Heme oxygenase-derived carbon monoxide promotes arteriolar endothelial dysfunction and contributes to salt-induced hypertension in Dahl salt-sensitive rats.
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.
Teran
Federico J
FJ
Dept. of Physiology, Tulane University Health Sciences Center, 1430 Tulane Avenue, SL39, New Orleans, LA 70112, USA.
Johnson
Robert A
RA
Stevenson
Blake K
BK
Peyton
Kelly J
KJ
Jackson
Keith E
KE
Appleton
Scott D
SD
Durante
William
W
Johnson
Fruzsina K
FK
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology*; D001794:Blood Pressure / Q000187:drug effects; D002248:Carbon Monoxide / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D008652:Mesoporphyrins / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000098:blood supply; D051381:Rats; D020303:Rats, Inbred Dahl; D012039:Regional Blood Flow; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D004791:Enzyme Inhibitors; D008652:Mesoporphyrins; D017673:Sodium Chloride, Dietary; D014665:Vasodilator Agents; C427471:chromium mesoporphyrin; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); D000109:Acetylcholine