Department of Physiology and Pharmacology, Texas A&M University, College Station, Texas.
Michael E. DeBakey Institute for Comparative Cardiovascular Science and Biomedical Devices, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas.
Am J Physiol Heart Circ Physiol. 2020 Oct 1;319(4):H915-H926. doi: 10.1152/ajpheart.00384.2020. Epub 2020 Aug 28.
We have previously reported enhanced Ca sensitivity of coronary arteries that is dependent upon collateral circulation for their blood supply. For the current study, we hypothesized that small collateral-dependent arteries would exhibit an enhanced KCl-mediated contractile response attributable to Ca sensitization and increased Ca channel current. Ameroid constrictors were surgically placed around the left circumflex (LCX) artery of female Yucatan miniature swine. Eight weeks postoperatively, pigs were randomized into sedentary or exercise-trained (treadmill run; 5 days/wk; 14 wk) groups. Small coronary arteries (150-300 μm luminal diameter) were isolated from myocardial regions distal to the collateral-dependent LCX and the nonoccluded left anterior descending arteries. Contractile tension and simultaneous measures of both tension and intracellular free Ca levels (fura-2) were measured in response to increasing concentrations of KCl. In addition, whole cell Ca currents were also obtained. Chronic occlusion enhanced contractile responses to KCl and increased Ca sensitization in collateral-dependent compared with nonoccluded arteries of both sedentary and exercise-trained pigs. In contrast, smooth muscle cell Ca channel current was not altered by occlusion or exercise training. Ca/calmodulin-dependent protein kinase II (CaMKII; inhibited by KN-93, 0.3-1 μM) contributed to the enhanced contractile response in collateral-dependent arteries of sedentary pigs, whereas both CaMKII and Rho-kinase (inhibited by hydroxyfasudil, 30 μM or Y27632, 10 μM) contributed to increased contraction in exercise-trained animals. Taken together, these data suggest that chronic occlusion leads to enhanced contractile responses to KCl in collateral-dependent coronary arteries via increased Ca sensitization, a response that is further augmented with exercise training. Small coronary arteries distal to chronic occlusion displayed enhanced contractile responses, which were further augmented after exercise training and attributable to enhanced calcium sensitization without alterations in calcium channel current. The calcium sensitization mediators Rho-kinase and CaMKII significantly contributed to enhanced contraction in collateral-dependent arteries of exercise-trained, but not sedentary, pigs. Exercise-enhanced contractile responses may increase resting arterial tone, creating an enhanced coronary flow reserve that is accessible during periods of increased metabolic demand.
我们之前曾报道过，依赖侧支循环供血的冠状动脉的钙敏感性增强。在当前的研究中，我们假设小的侧支依赖性动脉会表现出增强的 KCl 介导的收缩反应，这归因于钙敏化和增加的钙通道电流。用 Ameroid 缩窄器在雌性尤卡坦小型猪的左回旋支（LCX）动脉周围进行手术放置。术后 8 周，猪被随机分为久坐或运动训练（跑步机跑步；每周 5 天；14 周）组。从小猪心肌区域分离出远侧的侧支依赖性 LCX 和非闭塞的左前降支的小冠状动脉（150-300μm 管腔直径）。通过增加 KCl 的浓度来测量收缩张力以及张力和细胞内游离 Ca 水平（fura-2）的同时测量。此外，还获得了全细胞 Ca 电流。慢性闭塞增强了 KCl 对侧支依赖性动脉的收缩反应，并增加了与久坐和运动训练的猪的非闭塞动脉相比的钙敏化。相比之下，闭塞或运动训练并没有改变平滑肌细胞 Ca 通道电流。钙/钙调蛋白依赖性蛋白激酶 II（CaMKII；被 KN-93，0.3-1μM 抑制）对久坐猪的侧支依赖性动脉增强的收缩反应有贡献，而 CaMKII 和 Rho 激酶（被羟基法舒地尔，30μM 或 Y27632，10μM 抑制）对运动训练动物的收缩增加有贡献。总之，这些数据表明，慢性闭塞导致侧支依赖性冠状动脉对 KCl 的收缩反应增强，这是通过增加钙敏化来实现的，而运动训练进一步增强了这种反应。慢性闭塞后的小冠状动脉显示出增强的收缩反应，在运动训练后进一步增强，归因于增强的钙敏化，而钙通道电流没有改变。钙敏化介质 Rho 激酶和 CaMKII 显著促进了运动训练猪的侧支依赖性动脉的收缩增强，但对久坐猪没有作用。运动增强的收缩反应可能会增加静息动脉张力，从而在代谢需求增加期间创造增强的冠状动脉血流储备。
