Broderick Tom L, Paulson Dennis J, Gillis Melissa
Department of Physiology, Midwestern University, Glendale, Arizona 85308, USA.
Drugs R D. 2004;5(4):191-201. doi: 10.2165/00126839-200405040-00002.
Carnitine and its derivatives, namely propionyl-carnitine (PC), have been shown to protect cardiac metabolism and function in diabetes mellitus and ischaemic heart disease. Since diabetes is associated with abnormalities in mitochondrial metabolism of fuels, we examined the effects of PC on mitochondrial respiration in ischaemic hearts from streptozotocin-diabetic rats.
Diabetes was induced in Sprague-Dawley rats by an intravenous injection of streptozotocin. Following the diagnosis of diabetes, oral PC treatment was initiated for a period of 6 weeks. After treatment, cardiac function was determined from working hearts perfused under aerobic conditions and in a separate group of hearts subjected to ischaemia and reperfusion. Mitochondrial respiration was determined under aerobic conditions and following low-flow ischaemia.
Rates of state 3 mitochondria respiration with pyruvate were significantly lower in diabetic (n = 4) hearts compared with control (n = 6) hearts (80 +/- 5 vs 112 +/- 5 nanoatoms O2/mg protein/min, respectively), but those with palmitoylcarnitine were similar (101 +/- 11 vs 106 +/- 6 nanoatoms O2/mg protein/min). Diabetic rat heart (n = 8) function, expressed as rate pressure product, was also significantly decreased compared with control (n = 8) hearts (21.5 +/- 1.0 vs 29.5 +/- 0.9 beats x mm Hg x 10(-3)/min, respectively). In PC-treated diabetic (n = 6) hearts, state 3 respiration with pyruvate was increased, and a marked improvement in left ventricular function from 21.5 +/- 1.0 to 26.0 +/- 0.6 beats x mm Hg x 10(-3)/min was observed. During low-flow ischaemia, state 3 respiration with pyruvate remained lower in diabetic (n = 5) hearts compared with control (n = 5) hearts (64 +/- 3 vs 46 +/- 5 nanoatoms O2/mg protein/min, respectively). Following treatment with PC (n = 4), however, respiration with this substrate was significantly increased to 57 +/- 4 nanoatoms O2/mg protein/min. PC was also associated with a significant improvement in cardiac function in reperfused diabetic rat (n = 4) hearts (18.4 +/- 0.2 beats x mm Hg x 10(-3)/min).
Our results showed that PC has a beneficial effect on cardiac function and increases ischaemic tolerance of the diabetic rat heart. This beneficial effect of PC can be explained, in part, as an improvement in mitochondrial metabolism of pyruvate during the actual ischaemic period.
肉碱及其衍生物，即丙酰肉碱（PC），已被证明可保护糖尿病和缺血性心脏病中的心脏代谢与功能。由于糖尿病与燃料的线粒体代谢异常有关，我们研究了PC对链脲佐菌素诱导的糖尿病大鼠缺血心脏线粒体呼吸的影响。
通过静脉注射链脲佐菌素在Sprague-Dawley大鼠中诱导糖尿病。在确诊糖尿病后，开始口服PC治疗6周。治疗后，在有氧条件下灌注的工作心脏以及另一组经历缺血再灌注的心脏中测定心脏功能。在有氧条件下以及低流量缺血后测定线粒体呼吸。
与对照（n = 6）心脏相比，糖尿病（n = 4）心脏中丙酮酸的状态3线粒体呼吸速率显著降低（分别为80±5与112±5纳原子O2/毫克蛋白/分钟），但棕榈酰肉碱的呼吸速率相似（101±11与106±6纳原子O2/毫克蛋白/分钟）。以速率压力积表示的糖尿病大鼠（n = 8）心脏功能也与对照（n = 8）心脏相比显著降低（分别为21.5±1.0与29.5±0.9次搏动×毫米汞柱×10⁻³/分钟）。在PC治疗的糖尿病（n = 6）心脏中，丙酮酸的状态3呼吸增加，并且观察到左心室功能从21.5±1.0显著改善至26.0±0.6次搏动×毫米汞柱×10⁻³/分钟。在低流量缺血期间，与对照（n = 5）心脏相比，糖尿病（n = 5）心脏中丙酮酸的状态3呼吸仍然较低（分别为64±3与46±5纳原子O2/毫克蛋白/分钟）。然而，在用PC治疗（n = 4）后，该底物的呼吸显著增加至57±4纳原子O2/毫克蛋白/分钟。PC还与再灌注的糖尿病大鼠（n = 4）心脏的心脏功能显著改善有关（18.4±0.2次搏动×毫米汞柱×10⁻³/分钟）。
我们的结果表明，PC对心脏功能有有益作用，并增加糖尿病大鼠心脏的缺血耐受性。PC的这种有益作用部分可以解释为在实际缺血期间丙酮酸的线粒体代谢得到改善。
