Previous studies suggest that epoxyeicosatrienoic acids (EETs) are vasodilators of the mesenteric artery; however, the production and regulation of EETs in the mesenteric artery remain unclear. The present study was designed 1) to determine which epoxygenase isoform may contribute to formation of EETs in mesenteric arteries and 2) to determine the regulation of mesenteric artery cytochrome P-450 (CYP) enzymes in obese Zucker rats. Microvessels were incubated with arachidonic acid, and CYP enzyme activity was determined. Mesenteric arteries demonstrate detectable epoxygenase and hydroxylase activities. Next, protein and mRNA expressions were determined in microvessels. Although renal microvessels express CYP2C23 mRNA and protein, mesenteric arteries lacked CYP2C23 expression. CYP2C11 and CYP2J mRNA and protein were expressed in mesenteric arteries and renal microvessels. In addition, mesenteric artery protein expression was evaluated in lean and obese Zucker rats. Compared with lean Zucker rats, mesenteric arterial CYP2C11 and CYP2J proteins were decreased by 38 and 43%, respectively, in obese Zucker rats. In contrast, soluble epoxide hydrolase mRNA and protein expressions were significantly increased in obese Zucker rat mesenteric arteries. In addition, nitric oxide-independent dilation evoked by acetylcholine was significantly attenuated in mesenteric arteries of obese Zucker rats. These data suggest that the main epoxygenase isoforms expressed in mesenteric arteries are different from those expressed in renal microvessels and that decreased epoxygenases and increased soluble epoxide hydrolase are associated with impaired mesenteric artery dilator function in obese Zucker rats.

Romanko, Olga P., and David W. Stepp. Reduced constrictor reactivity balances impaired vasodilation in the mesenteric circulation of the obese Zucker rat. Am J Physiol Heart Circ Physiol 289: H2097-H2102, 2005. First published June 10, 2005; doi:10.1152/ajpheart.00213.2005.-Obesity causes whole body insulin resistance and impaired vasodilation to nitric oxide (NO). Because NO is a major contributor to the regulation of mesenteric blood flow, the mesenteric circulation of obese animals is faced with reduced capacity to increase flow and increased demand for flow associated with elevated consumption of food. This study hypothesized that insulin resistance impairs NO-mediated dilation but that constrictor reactivity would be reduced to compensate in obese animals. We further hypothesized that elevated superoxide levels caused impaired responses to NO in insulin resistance. Vasodilator reactivity and vasoconstrictor reactivity of mesenteric resistance arteries from lean (LZR) and obese (OZR) Zucker rats were examined in vitro using videomicroscopy. Insulin resistance independent of obesity was induced via fructose feeding in LZR (FF-LZR). Endothelium-dependent NO-mediated dilation was reduced in OZR and FF-LZR compared with LZR. Impairments in NO-mediated dilation were reversed with 1 mM tempol, a SOD mimetic. Constrictor reactivity to norepinephrine was reduced in OZR but not in FF-LZR relative to LZR. Basal mesenteric vascular resistance was similar in LZR and OZR despite impaired NO-dependent dilation in OZR. Mesenteric vascular resistance was increased in FF-LZR relative to LZR. These data indicate that there is reduced constrictor reactivity in OZR that may offset the impaired NO-mediated dilation and preserve mesenteric blood flow in hyperphagic, obese animals. microcirculation; adrenergic; nitric oxide; superoxide OBESITY IS AN EMERGING EPIDEMIC in Western cultures, especially in the United States, where an estimated 180 million people are overweight. The causes of obesity vary but include metabolic impairment, a high-fat diet, and overeating (hyperphagia). Functional hyperemia of the gut is required for food absorption and thus weight gain, but the effects of obesity and chronic hyperphagia on mesenteric perfusion are incompletely understood.Obesity also induces whole body insulin resistance, resulting in impaired control of plasma glucose, hyperinsulinemia, and chronic triglyceride dyslipidemia. Insulin resistance is considered an emerging risk factor for vascular disease and has been documented to impair nitric oxide (NO)-dependent mesenteric vasodilation in animal models of insulin resistance (20,(22)(23)(24). Given that NO is a major contributor to absorptive functional hyperemia (1, 9, 12, 17) and flow-mediated regulation (2,12,19), it raises the question of how the mesenteric circulation compensates for the impaired dilator response caused by insulin resistance against the elevated metabolic demands associated with increased ingestion of food in obese or hyperphagic individuals. Potential mechanisms in...

High-potassium diets can improve vascular function, yet the effects of potassium supplementation on ischemic stroke have not been studied. We hypothesized that dietary potassium supplementation would reduce ischemic cerebral infarct size by reversing cerebral artery hypertrophy. Six-week-old male stroke-prone spontaneously hypertensive rats (SHRSP) were fed diets containing 0.79% potassium (LK) or 2.11% potassium (HK) for 6 wk; Wistar-Kyoto (WKY) rats were fed the LK diet. The HK diet did not reduce blood pressure, as measured by telemetry, in the SHRSP. Cerebral ischemia was induced by middle cerebral artery (MCA) occlusion. The resultant infarct was smaller in the HK-SHRSP than in the LK-SHRSP: 55.1 +/- 6.3 vs. 71.4 +/- 2.4% of the hemisphere infarcted (P < 0.05). Infarcts were smaller in WKY rats (33.5 +/- 4.8%) than in LK-SHRSP or HK-SHRSP. The vessel wall of MCAs from LK-SHRSP was hypertrophied compared with WKY rats; this was reversed in HK-SHRSP. RT-PCR analysis of the cerebral vessels showed that expression of platelet-derived growth factor receptors-alpha and -beta, epidermal growth factor receptor, and collagen I and III was increased in the vessels from LK-SHRSP compared with WKY rats and reduced in HK-SHRSP. These results suggest that potassium supplementation provides neuroprotection in a model of ischemic stroke independent of blood pressure and possibly through changes in vascular structure.

Obesity and diabetes are major risk factors for the development of vascular disease in the lower limbs. Previous studies have demonstrated reduced nitric oxide (NO)-mediated vasodilation, increased adrenergic constriction and inward, atrophic remodeling in the limb circulation of obese Zucker rats but the component of the “metabolic syndrome” driving these changes is unclear. Because insulin resistance precedes the state of frank diabetes, the current study hypothesized that insulin resistance independent of obesity induced by fructose-feeding would impair microvascular function in the skeletal muscle circulation in Lean Zucker rats (LZR). A 66% fructose diet impaired glucose tolerance and induced moderate insulin resistance with no changes in whole body hemodynamics of anesthetized rats (FF-LZR) compared to control LZR. NO-mediated vasodilation of isolated gracilis arteries, assessed in vitro with acetylcholine and sodium nitroprusside, was reduced ~20% in FF-LZR vs. LZR. NO-independent cGMP-mediated vasodilation was unimpaired. Pre-treatment of isolated vessels with super-oxide scavenger Tempol improved responses to both vasodilators. Reactivity to adrenergic stimulation was unaltered in FF-LZR vs. LZR, through constriction to endothelin was increased. Structural and passive mechanical characteristics of isolated gracilis arteries were similar in both LZR and FF-LZR. Taken together, these findings indicate that moderate insulin resistance is sufficient to impair endothelial function in an oxidant-dependent manner in the rat hindlimb circulation. Other aspects of skeletal muscle vascular function documented in obese models, specifically adrenergic tone and inward remodeling, must reflect either severe insulin resistance or other aspects of obesity. The factors accounting for non-endothelial vasculopathies remain unknown.