyme Inhibitors
  • Mesoporphyrins
  • Sodium Chloride, Dietary
  • Vasodilator Agents
  • chromium mesoporphyrin
  • Carbon Monoxide
  • Heme Oxygenase (Decyclizing)
  • Acetylcholine