Bender Shawn B, Tune Johnathan D, Borbouse Lena, Long Xin, Sturek Michael, Laughlin M Harold
E102 Vet Med Bldg, Dept. of Biomedical Sciences, University of Missouri, Columbia, MO 65211, USA.
Exp Biol Med (Maywood). 2009 Jun;234(6):683-92. doi: 10.3181/0812-RM-350. Epub 2009 Mar 23.
Onset of the combined metabolic syndrome (MetS) is a complex progressive process involving numerous cardiovascular risk factors. Although patients with established MetS exhibit reduced coronary flow reserve and individual components of the MetS reduce microvascular vasodilation, little is known concerning the impact of early-stage MetS on the mechanisms of coronary flow control. Therefore, we tested the hypothesis that coronary arteriolar dilation to adenosine is attenuated in early-stage MetS by reduced A2 receptor function and diminished K+ channel involvement. Pigs were fed control or high-fat/cholesterol diet for 9 weeks to induce early-stage MetS. Coronary atheroma was determined in vivo with intravascular ultrasound. In vivo coronary dilation was determined by intracoronary adenosine infusion. Further, apical coronary arterioles were isolated, cannulated and pressurized to 60 cmH2O for in vitro pharmacologic assessment of adenosine dilation. Coronary atheroma was not different between groups, indicating early-stage MetS. Coronary arteriolar dilation to adenosine (in vivo) and 2-chloroadenosine (2-CAD; in vitro) was similar between groups. In control arterioles, 2-CAD-mediated dilation was reduced only by selective A(2A) receptor inhibition, whereas only dual A(2A/2B) inhibition reduced this response in MetS arterioles. Arteriolar A(2B), but not A(2A), receptor protein expression was reduced by MetS. Blockade of voltage-dependent K+ (K(v)) channels reduced arteriolar sensitivity to 2-CAD in both groups, whereas ATP-sensitive K+ (K(ATP)) channel inhibition reduced sensitivity only in control arterioles. Our data indicate that the mechanisms mediating coronary arteriolar dilation to adenosine are altered in early-stage MetS prior to overt decrements in coronary vasodilator reserve.
合并代谢综合征（MetS）的发病是一个复杂的渐进过程，涉及众多心血管危险因素。虽然已确诊MetS的患者表现出冠状动脉血流储备降低，且MetS的各个组成部分会降低微血管舒张功能，但关于早期MetS对冠状动脉血流控制机制的影响知之甚少。因此，我们检验了以下假设：在早期MetS中，由于A2受体功能降低和钾通道参与减少，冠状动脉小动脉对腺苷的舒张作用减弱。将猪喂食对照或高脂/高胆固醇饮食9周以诱导早期MetS。通过血管内超声在体内测定冠状动脉粥样硬化。通过冠状动脉内注入腺苷在体内测定冠状动脉舒张功能。此外，分离心尖冠状动脉小动脉，插管并加压至60 cmH2O，用于体外药理学评估腺苷舒张功能。两组之间冠状动脉粥样硬化无差异，表明处于早期MetS阶段。两组之间冠状动脉小动脉对腺苷（体内）和2-氯腺苷（2-CAD；体外）的舒张反应相似。在对照小动脉中，2-CAD介导的舒张仅通过选择性A(2A)受体抑制而降低，而在MetS小动脉中只有双重A(2A/2B)抑制才能降低这种反应。MetS降低了小动脉A(2B)受体蛋白表达，但未降低A(2A)受体蛋白表达。阻断电压依赖性钾（K(v)）通道降低了两组小动脉对2-CAD的敏感性，而ATP敏感性钾（K(ATP)）通道抑制仅降低了对照小动脉的敏感性。我们的数据表明，在冠状动脉舒张储备明显下降之前，早期MetS就改变了介导冠状动脉小动脉对腺苷舒张的机制。
