Article Text

  1. B. K. Stevenson1,
  2. R. A. Johnson1,
  3. K. E. Jackson1,
  4. K. J. Peyton1,
  5. W. Durante1,
  6. F. K. Johnson1
  1. 1Department of Physiology, Tulane University Health Sciences Center, New Orleans


Vascular heme oxygenase (HO) metabolizes heme to form carbon monoxide (CO). Heme-derived CO inhibits nitric oxide synthase and promotes endothelial dysfunction (ED) in salt-induced hypertension. The obese Zucker rat (ZR) is a model of type 2 diabetes showing hypertension and vascular ED. This study tests the hypothesis that HO-derived CO contributes to arteriolar ED and hypertension in obese ZR. Male obese (548 ± 12 g, n = 22) and lean (309 ± 14 g, n = 12) ZR were used for the study. Obese ZR had elevated mean arterial blood pressure (154 ± 3 mm Hg vs. 121 ± 4 mm Hg), blood glucose (186 ± 7 mg/dL vs. 140 ± 3 mg/dL) and blood carboxyhemoglobin (HbCO) levels (3.9 ± 0.1% vs. 3.0 ± 0.1%). Experiments used isolated skeletal muscle arterioles with constant (80 mm Hg) pressure and no flow, or constant midpoint, but altered endpoint pressures to establish graded levels of luminal flow (0-50 μL/min). In obese ZR arterioles, responses to an endothelium-dependent vasodilator, acetylcholine (ACh, 1 nmol/L - 3 μmol/L) (Δmax 32 ± 4 μm, n = 8 vs. 62 ± 7 μm, n = 5) and flow (Δmax-1 ± 1 μm, n = 4 vs. 21 ± 2 μm, n = 4) were attenuated. Acute in vitro pretreatment with a HO inhibitor, chromium mesoporphyrin (CrMP, 15 μmol/L), enhanced ACh (Δmax 59 ± 8 μm, n = 7 vs. 58 ± 13 μm, n = 5) and flow-induced dilation (Δmax 19 ± 2 μm, n = 4 vs. 20 ± 3 μm, n = 3) and abolished the differences between lean and obese ZR arterioles. Furthermore, exogenous CO (100 μmol/L) prevented the restoration of flow-induced dilation by the HO inhibitor (Δmax-1 ± 3 μm, n = 4) in obese ZR arterioles. In awake obese ZR instrumented with chronic femoral arterial catheters, administration of a HO inhibitor (25 μmol/kg/day zinc deuteroporphyrin 2,4-bisglycol IP for 3 days) lowered the blood pressure (151 ± 1 to 109 ± 1 mm Hg, n = 3). These data show that HbCO levels are increased, and arteriolar endothelium-dependent vasodilation is decreased in obese ZR. Acute in vitro treatment with a HO inhibitor restores endothelium-dependent responses to lean ZR levels, but exogenous CO prevents this effect. Furthermore, HO inhibition lowers blood pressure in obese ZR. These results suggest that heme-derived CO production is increased and contributes to arteriolar ED and hypertension in obese ZR, and hence identify vascular HO as a novel therapeutic target to prevent ED and hypertension in obesity and type 2 diabetes.

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