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      Impaired Endothelium-Mediated Relaxation in Coronary Arteries from Insulin-Resistant Rats<footref rid="foot01"> 1</footref>


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          Objective: The insulin resistance syndrome is associated with atherosclerosis and cardiovascular events; however, the underlying mechanism of vascular dysfunction is unknown. The purpose of the current study was to assess endothelium- and smooth-muscle-mediated vasodilation in isolated coronary arteries from insulin-resistant rats and to determine whether insulin resistance alters the activity of the specific endothelium-derived relaxing factors. Methods: Male Sprague-Dawley rats were randomized to insulin resistance or control. Insulin resistance was induced by a fructose-rich diet. After 4 weeks of diet, coronary arteries were removed and vascular function was assessed in vitro using videomicroscopy. Acetylcholine (10<sup>–9</sup>–3 × 10<sup>–5</sup>  M)- or sodium-nitroprusside (10<sup>–9</sup>–3 × 10<sup>–4</sup>  M)-induced relaxations were determined. To evaluate the role of the specific endothelium-derived relaxing factors, several inhibitors were used, including N-nitro- L-arginine (LNNA), charybdotoxin/apamin (CTX/apamin), and indomethacin. Results: Studies with nitroprusside showed that smooth-muscle-dependent relaxation did not differ between insulin resistance and control groups. In contrast, maximal relaxation (E<sub>max</sub>) to acetylcholine was decreased in the insulin resistance group (56 ± 7%) versus control (93 ± 3%). LNNA pretreatment further impaired E<sub>max</sub> in the IR group from 56 ± 7 to 17 ± 2% (p < 0.01). In control, E<sub>max</sub> was only slightly impaired by LNNA (93 ± 3 to 63 ± 6%; p < 0.05). The addition of CTX/apamin also decreased relaxation in the control group (93 ± 3 to 47 ± 7%; p < 0.05), whereas relaxation in insulin-resistant rats was not affected (45 ± 5% with CTX/apamin vs. 56 ± 7% with acetylcholine alone, NS). Pretreatment with indomethacin did not affect relaxation in either group, while pretreatment with the combination of LNNA and CTX/ apamin completely abolished relaxation in both groups. Conclusions: Endothelium-dependent relaxation is impaired in small coronary arteries from insulin-resistant rats. The mechanism of this defect is related to a decrease in an endothelium-dependent, nitric oxide/prostanoid-independent relaxing factor or endothelium-derived hyperpolarizing factor.

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          Hyperinsulinemia as an independent risk factor for ischemic heart disease.

          Prospective studies suggest that hyperinsulinemia may be an important risk factor for ischemic heart disease. However, it has not been determined whether plasma insulin levels are independently related to ischemic heart disease after adjustment for other risk factors, including plasma lipoprotein levels. In 1985 we collected blood samples from 2103 men from suburbs of Quebec City, Canada, who were 45 to 76 years of age and who did not have ischemic heart disease. A first ischemic event (angina pectoris, acute myocardial infarction or death from coronary heart disease) occurred in 114 men (case patients) between 1985 and 1990. Each case patient was matched for age, body-mass index, smoking habits, and alcohol consumption with a control selected from among the 1989 men who remained free of ischemic heart disease during follow-up. After excluding men with diabetes, we compared fasting plasma insulin and lipoprotein concentrations at base line in 91 case patients and 105 controls. Fasting insulin concentrations at base line were 18 percent higher in the case patients than in the controls (P<0.001). Logistic-regression analysis showed that the insulin concentration remained associated with ischemic heart disease (odds ratio for ischemic heart disease with each increase of 1 SD in the insulin concentration, 1.7; 95 percent confidence interval, 1.3 to 2.4) after adjustment for systolic blood pressure, use of medications, and family history of ischemic heart disease. Further adjustment by multivariate analysis for plasma triglyceride, apolipoprotein B, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol concentrations did not significantly diminish the association between the insulin concentration and the risk of ischemic heart disease (odds ratio, 1.6; 95 percent confidence interval, 1.1 to 2.3). High fasting insulin concentrations appear to be an independent predictor of ischemic heart disease in men.
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            K+ is an endothelium-derived hyperpolarizing factor in rat arteries.

            In arteries, muscarinic agonists such as acetylcholine release an unidentified, endothelium-derived hyperpolarizing factor (EDHF) which is neither prostacyclin nor nitric oxide. Here we show that EDHF-induced hyperpolarization of smooth muscle and relaxation of small resistance arteries are inhibited by ouabain plus Ba2+; ouabain is a blocker of Na+/K+ ATPase and Ba2+ blocks inwardly rectifying K+ channels. Small increases in the amount of extracellular K+ mimic these effects of EDHF in a ouabain- and Ba2+-sensitive, but endothelium-independent, manner. Acetylcholine hyperpolarizes endothelial cells and increases the K+ concentration in the myoendothelial space; these effects are abolished by charbdotoxin plus apamin. Hyperpolarization of smooth muscle by EDHF is also abolished by this toxin combination, but these toxins do not affect the hyperpolarizaiton of smooth muscle by added K+. These data show that EDHF is K+ that effluxes through charybdotoxin- and apamin-sensitive K+ channels on endothelial cells. The resulting increase in myoendothelial K+ concentration hyperpolarizes and relaxes adjacent smooth-muscle cells by activating Ba2+-sensitive K+ channels and Na+/K+ ATPase. These results show that fluctuations in K+ levels originating within the blood vessel itself are important in regulating mammalian blood pressure and flow.
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              The importance of the hyperpolarizing mechanism increases as the vessel size decreases in endothelium-dependent relaxations in rat mesenteric circulation.

              Endothelium-dependent relaxations are achieved by a combination of endothelium-derived prostacyclin (PGI2), nitric oxide (NO), and endothelium-derived hyperpolarizing factor (EDHF). However, it remains to be fully clarified whether the relative contribution of these three mechanisms to endothelium-dependent relaxations varies as a function of the vessel size. This study was designed to clarify this point. Acetylcholine (ACh)-induced endothelium-dependent relaxations were examined in isolated blood vessels taken from the aorta and the proximal and distal mesenteric arteries of the rat. The contributions of PGI2, NO, and EDHF were evaluated by the inhibitory effects of indomethacin, N omega-nitro-L-arginine methyl ester (L-NAME) in the presence of indomethacin, and KCl in the presence of indomethacin and L-NAME, respectively. The membrane potentials were recorded with microelectrodes. The expression of endothelial No synthase (eNOS) was examined by both immunostaining and immunoblotting. The contribution of PGI2 was negligible in three different-sized blood vessels. The contribution of NO was most prominent in the aorta, whereas that of EDHF was most prominent in the distal mesenteric arteries. The resting membrane potential was significantly deeper and the ACh-induced hyperpolarization was greater in the distal mesenteric arteries than those in the aorta. The expression of eNOS was the highest in the aorta and the lowest in the distal mesenteric arteries. These results indicate that the importance of EDHF increases as the vessel size decreases in endothelium-dependent relaxations in the rat mesenteric circulation.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                October 1999
                28 October 1999
                : 36
                : 5
                : 385-392
                aUniversity of Georgia College of Pharmacy, bMedical College of Georgia School of Medicine, and cAugusta VA Medical Center, Augusta, Ga., USA
                25678 J Vasc Res 1999;36:385–392
                © 1999 S. Karger AG, Basel

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                Figures: 5, Tables: 2, References: 30, Pages: 8
                Research Paper


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