Metabolic syndrome elevates heme oxygenase‐derived carbon monoxide formation to promote hypertension via endothelial dysfunction

Vascular heme oxygenase (HO) metabolizes heme to form carbon monoxide (CO). Increased heme‐derived CO inhibits nitric oxide synthase and contributes to hypertension via endothelial dysfunction in Dahl salt‐sensitive rats. Obese Zucker rats (OZR) are models of metabolic syndrome. This study tests the hypothesis that endogenous CO formation is increased and contributes to hypertension via endothelial dysfunction in OZR. OZR showed increased respiratory CO excretion and blood pressure which were lowered by HO inhibitor administration (ZnDPBG, 25μmol/kg/24hr ip). Body weight, blood glucose, HbA1c, plasma insulin, total and LDL cholesterol, oxidized LDL, and triglyceride levels were elevated in OZR, and were unchanged by HO inhibition. In OZR arterioles, responses to acetylcholine and flow were attenuated. Acute in vitro pretreatment with a HO inhibitor, CrMP, enhanced acetylcholine and flow‐induced dilation and abolished the differences between groups. Furthermore, exogenous CO prevented the restoration of flow‐induced dilation by the HO inhibitor in OZR arterioles. These results suggest that HO‐derived CO production is increased and promotes hypertension and arteriolar endothelial dysfunction in OZR with metabolic syndrome independent of any change in metabolic parameters. Supported by NIH/NCRR grant P20 RR017659 (FKJ), NIH/NHLBI RO1 grants HL76187 (RAJ), HL59976 (WD) and HL74966 (WD).