Iraqi J Pharm Sci, Vol.20(1) 2011 Antioxidant vitamin C 50 Possible Augmentive Effect of Antioxidant Vitamin C in Patients with Essential Hypertension Treated with Amlodipin or Enalapril Maitham A. Al-Rikaby* , Kasim J. Al – Shamma** ,1 , Ibrahim A. Majeed** and Saad SH.Hamondi*** * Department of Clinical Pharmacy and Pharmaceutics ,College of Pharmacy,University of Basrah, Iraq. **Department of Clinical Pharmacy, College of Pharmacy, University of Baghdad, Baghdad, Iraq. ***Department of Internal Medicine, College of Medicine , University of Basrah ,Basrah ,Iraq. Abstract Hypertension is identified as one of the most significant risk factors for cardiovascular diseases (CVDs). There is growing evidence showing that oxidative stress plays a major role in hypertension. Increased production of reactive oxygen species and decrease bioavailability of antioxidant have been demonstrated in experimental and human hypertension. The present study was directed to determine the beneficial effect of the antioxidant vitamin C in patients with essential hypertension treated with the calcium channel blocker (amlodipine) or with the angiotensin converting enzyme inhibitor (enalapril). Ninety six patients (50 females and 46 males) with essential hypertension and treated with amlodipine or enalapril, age (50.43 ± 0.55 year) were participated in this study and divided in to: Twenty five patients received amlodipine 5mg tablet once daily (group 1), twenty five patients received the same dose of amlodipine plus 500mg of vitamin C tablet twice daily (group 2), twenty three patients received enalapril 5 mg tablet once daily (group 3), and twenty three patients received the same dose of enalapril plus 500mg of vitamin C tablet twice daily (group 4). Twenty apparently healthy subjects (11 females and 9 males) also participated in this study as control group (group 5). All patients were treated and followed up for one month. The mean blood pressures were measured for each patient before treatment and one, two, three and four weeks after treatment. Serum malondialdehyde (MDA), lipid profile, electrocardiogram (ECG) parameters and heart rate were measured for each patient before treatment and two and four weeks after treatment. The addition of vitamin C to amlodipine or enalapril treated patients had resulted in a significant (p<0.05) lowering effect on mean blood pressure after two, three and four weeks. On the other hand, the addition of vitamin C to amlodipine or enalapril treated patients had resulted in a significant lowering of serum MDA after two and four weeks of treatment. While there was no significant change in lipid profile or ECG parameters and heart rate of patients in group two and four after two and four weeks of vitamin C treatment as compared to their values at zero time and to patients in group one and three respectively. The study indicates that oxidative stress may have a significant role in essential hypertension, and addition of the antioxidant vitamin C to antihypertensive drugs used in this study can give a good blood pressure lowering effect and good protection against lipid peroxidation. Key words: Antioxidant ,Vitamin C, Essential Hypertension, Amlodipin , Enalapril الخالصة اسذفاع ػغؾ انذو ٔاحذ يٍ أكصشانعٕايم نالطاتح تأيشاع انقهة ٔاالٔعٛح . ُْاك دالئم يرُايٛح ذشٛش انٗ أٌ انعٓذ انرأكسذ٘ ٚهعة دٔسا سئٛسٛا فٙ يشع فشؽ ػغؾ انذو. انذساسح انحانٛح ٔظٓد َحٕ ذحذٚذ انرأشٛش انًفٛذ انًرٕقع نًؼاد انرأكسذ فٛرايٍٛ ز نذٖ غؾ انذو انعْٕش٘ ٔانزٍٚ ٚرى يعانعرٓى تاسرخذاو عقاقٛش يؼادج السذفاع ػغؾ انذو ْٙ انساد نقُاج انًشػٗ انًظاتٍٛ تفشؽ ػ انكانسٕٛو )ايهٕدتٍٛ ( ٔانًصثؾ نالَزٚى انًحٕل نالَعٕٛذُسٍٛ )اَانثشٚم(. سد ٔذسعٌٕ شخض يظاب تفشؽ ػغؾ انذو انعْٕش٘ ± 5.77َانثشٚم نكٍ نى ٚظهٕا انٗ انٓذف تؼغؾ انذو ٔتًعذل أعًاس )( ركٕس ٚعانعٌٕ تاسرخذاو االيهٕدتٍٛ أ اال68(اَاز ٔ )75) ( يهغهشاو ٕٚيٛا يٍ )ايهٕدتٍٛ( انًعًٕعح االٔنٗ ٔ 7( يشٚغ اسرهًٕا )57( سُح شاسكٕا فٙ ْزِ انذساسح ٔقسًٕا انٗ : ) 75.65 ( يشٚغ 55يٍٛ ز انًعًٕعح انصاَٛح ٔ )( يهغشاو يشذٍٛ ٕٚيٛا يٍ فٛرا755( يشٚغ اسرهًٕا َفس انعشعح يٍ )ايهٕدتٍٛ( ٔ )57) ( يهغشاو ٕٚيٛا 755(يشٚغ اسرهًٕا َفس انعشعح يٍ )اَانثشٚم( ٔ )55( يهغشاو ٕٚيٛا يٍ )اَانثشٚم( انًعًٕعح انصانصح ٔ )7اسرهًٕا ) سكٕا فٙ ( ركٕس انًعًٕعح انخايسح شا9( اَاز ٔ ) 11( شخض يظح يعًٕعح انسٛطشج )55يٍ فٛرايٍٛ ز انًعًٕعح انشاتعح. ) ( 6،5،5،1انذساسح. حٛس اسرًش انعالض ٔيشاقثح انًشػٗ نًذج شٓش ٔاحذ ٔيعذل ػغؾ انذو ذى قٛاسّ نكم يشٚغ قثم انعالض ٔتعذ ) اساتٛع يٍ انًعانعح ، يسرٕٖ انًانَٕذاٚهذٚٓاٚذ ٔيسرٕٖ انذٌْٕ، تٛاَاخ ذخطٛؾ انقهة ٔيعذل َثؼاخ انقهة ذى قٛاسٓا نكم يشٚغ قثم ( اساتٛع يٍ انًعانعح. إٌ إػافح يؼاد انرأكسذ فٛرايٍٛ ز نهًشػٗ انزٍٚ ٚعانعٌٕ تاسرخذاو ايهٕدتٍٛ أ 6،5عح ٔتعذ )انثذء تانًعان ( اساتٛع يٍ تذء انًعانعح. ٔيٍ َاحٛح اخشٖ إٌ إػافح يؼاد 6،5،5االَانثشٚم َرط عُّ اَخفاػا يعُٕٚا فٙ يعذل انؼغؾ تعذ يشٔس) ( 6،5عًٕعح انصاَٛح أٔ انشاتعح َرط عُّ اَخفاػا يعُٕٚا فٙ يسرٕٖ انًانَٕذاٚهذٚٓاٚذ تعذ يشٔس)انرأكسذ فٛرايٍٛ ز نهًشػٗ فٙ انً اساتٛع يٍ تذء انًعانعح تًُٛا نى ٚحذز ا٘ ذغٛش يعُٕ٘ فٙ يسرٕٖ انذٌْٕ، تٛاَاخ ذخطٛؾ انقهة ٔيعذل َثؼاخ انقهة نهًشػٗ فٙ ذء انًعانعح تفٛرايٍٛ ز عُذ يقاسَرٓى تانقٛى ٔقد انظفش ٔاالشخاص فٙ ( اساتٛع يٍ ت6،5انًعًٕعح انصاَٛح ٔانشاتعح تعذ يشٔس ) انًعًٕعح االٔنٗ ٔانصانصح ذراتعا. خراياً إٌ ْزِ انذساسح أظٓشخ إٌ نهعٓذ انرأكسذ٘ دٔسا يعُٕٚا فٙ يشع فشؽ ػغؾ انذو انعْٕش٘ ٔ شٚم( نعالض انًشػٗ قذ أعطٗ اَخفاػاً يعُٕٚاً ظٛذاً فٙ ػغؾ إٌ اػافح ياَع انرأكسذ فٛرايٍٛ ز نهعقاقٛش انًسرخذيح ) ايهٕدتٍٛ أٔ اَانث .انذو ٔٔقاٚح ظٛذج ػذ أكسذج انذٌْٕ. 1 Corresponding author E- mail : drkassim_alshamaa@yahoo.com Received : 13/3/2010 Accepted : 5/4/2011 Iraqi J Pharm Sci, Vol.20(1) 2011 Antioxidant vitamin C 51 Introduction Hypertension is a common disease that is defined simply as persistently elevated blood pressure (B.P). Hypertension is identified as one of the most significant risk factors for cardiovascular diseases (CVDs) (1) . Hypertension adversely affects many organ systems throughout the body. Target organ damage includes Brain (Stroke or transient ischemic attack), Eyes (Retinopathy), Heart (Left ventricular hypertrophy, angina, prior myocardial infarction, prior coronary revascularization and heart failure). Kidney (Chronic kidney disease) and peripheral vasculature (peripheral arterial disease) (2) . The overall goal of treating hypertension is to reduce hypertension-associated cardiovascular and renal morbidity and mortality (3) . Pharmacological therapy involves prescribing of different antihypertensive drug classes. These agents can be given alone or in combination to treat the majority of hypertensive patients depending on B.P stage (4) . The role of oxidative stress in genesis and maintenance of hypertension is supported by amelioration of hypertension with antioxidant administration (5) . Vitamin C (ascorbic acid) is an essential micronutrient required for normal metabolic function of the human body which is considered a very efficient water soluble antioxidant (6) .Several studies have been shown that human with essential hypertension have a decreased antioxidant capacity (7,8) .A number of epidemiological studies have been shown a negative correlation between B.P. and vitamin C level (9,10) .Vitamin C might influence B.P. by acting as a free radical scavenging properly preventing prostacyclin synthetase inhibition. It has been found a lower levels of vitamin C in sustained hypertensive than normotensives human, this could be a result of greater antioxidant consumption, either for direct reactions or for regeneration of vitamin E to its reduce form, in response to an increased oxidant load associated with sustained hypertension (11) . The present study was directed to determine the beneficial effect of the antioxidant vitamin C in patients with essential hypertension treated with the calcium channel blocker (amlodipine) or with the angiotensin converting enzyme inhibitor (enalapril). Patients and Methods This study was carried out over nine months from November 2006 till July 2007. Many patients were interviewed according to patient's information sheet. Patients who enrolled in our study were diagnosed as they having essential hypertension and treated by specialist physicians while attending AL-Sadr Teaching Hospital in Basrah city. Ninety six patients (50 females and 46 males) with essential hypertension treated with calcium channel blocker (amlodipine), or with angiotensin converting enzyme inhibitor (enalapril), but did not reach the target blood pressure, and twenty apparently healthy subjects (11 females and 9 males) participated in this study. Inclusion and Exclusion Criteria The inclusion and exclusion criteria of all patients in this study are summarized as follow: Inclusion and exclusion criteria of hypertensive patients enrolled in the study Inclusion criteria Patients with mild to moderate essential hypertension treated with calcium channel blocker (5mg daily of amlodipine), or with angiotensin converting enzyme inhibitor (5 mg daily of enalapril), but did not reach the target blood pressure. Exclusion criteria Secondary hypertension. Smoking or alcohol consumption. History of myocardial infraction (Ml), angina pectoris, heart failure (HF), thyrotoxicosis, pregnant women, diabetes mellitus, malabsorption, uncontrolled arrhythmias and significant renal, hepatic or hematological diseases.Use of nonsteroid anti- inflammatory drugs, steroids, oestrogen containing preparation (like oral contraceptive pills and hormonal replacement therapy), cyclosporine, erythropoietin and sympathomimetic containing drugs or other medications that effect blood pressure,lipid profile, ECG or antioxidant status. Patients were divided as follows: Group 1: twenty five patients with essential hypertension treated with amlodipine 5 mg tablet once daily. Group 2: twenty five patients with essential hypertension received the same dose of amlodipine plus 500 mg vitamin C twice daily. Group 3: twenty patients with essential hypertension treated with enalapril 5 mg tablet once daily. Group 4: twenty three patients with essential hypertension received the same dose of enalapril plus 500 mg vitamin C twice daily. Group 5: twenty apparently healthy subjects. All patients in each group were followed up for four weeks, and mean blood pressure had Iraqi J Pharm Sci, Vol.20(1) 2011 Antioxidant vitamin C 52 been taken for each patient before and one, two, three and four weeks after starting treatment (1) . Serum MDA, lipid profile (TC, TG, HDL-C, LDL-C and VDL-C), ECG parameters (PR, QRS, and P- wave), and heart rate have been taken for each patient before and two and four weeks after starting treatment. Twenty apparently healthy subjects have also participated in this study. The thiobarbituric acid essay of Buege and Aust (1978) was used to measure serum MDA levels (12) . The estimation of total cholesterol depends on enzymatic colorimetric method of Richmond and Allain et al.,(1974) (13,14) . The estimation of Triglycerides depends on the enzymatic colorimetric method of fossati and Principe (15) . The estimation of High Density Lipoprotein-Cholesterol depends on the enzymatic method of Burestien et al, (1970) (16) . The LDL-C was calculated by the Friedwald formula as follows (17) : LDL-C= total cholesterol - [(HDL-C) + (triglyceride/5)]. The VLDL-C is calculated from the formula: VLDL – C = triglyceride/5 All values are expressed as mean ± standard error of the mean. Data are entered in to computer system using Microsoft office Excel 2003 software for all mathematics and statistical analysis. the student's test was used to determine the significant difference in means of groups. P < 0.05 was considered to be the lowest limit of significance. Results Table (1) showed the serum levels of MDA in patients with essential hypertension treated with amlodipine (group 1) or with enalapril (group 3) at zero time, these values were significantly higher than their values in control group. Table (2) showed that patients received amlodipine and vitamin C (group two) or enalapril and vitamin C (group four) showed significant lowering in average mean blood pressure after two, three and four weeks of treatment as compared with their values at zero time and their values in group one or three. Table (3) showed that the addition of vitamin C caused a significant lowering in serum MDA after two and four weeks of treatment in amlodipine and vitamin C treated group (group two) or enalapril and vitamin C treated group (group four), as compared with zero time values and their values in group one or three. The lowering in serum MDA was more prominent after four weeks of amlodipine or enalapril and vitamin C treatment as compared with their values after two weeks of treatment. The serum level of MDA in patients treated with enalapril and vitamin C (group four) were significantly lower than their values in those patients treated with amlodipine and vitamin C (group two) after two and four weeks of treatment. Table 1: Serum malondialde(µmol/I) of control group, patients treated with amoldipine (group one), or with enalapril (group three) at zero time. Values are presented as mean± standard error; p<0.05 indicated significant changes from control group. Group Number of patients Serum malondialdehyde. (μmol/I) Control group 20 0.5 ±0.03 Group one 25 1.39 ±0.04* Group three 23 1.13 ±0.03* * Significant at p<0.05 as compared with control group. Table 2 : Mean blood pressure (mmHg) of patients in group one, two, three and four. Mean blood pressure in (mmHg) Time Group 1 Amlodipine n=25 Group 2 Amlodipine +vit.C n=25 Group 3 Enalapril n=23 Group 4 Enalalpril + vit.C n=23 Zero time 119.06 ±0.68 118.8 ± 0.82 117.48 ± 1.06 117.97 ± 1.02 1 st week 118.62 ± 0.64 117.2 ± 0.78 117.01 ± 0.95 116.37 ± 1.02 2 nd week 117.82 ± 0.61 114.4 ± 0.83 * a 116.52 ± 0.93 114.03± 0.97 *b 3 rd week 117.7 ± 0.62 111.57 ± 0.85* a 116.08 ± 0.97 114.36 ± 0.94*b 4 th week 117.28 ± 0.52 108.08 ± 0.78* a 115.16 ± 0.85 110.66 ± 0.93*b *significant at p<0.05 as compared with zero time value. a significant at p<0.05 as compared with group one. b significant at p<0.05 as compared with group three. Iraqi J Pharm Sci, Vol.20(1) 2011 Antioxidant vitamin C 53 Table 3 : Serum malondialdehyde (μmol/l) of patients in group one, two, three and group four. Serum malondialdehyde (μmol/l) Time Group 1 Amlodipine Group 2 Amlodipine + vit.C Group 3 Enalapril Group 4 Enalalpril + vit.C Zero time 1.39 ± 0.05 1.37 ± 0.4 1.13 ± 0.03 1.06 ±0.03 2 nd week 1.34 ± 0.5 1.16 ± 0.4 * a 1.13 ± 0.03 0.97± 0.03 *bc 4 th week 1.34 ± 0.04 0.83 ± 0.03* a 1.11 ± 0.03 0.77±0.03*bc a significant at p<0.05 as compared with group one. b significant at p<0.05 as compared with group three. c significant at p<0.05 as compared with group two. There was a significant change in lipid profile in hypertensive patients treated with amlodipine or enalapril at zero time as compared to their values in control group (Table 4). This change includes an elevation in serum level of (TC,TG, LDL-C and VLDL-C), while there was slight, but not significant reduction in serum level of HDL-C in hypertensive patients as compared to their values in control group. There were no significant changes in lipid profile, ECG parameters and heart rate of patients treated with amlodipine pulse vitamin C (group two) or patients treated with enalapril plus vitamin C (group four) compared to their values at zero time or to patients received amlodipine or enalapril alone (group one and two). (Table 5and 6). Table 4 : Lipid profile parameters (TC, TG, LDL-CHDL-C and VLDL-C) of control group, patients in group one and in group three at zero time. Lipid profile parameters Control group n=20 Group 1 n=25 Group 3 n=23 TC (mmol/L) 4.18±0.15 5.0 ± 0.09* 4.87 ± 0.1* TG (mmol/L) 1.94 ±0.09 2.51± 0.04* 2.43 ± 0.04* HDL-C (mmol/L) 1.22± 0.02 1.1 ±0.02 1.08 ±0.03 LDL-C (mmol/L) 2.57 ±0.14 3.41 ± 0.09* 3.36 ±0.09* VLDL-C (mmol/L) 0.39± 0.02 0.5 ±0.01* 0.49 ± 0.01* * Significant at p<0.05 as compared with control group. TC: Total cholesterol; TG: Triglyceride; HDL-C: High density lipoprotein cholesterol; LDL-C: Low density lipoprotein cholesterol; VLDL-C: Very low density lipoprotein cholesterol; N: number of patients. Table 5 : lipid profile (TC, TG,HDL-C, LDL-C and VLDL-C) in patients treated with amlodipine (group one), patients treated with amlodipine and vitamin C (group two), patients treated with enalapril (group three), and patients treated with enalapril and vitamin C (group four). Lipid profil parameters Group 1 Amlodipine Group 2 Amlodipine + vit C Group 3 Enalapril Group 4 Enalapril + vit C Zero time 4th week Zero time 4th week Zero time 4th week Zero time 4th week TC (mmol/L) 5.02 ± 0.09 5 ± 0.09 5.03 ± 0.11 4.87 ± 0.12 4.87 ± 0.1 4.82 ± 0.1 4.89 ± 0.1 4.84 ± 0.1 TG (mmol/L) 2.51 ± 0.04 2.49±0.04 2.46 ± 0.04 2.39 ± 0.04 2.43 ± 0.04 2.39 ± 0.04 2.42 ± 0.05 2.38 ± 0.05 HDL-C (mmol/L) 1.1 ± 0.02 1.13±0.02 1.08 ± 0.02 1.15 ± 0.02 1.08 ± 0.03 1.12 ± 0.02 1.11 ± 0.01 1.18 ± 0.02 LDL-C (mmol/L) 3.41 ± 0.09 3.38±0.04 3.43 ± 0.12 3.35 ± 0.12 3.31 ± 0.09 3.25 ± 0.1 3.29 ± 0.1 3.23 ± 0.1 VLDL-C (mmol/L) 0.53 ± 0.01 0.51±0.01 0.5 ± 0.01 0.46 ± 0.01 0.5 ± 0.01 0.51 ± 0.01 0.49 ± 0.01 0.46 ± 0.01 TC: Total cholesterol; TG: Triglyceride; HDL-C: High density lipoprotein cholesterol; LDL-C: Low density lipoprotein cholesterol; VLDL-C: Very low density lipoprotein cholesterol Iraqi J Pharm Sci, Vol.20(1) 2011 Antioxidant vitamin C 54 Table 6 : ECG parameters (PR,P-wave, and QRS) and heart rate in patients treated with amlodipine (group one), patients treated with amlodipine and vitamin C (group two), patients treated with enalapril (group three), and patients treated with enalapril and vitamin C (group four). Values are presented as mean ± standard error. ECG parameters Group 1 Amlodipine Group 2 Amlodipine + vit C Group 3 Enalapril Group 4 Enalapril + vit C Zero time 4 t h w eek Zero time 4 t h w eek Zero time 4 t h w eek Zero time 4 t h w eek HR(bpm) 68±0.16 69.28±0.92 66.64±1.18 71.64±1.11 69.04±1.03 71.2±0.93 68.78±1.07 72.12±0.98 PR(ms) 167.12±3.33 167.84±3.4 167.52±2.74 162.44±2.28 167.04±2.59 163.57 ±2.43 169.39±2.18 163.83±1.96 P-wave(ms) 95.84±1.81 98.12±1.64 94.62±2.33 100.16±1.86 95.91±1.83 101.39±1.67 98.39±1.92 103.83±1.69 QRS (ms) 103.32±2.66 105.84±2.73 102.8±2.89 108.2±2.41 104.09±2.26 107.48±2.19 103.83±2.14 108±2.1 Discussion Results in this study showed that patients with essential hypertension treated with amlodipine or enalapril had significantly higher levels of malondialdehyde as compared to control group. This is in agreement with other worker who demonstrated an increase in ROS production in patients with essential hypertension, based in general, on increased levels of serum thiobarbituric acid-reactive substance and other biomarkers of lipid peroxidation and oxidative stress (11) . Animals and human studies demonstrated that reactive oxygen species play an important pathophysiological role in the development of hypertension, this is due to excessive superoxide formation, decreased nitric oxide bioavailability in the vasculature and kidney, and ROS- mediate cardiovascular remodeling (18) . In both endothelial and vascular smooth muscle cells mechanical stretch has been shown to activate the NAD(P)H oxides which is an important source for ROS production (19) . Our results showed that patients with essential hypertension treated with amoldipine or enalapril showed a significant change in lipid profile as compared with control group. This is consistent with Sarkar et al (2007), who showed that TC, TG, and LDL-C in forty hypertensive patients were significant higher than their values in thirty normotensive and healthy subjects (20) .The addition of vitamin C in a dose of 1000 mg for one month for patients with essential hypertension treated with amlodipine or enalapril produced significant lowering in serum levels of MDA after two and four weeks of treatment, this lowering could be due to the activity of vitamin C as free radicals scavenger, that helps to terminate the free radicals damaging effect and to prevent lipid per- oxidation (21) .The lowering of serum level of MDA in patients treated with enalapril plus vitamin C was significantly greater than that observed in amlodipine plus vitamin C treated patients after two and four weeks of treatment. This could be due to the different mechanism of action of angiotensin converting enzyme inhibitor (enalapril) and calcium channel blockers (amlodipine). Where the activation of rennin-angiotensin system has-been proposed as mediator of NAD(P)H oxidase activation and ROS production (22) . In fact, some mechanism of action of angiotensin - converting enzyme inhibitors have been attributed to NAD(P)H oxidase inhibition and decreased in ROS production (23) . Likewise the addition of vitamin C in the same dose and for the same period had result in significant loweing effect in mean blood pressure after two, three and four weeks of treatment. This is consistent with Hajjar et al (2002), who demonstrated that both systolic and diastolic blood pressure decreased during the vitamin C supplementation phase in thirty one patients treated with antihypertensive drugs and vitamin c (24) and with Jennifer (2004) who showed that the antioxidant supplementation might reduce dependence on blood pressure lowering effect of calcium channel blocker nifedipine in 58 adults with essential hypertension (25) .The role of vitamin C in reducing blood pressure has different ways including, its direct free radicals scavenging ability and termination their damaging effect on blood vessels and prevent lipid peroxidation (26) ,the second way is its ability to regulate nitric oxide synthase that generate nitric oxide a potents vasodilator that play a key role in controlling the cardiovascular system, the third way is its ability to regulate the NAD(P)H oxidase activity and ROS production, the fourth way is its ability to regulate antioxidant enzyme including superoxide dismutase and glutathione, in addition to their ability to reduce vitamin E to its active form; the fifth way is that ascorbic acid increase tetrahydrobiopterin an important cofactor of nitric oxide synthase enzyme by Iraqi J Pharm Sci, Vol.20(1) 2011 Antioxidant vitamin C 55 preventing its oxidation (chemical stability) (27) . Finally it has been demonstrated that oxidative stress and hypertension are closely associated with higher sympathetic activity (28) . Thus, it could be argued that vitamin C induce change in blood pressure observed in the present study may be in part attributed to its inhibitory effect on the sympathetic activity or antioxidant induced change in the release of norepinephrine from the nerve terminal (29) .In the first week of treatment with vitamin C there was no significant lowering effect on the mean blood pressure, this would indicate that the blood pressure lowering effect of vitamin C was in long-term, where long period required to restore nitric oxide cofactor (tetrahydrobiopterin) level by preventing its oxidation (26) .In conclusion the lowering in mean blood pressures were not differ significantly when comparing patients treated with enalapril plus vitamin C to those treated with amlodipine plus vitamin C. Reference 1. Chobanian AV, Bakris GL, Black HR, et al. 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