Ajay Machha, Mustafa Mohd Rais
Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, 50603, Malaysia.
Vascul Pharmacol. 2006 Aug;45(2):127-33. doi: 10.1016/j.vph.2006.05.001. Epub 2006 May 9.
Impaired vascular reactivity is a hallmark of several cardiovascular diseases that include hypertension and diabetes. This study compared the changes in vascular reactivity in age-matched experimental hypertension and diabetes, and, subsequently, tested whether these changes could be affected directly by ascorbic acid (10 microM). Endothelium-derived nitric oxide (NO) modulation of ascorbic acid effects was also investigated. All the experiments were performed in the presence of a cyclooxygenase inhibitor, indomethacin (10 microM). Results showed that the endothelium-dependent and -independent relaxations induced by acetylcholine (ACh) and sodium nitroprusside (SNP), respectively, were blunted to a similar extent in isolated aortic rings from age-matched spontaneously hypertensive (SHR) (R(max): ACh = 72.83+/-1.86%, SNP = 96.6+/-1.90%) and diabetic (Rmax: ACh = 64.09+/-5.14%, SNP = 95.84+/-1.41%) rats compared with aortic rings of normal rats (Rmax: ACh = 89%, SNP = 104.0+/-1.0%). The alpha1-receptor-mediated contractions induced by phenylephrine (PE) were augmented in diabetic (Cmax = 148.8+/-9.0%) rat aortic rings compared to both normal (Cmax = 127+/-6.9%) and SHR (Cmax = 118+/-4.5%) aortic rings. Ascorbic acid pretreatment was without any significant effects on the vascular responses to ACh, SNP and PE in aortic rings from normal rats. Ascorbic acid significantly improved ACh-induced relaxations in SHR (Rmax = 89.09+/-2.82%) aortic rings to a level similar to that observed in normal aortic rings, but this enhancement in ACh-induced relaxations was only partial in diabetic aortic rings. Ascorbic acid lacked any effects on SNP-induced relaxations in both SHR and diabetic aortic rings. Ascorbic acid markedly attenuated contractions induced by PE in aortic rings from both SHR (Cmax = 92.9+/-6.68%) and diabetic (Cmax = 116.9+/-9.4%) rats. Additionally, following inhibition of nitric oxide synthesis with l-NAME, ascorbic acid attenuated PE-induced contractions in all aortic ring types studied. These results suggest that (1) vascular hyper-responsiveness to alpha(1)-receptor agonists in diabetic arteries is independent of endothelial nitric oxide dysfunction; (2) ascorbic acid directly modulates contractile responses of hypertensive and diabetic rat aortas, likely through mechanisms in part independent of preservation of endothelium-derived nitric oxide.
血管反应性受损是包括高血压和糖尿病在内的几种心血管疾病的一个标志。本研究比较了年龄匹配的实验性高血压和糖尿病中血管反应性的变化，随后测试了这些变化是否会受到抗坏血酸（10微摩尔）的直接影响。还研究了内皮衍生的一氧化氮（NO）对抗坏血酸作用的调节。所有实验均在环氧化酶抑制剂吲哚美辛（10微摩尔）存在的情况下进行。结果表明，与正常大鼠主动脉环（Rmax：乙酰胆碱=89%，硝普钠=104.0±1.0%）相比，年龄匹配的自发性高血压（SHR）（Rmax：乙酰胆碱=72.83±1.86%，硝普钠=96.6±1.90%）和糖尿病（Rmax：乙酰胆碱=64.09±5.14%，硝普钠=95.84±1.41%）大鼠分离的主动脉环中，分别由乙酰胆碱（ACh）和硝普钠（SNP）诱导的内皮依赖性和非依赖性舒张均在相似程度上减弱。与正常（Cmax=127±6.9%）和SHR（Cmax=118±4.5%）主动脉环相比，糖尿病大鼠主动脉环中由去氧肾上腺素（PE）诱导的α1受体介导的收缩增强（Cmax=148.8±9.0%）。抗坏血酸预处理对正常大鼠主动脉环中对ACh、SNP和PE的血管反应没有任何显著影响。抗坏血酸显著改善了SHR（Rmax=89.09±2.82%）主动脉环中ACh诱导的舒张，使其达到与正常主动脉环中观察到的水平相似，但这种ACh诱导舒张的增强在糖尿病主动脉环中只是部分的。抗坏血酸对SHR和糖尿病主动脉环中SNP诱导的舒张均无影响。抗坏血酸显著减弱了SHR（Cmax=92.9±6.68%）和糖尿病（Cmax=116.9±9.4%）大鼠主动脉环中由PE诱导的收缩。此外，在用L-NAME抑制一氧化氮合成后，抗坏血酸减弱了所有研究的主动脉环类型中PE诱导的收缩。这些结果表明：（1）糖尿病动脉中对α1受体激动剂的血管高反应性独立于内皮一氧化氮功能障碍；（2）抗坏血酸直接调节高血压和糖尿病大鼠主动脉的收缩反应，可能通过部分独立于保存内皮衍生一氧化氮的机制。
