Protein kinase βII in Zucker obese rats compromises oxygen and flow-mediated regulation of nitric oxide formation
- 1 February 2004
- journal article
- Published by American Physiological Society in American Journal of Physiology-Heart and Circulatory Physiology
- Vol. 286 (2) , H492-H497
- https://doi.org/10.1152/ajpheart.00818.2003
Abstract
In severe obesity, microvascular endothelial regulation of nitric oxide (NO) formation is compromised in response to muscarinic stimulation, and major arteries have suppressed flow-mediated dilation. Because normal microvessels are highly dependent on flow-mediated stimulation of NO generation and are responsive to intra- and extravascular oxygen availability, they are likely a major site of impaired endothelial regulation. This study evaluated the blood flow and oxygen-dependent aspects of intestinal microvascular regulation and NO production in Zucker obese rats just before the onset of hyperglycemia. Ruboxistaurin (LY-333531) was used to inhibit PKC-βII to determine whether flow or oxygen-related NO regulation was improved. Blood flow velocity was increased by forcing arterioles to perfuse ∼50% larger tissue areas by occlusion of nearby arterioles, and oxygen tension in the bath was lowered to create a modest oxygen depletion. When compared with lean Zucker rats, the periarteriolar NO concentration ([NO]) for obese rats was ∼30% below normal. At elevated shear rates, the [NO] for arterioles of obese animals was 20–30% below those in the arterioles of lean rats, and the NO response to decreased oxygen was about half normal in obese rats. All of these regulatory problems were essentially corrected in obese rats by PKC blockade with only minor changes in the microvascular behavior in lean rats. Therefore, activation of PKC-βII in endothelial cells during obesity suppressed NO regulation both at rest and in response to increased flow velocity and decreased oxygen availability.Keywords
This publication has 26 references indexed in Scilit:
- Body fat distribution and flow-mediated endothelium-dependent vasodilation in older menInternational Journal of Obesity, 2002
- Control of the forearm microcirculation: interactions with measures of obesity and noradrenaline kineticsClinical Science, 1998
- Inhibition of nitric oxide generation unmasks vascular dysfunction in insulin‐resistant, obese JCR:LA‐cp ratsBritish Journal of Pharmacology, 1998
- Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance.Journal of Clinical Investigation, 1996
- Amelioration of Vascular Dysfunctions in Diabetic Rats by an Oral PKC β InhibitorScience, 1996
- Intestinal Absorption of Sodium and Nitric OxideDependent Vasodilation Interact to Dominate Resting Vascular ResistanceCirculation Research, 1996
- Interactions between insulin and norepinephrine on blood pressure and insulin sensitivity. Studies in lean and obese men.Journal of Clinical Investigation, 1994
- Structural and functional origins of suppressed acetylcholine vasodilation in diabetic rat intestinal arterioles.Circulation Research, 1991
- Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance.Journal of Clinical Investigation, 1990
- An optical Doppler intravital velocimeterMicrovascular Research, 1984