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Contribution of Captopril Thiol Group to the Prevention of Spontaneous Hypertension

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Contribution of Captopril Thiol Group to the Prevention of Spontaneous Hypertension Physiol. Res. 56 (Suppl. 1): S41-S48, 2007 Contribution of Captopril Thiol Group to the Prevention of Spontaneous Hypertension O. PECHÁŇOVÁ1,2 1Institute of Normal and Pathological Physiology and Centre of Excellence for Cardiovascular Research, Slovak Academy of Sciences, Bratislava, Slovak Republic, 2CRC and Institute of Physiology, AS CR, Prague, Czech Republic Received July 4, 2007 Accepted August 28, 2007 On-line available September 5, 2007 Summary We aimed to compare the effect of angiotensin converting enzyme (ACE) inhibitors captopril (containing thiol group) and enalapril (without thiol group) on the development of spontaneous hypertension and to analyze mechanisms of their actions, particularly effects on oxidative stress and NO production. Six-week-old SHR were divided into three groups: control, group receiving captopril (50 mg/kg/day) or enalapril (50 mg/kg/day) for 6 weeks. At the end of experiment, systolic blood pressure (SBP) increased by 41 % in controls. Both captopril and enalapril prevented blood pressure increase, however, SBP in the captopril group (121±5 mmHg) was significantly lower than that in the enalapril group (140±5 mmHg). Concentration of conjugated dienes in the aorta was significantly lower in the captopril group compared to the enalapril group. Captopril and enalapril increased NO synthase activity in the heart and aorta to the similar level. Neither captopril nor enalapril was, however, able to increase the expression of eNOS. Both ACE inhibitors increased the level of cGMP. However, cGMP level was significantly higher in the aorta of captopril group. We conclude that captopril, beside inhibition of ACE, prevented hypertension by increasing NO synthase activity and by simultaneous decrease of oxidative stress which resulted in increase of cGMP concentration. Key words Spontaneous hypertension • Captopril • Enalapril • Nitric oxide synthase • Thiols • Reactive oxygen species Introduction may, except inhibition of angiotensin II production, stimulate synthesis of prostaglandins and bradykinin, Angiotensin converting enzyme (ACE) inhibitors inhibit production of superoxides, scavenge free radicals, are well established drugs in the treatment of hypertension and increase expression of endothelial nitric oxide synthase (Williams 1988, Šimko and Šimko 1999, 2000) and (eNOS), (Mak et al. 1990, Pecháňová et al. 1997, 2006, protection of the cardiovascular system during congestive Kojšová et al. 2006). Moreover, captopril and enalapril heart failure (Šimko 2002, Šimko et al. 2003). Although were shown to have direct effects on pathological voltage- the pharmacological mechanisms of ACE inhibitors are not operated calcium channel in cardiac myocytes (Wang et al. fully understood, various studies suggest that these agents 1996). PHYSIOLOGICAL RESEARCH ISSN 0862-8408 © 2007 Institute of Physiology, v.v.i., Academy of Sciences of the Czech Republic, Prague, Czech Republic Fax +420 241 062 164 E-mail: [email protected] http://www.biomed.cas.cz/physiolres S42 Pecháňová et al. Vol. 56 Captopril, in contrast to enalapril, is the ACE approved by the Ethical Committee of the Institute of inhibitor involving thiol group, which might participate Normal and Pathological Physiology SAS, and conform in formation of thiols and therefore it may have stronger to the European Convention on Animal Protection and antioxidant effect than other ACE inhibitors. Guidelines on Research Animal Use. Nevertheless, there are concerns with respect to the Young 6-week-old male spontaneously intensity of antioxidant effects of thiol-group-containing hypertensive rats (SHR) were randomly divided into and non-thiol ACE inhibitors (Bartosz et al. 1997, Šimko water drinking control group and groups receiving et al. 2002a,b). Clearfield et al. (1994) documented that captopril or enalapril in the dose of 50 mg/kg/day in tap captopril and enalapril were approximately equally water for 6 weeks (n=7 in each group). All animals were active in the prevention of LDL oxidation. Both these housed in the room with a stable temperature of 23±1 oC ACE inhibitors were shown to increase similarly the and fed a regular pellet diet ad libitum. Daily water activity of superoxide dismutase and glutathione consumption was estimated individually for every peroxidase in the liver (de Cavanagh et al. 1995) as well animal one week before the experiment. During the as Na+/K+-ATPase and Ca2+-ATPase activities in experiment, drinking fluid consumption was controlled erythrocytes (Golik et al. 1996). However, Temel and and adjusted, if necessary. Systolic blood pressure (SBP) Akyuz (2007) reported that captopril had an inhibitory was measured by non-invasive tail-cuff plethysmography effect on red cell plasma membrane Na+/K+-ATPase every week. After 6 weeks of treatment, the animals activity. Aznaouridis et al. (2007) showed that acute were sacrificed and body weight (BW) and heart weight inhibition of renin-angiotensin system with quinapril (HW) were determined. The HW/BW was calculated. may be more beneficial in terms of arterial function and Concentration of conjugated dienes (CD, the marker of central hemodynamics compared to captopril. On the membrane oxidative damage), total NO synthase other hand, only captopril, but not enalapril, improved activity, expression of eNOS protein, and cGMP level the endothelium-dependent and were determined in the heart and aorta. -independent relaxation responses in the isolated rat aorta of obese Zucker rats (Duarte et al. 1999). Conjugated diene concentrations Analogically, while collagen-induced platelet The concentration of CD was measured in lipid aggregation was significantly reduced by captopril, no extracts of the heart and aorta homogenates according to change was seen with enalapril (Skowasch et al. 2006). Kogure et al. (1982). Briefly, after chloroform Moreover, captopril in contrast to non-thiol group ACE evaporation under the inert atmosphere and addition of inhibitors was able to protect the heart against cyclohexane, CD concentration was determined arrhythmias induced by ischemia/reperfusion (van Gilst spectrophotometrically (λ=233 nm, Bio-Rad, GBC et al. 1986). 911A). The aim of this study was to compare the effect of captopril and enalapril on the development of Total NO synthase activity hypertension in spontaneously hypertensive rats (SHR) Total NO synthase activity was determined in and to analyze mechanisms of their actions, particularly crude homogenates of the heart and aorta by measuring effects on oxidative stress, NO synthase activity, eNOS the formation of L-[3H]citrulline from L-[3H]arginine protein expression, and cGMP level in the heart and (Amersham, UK) as previously described by Bredt and aorta. Snyder (1990) with minor modifications (Pecháňová et al. 1997). Methods Western blot analysis of eNOS Chemicals and drugs Samples of the heart and aorta (40 mg of wet All the chemicals used were purchased from tissue) were homogenized in 25 mmol/l Tris-HCl, pH Sigma Chemicals Co. (Germany) except of those defined 7.4, containing 5 mmol/l EDTA, 50 mmol/l NaCl, 1 in the text. μmol/l leupeptin, 0.3 μmol/l aprotinin, 0.1 mmol/l PMSF, 1 mmol/l pepstatin and 1 % SDS. After the Animals and treatment centrifugation (15000 x g, 20 min, twice) supernatants All procedures and experimental protocols were were subjected to SDS-PAGE using 10 % gels. 2007 Captopril Thiol Group and Hypertension S43 Table 1. Body weight (BW) and relative heart weight (HW/BW) in control SHR and SHR treated with captopril and enalapril for 6 weeks. SHR controls SHR + captopril SHR + enalapril n 7 7 7 BW (g) 311.7±10.2 287.4±12.9 294.0±10.6 HW/BW (mg/g) 3.25±0.07 2.36±0.11* 2.48±0.10* Data are means ± S.E.M., Significant differences: * p<0.05 compared to SHR controls. 220 HEART 200 500 180 CONT 160 * ENA P * * * * 400 * CAP ressure ressure 140 p * * 120 * + * 300 Blood Blood + * + * 100 0123456 200 Week tissue] [nmol/g CD 100 Fig. 1. Effect of 6-week captopril and enalapril treatment on systolic blood pressure of SHR. Control SHR (CONT), enalapril 0 (ENAP), captopril (CAP), significant differences: * p<0.05 CONT ENAP CAP compared to SHR controls, + p<0.05 compared to enalapril treated SHR. AORTA Following the electro-phoresis, proteins were transferred 700 to nitrocellulose-membranes and were probed with a 600 polyclonal rabbit anti-endothelial NO synthase (Alexis 500 * Biochemicals, Germany). Bound antibody was detected +* using a secondary peroxidase-conjugated anti-rabbit 400 antibody (Alexis Biochemicals, Germany). The bands 300 were visualized using the enhanced chemiluminescence 200 CD [nmol/g tissue] [nmol/g CD system (ECL, Amersham, UK) and analyzed 100 densitometrically using Photo-Capt V.99 software. 0 CONT ENAP CAP Cyclic GMP concentration Cyclic GMP concentration was measured in the Fig. 2. Effect of 6-week captopril and enalapril treatment on conjugated diene (CD) concentration in the heart and aorta. heart and aorta using commercial available Control SHR (CONT), enalapril (ENAP), captopril (CAP), radioimmunoassay kit (Immunotech, S.A., France) based significant differences: * p<0.05 compared to SHR controls, + p<0.05 compared to enalapril treated SHR. on the competition between succinylated cGMP of the sample and 125I labeled tracer for binding to polyclonal antibody coated onto tubes. Concentration of the cGMP Results in the sample was calculated from the standard curve and expressed as pmol/g tissue. Blood pressure and cardiac hypertrophy In young SHR, the chronic captopril and Statistical Analysis enalapril
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