Chronic aerobic exercise associated to low-dose L-NAME improves contractility without changing calcium handling in rat cardiomyocytes

Nitric oxide (NO) inhibition by high-dose NG-nitro-L-arginine methyl ester (L-NAME) is associated with several detrimental effects on the cardiovascular system. However, low-dose L-NAME increases NO synthesis, which in turn induces physiological cardiovascular benefits, probably by activating a protective negative feedback mechanism. Aerobic exercise, likewise, improves several cardiovascular functions in healthy hearts, but its effects are not known when chronically associated with low-dose L-NAME. Thus, we tested whether the association between low-dose L-NAME administration and chronic aerobic exercise promotes beneficial effects to the cardiovascular system, evaluating the cardiac remodeling process. Male Wistar rats were randomly assigned to control (C), L-NAME (L), chronic aerobic exercise (Ex), and chronic aerobic exercise associated to L-NAME (ExL). Aerobic training was performed with progressive intensity for 12 weeks; L-NAME (1.5 mg·kg-1·day-1) was administered by orogastric gavage. Low-dose L-NAME alone did not change systolic blood pressure (SBP), but ExL significantly increased SBP at week 8 with normalization after 12 weeks. Furthermore, ExL promoted the elevation of left ventricle (LV) end-diastolic pressure without the presence of cardiac hypertrophy and fibrosis. Time to 50% shortening and relaxation were reduced in ExL, suggesting a cardiomyocyte contractile improvement. In addition, the time to 50% Ca2+ peak was increased without alterations in Ca2+ amplitude and time to 50% Ca2+ decay. In conclusion, the association of chronic aerobic exercise and low-dose L-NAME prevented cardiac pathological remodeling and induced cardiomyocyte contractile function improvement; however, it did not alter myocyte affinity and sensitivity to intracellular Ca2+ handling.

大剂量NG-硝基-L-精氨酸甲酯（L-NAME）抑制一氧化氮（NO）会对心血管系统产生多种不良影响。然而，低剂量L-NAME可增加NO合成，进而诱导生理性心血管获益，其机制可能是激活了保护性负反馈通路。有氧运动同样可改善健康心脏的多项心血管功能，但当长期联合低剂量L-NAME时，其作用尚未明确。因此，本研究旨在探讨低剂量L-NAME给药联合慢性有氧运动是否可对心血管系统产生获益，并评估心脏重构过程。将雄性Wistar大鼠随机分为对照组（C组）、L-NAME组（L组）、慢性有氧运动组（Ex组）以及慢性有氧运动联合L-NAME组（ExL组）。有氧运动训练采用渐进式强度方案，持续12周；L-NAME（1.5 mg·kg⁻¹·d⁻¹）通过经口灌胃给药。单独使用低剂量L-NAME并未改变收缩压（SBP），但ExL组在第8周时SBP显著升高，12周后恢复至正常水平。此外，ExL组左心室（LV）舒张末期压力升高，但未出现心肌肥厚与纤维化。ExL组的心肌细胞50%缩短时长及舒张时长均缩短，提示心肌收缩功能得到改善。此外，50%钙峰到达时长延长，但钙振幅及50%钙衰减时长无明显变化。综上，慢性有氧运动联合低剂量L-NAME可预防心脏病理性重构，并改善心肌细胞收缩功能，但未改变心肌细胞对细胞内钙处理的亲和力与敏感性。