Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
Am J Physiol Heart Circ Physiol. 2012 Jul 15;303(2):H216-23. doi: 10.1152/ajpheart.00011.2012. Epub 2012 May 18.
We have previously shown transient receptor potential vanilloid subtype 1 (TRPV1) channel-dependent coronary function is compromised in pigs with metabolic syndrome (MetS). However, the mechanisms through which TRPV1 channels couple coronary blood flow to metabolism are not fully understood. We employed mice lacking TRPV1 [TRPV1((-/-))], db/db diabetic, and control C57BKS/J mice to determine the extent to which TRPV1 channels modulate coronary function and contribute to vascular dysfunction in diabetic cardiomyopathy. Animals were subjected to in vivo infusion of the TRPV1 agonist capsaicin to examine the hemodynamic actions of TRPV1 activation. Capsaicin (1-100 μg·kg(-1)·min(-1)) dose dependently increased coronary blood flow in control mice, which was inhibited by the TRPV1 antagonist capsazepine or the nitric oxide synthase (NOS) inhibitor N-nitro-l-arginine methyl ester (L-NAME). In addition, the capsaicin-mediated increase in blood flow was attenuated in db/db mice. TRPV1((-/-)) mice exhibited no changes in coronary blood flow in response to capsaicin. Vasoreactivity studies in isolated pressurized mouse coronary microvessels revealed a capsaicin-dependent relaxation that was inhibited by the TRPV1 inhibitor SB366791 l-NAME and to the large conductance calcium-sensitive potassium channel (BK) inhibitors iberiotoxin and Penetrim A. Similar to in vivo responses, capsaicin-mediated relaxation was impaired in db/db mice compared with controls. Changes in pH (pH 7.4-6.0) relaxed coronary vessels contracted to the thromboxane mimetic U46619 in all three groups of mice; however, pH-mediated relaxation was blunted in vessels obtained from TRPV1((-/-)) and db/db mice compared with controls. Western blot analysis revealed decreased myocardial TRPV1 protein expression in db/db mice compared with controls. Our data reveal TRPV1 channels mediate coupling of myocardial blood flow to cardiac metabolism via a nitric oxide-dependent, BK channel-dependent pathway that is corrupted in diabetes.
我们之前已经证明，代谢综合征（MetS）猪的瞬时受体电位香草酸亚型 1（TRPV1）通道依赖性冠状动脉功能受损。然而，TRPV1 通道将冠状动脉血流与代谢联系起来的机制尚不完全清楚。我们使用缺乏 TRPV1 [TRPV1((-/-))]的小鼠、db/db 糖尿病小鼠和对照 C57BKS/J 小鼠，以确定 TRPV1 通道在多大程度上调节冠状动脉功能并导致糖尿病心肌病中的血管功能障碍。动物接受 TRPV1 激动剂辣椒素的体内输注，以检查 TRPV1 激活的血液动力学作用。辣椒素（1-100μg·kg(-1)·min(-1))剂量依赖性地增加对照小鼠的冠状动脉血流，该作用被 TRPV1 拮抗剂辣椒素或一氧化氮合酶（NOS）抑制剂 N-硝基-L-精氨酸甲酯（L-NAME）抑制。此外，db/db 小鼠中辣椒素介导的血流增加被减弱。TRPV1((-/-))小鼠对辣椒素无反应，冠状动脉血流无变化。在分离的加压小鼠冠状动脉微血管中进行的血管反应性研究显示，存在一种依赖于辣椒素的舒张作用，该作用被 TRPV1 抑制剂 SB366791、L-NAME 和大电导钙敏钾通道（BK）抑制剂 Iberiotoxin 和 Penetrim A 抑制。与体内反应相似，与对照相比，db/db 小鼠中辣椒素介导的舒张作用受损。在三组小鼠中，pH（7.4-6.0）变化使被血栓烷类似物 U46619 收缩的冠状动脉血管舒张；然而，与对照相比，来自 TRPV1((-/-))和 db/db 小鼠的血管中 pH 介导的舒张作用减弱。Western blot 分析显示，与对照相比，db/db 小鼠的心肌 TRPV1 蛋白表达减少。我们的数据表明，TRPV1 通道通过依赖于一氧化氮的、BK 通道依赖性途径将心肌血流与心脏代谢偶联，而在糖尿病中这种途径被破坏。
