Abstract
Increased production of free radicals and impairment of mitochondrial function are important factors in the pathogenesis of hypertension. This study examined the impact of hypertension on mitochondrial respiratory chain function, coenzyme Q9 (CoQ9), coenzyme Q10 (CoQ10), and α-tocopherol content in brain mitochondria, and the effect of blockade of angiotensin II type 1 receptors (AT1R) in the prehypertensive period on these parameters. In addition, blood pressure, heart and brain weight to body weight ratios, and the geometry of the basilar artery supplying the brain were evaluated. In the 9th week blood pressure and heart weight/body weight ratio were significantly increased and brain weight/body weight ratio was significantly decreased in spontaneously hypertensive rats (SHR) when compared to Wistar rats (WR). The cross-sectional area of the basilar artery was increased in SHR. Glutamate-supported respiration, the rate of ATP production, and concentrations of CoQ9, CoQ10, and α-tocopherol were decreased in SHR. The succinate-supported function and cytochrome oxidase activity were not changed. The treatment of SHR with losartan (20 mg/kg/day) from 4th to 9th week of age exerted preventive effect against hypertension, heart and arterial wall hypertrophy, and brain weight/body weight decline. After the therapy, the rate of ATP production and the concentration of CoQ increased in comparison to untreated SHR. The impairment of energy production and decreased level of lipid-soluble antioxidants in brain mitochondria as well as structural alterations in the basilar artery may contribute to increased vulnerability of brain tissue in hypertension. Long-term treatment with AT1R blockers may prevent brain dysfunction in hypertension.
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Ando H, Jezova M, Zhou J, Saavedra JM (2004a) Angiotensin II AT1 receptor blockade decreases brain artery inflammation in a stress-prone rat strain. Ann N Y Acad Sci 1018:345–350
Ando H, Zhou J, Macova M, Imboden H, Saavedra JM (2004b) Angiotensin II AT1 receptor blockade reverses pathological hypertrophy and inflammation in brain microvessels of spontaneously hypertensive rats. Stroke 35:1726–1731
Benicky J, Sánchez-Lemus E, Pavel J, Saavedra JM (2009) Anti-inflammatory effects of angiotensin receptor blockers in the brain and the periphery. Cell Mol Neurobiol 29:781–792
Berecek KH, Kirk KA, Nagahama S, Oparil S (1987) Sympathetic function in spontaneously hypertensive rats after chronic administration of captopril. Am J Physiol 252:H796–H806
Bosetti F, Brizzi F, Barogi S, Mancuso M, Siciliano G, Tendi AA, Murri L, Rapoport SI, Solaini G (2002) Cytochrome c oxidase and mitochondrial F1F0-ATPase (ATP synthase) activities in platelets and brain from patients with Alzheimer’s disease. Neurobiol Aging 23:371–376
Cadenas E, Davis K (2000) Mitochondrial free radical generation, oxidative stress, and aging. Free Rad Biol Med 29:222–230
Czernichow S, Bertrais S, Blacher J, Galan P, Briançon S, Favier A, Safar M, Hercberg S (2005) Effect of supplementation with antioxidants upon long-term risk of hypertension in the SU.VI.MAX study: association with plasma antioxidant levels. J Hypertens 23:2013–2018
Dantas AP, Franco Mdo C, Silva-Antonialli MM, Tostes RC, Fortes ZB, Nigro D, Carvalho MH (2004) Gender differences in superoxide generation in microvessels of hypertensive rats: role of NAD(P)H-oxidase. Cardiovasc Res 61:22–29
De Cavanagh EM, Toblli JE, Ferder L, Piotrkowski B, Stella I, Inserra F (2006) Renal mitochondrial dysfunction in spontaneously hypertensive rats is attenuated by losartan but not by amlodipine. Am J Physiol Regul Integr Comp Physiol 290:R1616–R1625
De Cavanagh EMV, Inserra F, Ferder M, Ferder L (2007) From mitochondria to disease: role of the renin-angiotensin system. Am J Nephrol 27:545–553
Dmitrieva NI, Bachmanov AA (1990) The behavioral and neuromorphological characteristics of rats with spontaneous hypertension. Zh Evol Biokhim Fiziol 26:78–84
Doroshchuk AD, Postnov AOIu, Afanas’eva GV, Budnikov EIu, Postnov IuV (2004) Decreased ATP-synthesis ability of brain mitochondria in spontaneously hypertensive rats. Kardiologiia 44:64–65
Doughan AK, Harrison DG, Dikalov SI (2008) Molecular mechanisms of angiotensin II-mediated mitochondrial dysfunction: linking mitochondrial oxidative damage and vascular endothelial dysfunction. Circ Res 102:488–496
Duszyński J, Kozieł R, Brutkowski W, Szczepanowska J, Zabłocki K (2006) The regulatory role of mitochondria in capacitative calcium entry. Biochim Biophys Acta 1757:380–387
Eshginia S, Gapparov MM (2006) The influence of phospholipids food and antioxidant at patients with hypertension. Vopr Pitan 75:37–39
Estabrook RW (1967) Mitochondrial respiratory control and the polarographic measurement of the ADP:O ratios. Methods Enzymol 10:41–47
Fato R, Bernardo SD, Estornell E, Parentic Castelli G, Lenaz G (1997) Saturation kinetics of coenzyme Q in NADH oxidation: rate enhancement by incorporation of excess quinone. Mol Aspects Med 18(Suppl):S269–S273
Ferrario CM (2004) The role of angiotensin antagonism in stroke prevention in patients with hypertension: focus on losartan. Curr Med Res Opin 20:1797–1804
Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW (1994) Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res 74:1141–1148
Hutchinson JS, Mendelsohn FA (1980) Hypotensive effects of captopril administered centrally in intace conscious spontaneously hypertensive rats and peripherally in anephric anaesthetized spontaneously hypertensive rats. Clin Exp Pharmacol Physiol 7:555–558
Johansson BB (1999) Hypertension mechanisms causing stroke. Clin Exp Pharmacol Physiol 26:563–565
Kawano Y, Yoshida K, Matsuoka H, Omae T (1994) Chronic effects of central and systemic administration of losartan on blood pressure and baroreceptor reflex in spontaneously hypertensive rats. Am J Hypertens 7:536–542
Kazama K, Anrather J, Zhou P, Girouard H, Frys K, Milner TA, Iadecola C (2004) Angiotensin II impairs neurovascular coupling in neocortex through NADPH oxidase-derived radicals. Circ Res 95:1019–1026
Kimura S, Zhang GX, Nishiyama A, Shokoji T, Yao L, Fan YY, Rahman M, Abe Y (2005) Mitochondria-derived reactive oxygen species and vascular MAP kinases: comparison of angiotensin II and diazoxide. Hypertension 45:438–444
Knopman DS, Mosley TH Jr, Bailey KR, Jack CR Jr, Schwartz GL, Turner ST (2008) Associations of microalbuminuria with brain atrophy and white matter hyperintensities in hypertensive sibships. J Neurol Sci 271:53–60
Koprdova R, Cebova M, Kristek F (2009) Long-term effect of losartan administration on blood pressure, heart and structure of coronary artery of young spontaneously hypertensive rats. Physiol Res 58:327–335
Kravtsov GM, Orlov SN, Pokudin NI, Postnov YuV (1983) Calcium transport in synaptosomes and subcellular membrane fractions of brain tissue in spontaneously hypertensive rats. Clin Sci (Lond) 65:127–135
Kristek F (1998) Long-term administration of L-arginine did not influence blood pressure, heart rate, cardiac hypertrophy or arterial wall thickness of spontaneously hypertensive rats. Exp Physiol 83:595–603
Kristek F, Koprdová R, Cebová M (2007) Long-term effects of early administered sildenafil and NO donor on the cardiovascular system of SHR. J Physiol Pharmacol 58:33–43
Kucharská J, Gvozdjáková A, Mizera S, Braunová Z, Schrameková E, Schreinerová Z, Pecháň I, Fabián J (1998) Participation of coenzyme Q10 in the rejection development of the transplanted heart: a clinical study. Physiol Res 47:399–404
Kucharská J, Sumbalová Z, Gvozdjáková A, Bernátová I, Pecháňová O (2001) Depletion of mitochondrial coenzyme Q in spontaneously hypertensive rats restored by red wine polyphenolic compounds (Provinol). Physiol Res 50:P37
Kucharská J, Sumbalová Z, Gvozdjáková A, Bada V, Adriantsitohaina R, Bernátová I, Pecháňová O (2005) Red wine polyphenolic compounds prevented depletion of brain mitochondrial coenzyme Q in spontaneously hypertensive rats. Possible mechanism of brain protection in hypertension. Physiol Res 54:55P
Kucuk M, Kaya M, Kalayci R, Cimen V, Kudat H, Arican N, Elmas I, Korkut F (2002) Effects of losartan on the blood-brain barrier permeability in long-term nitric oxide blockade-induced hypertensive rats. Life Sci 71:937–946
Lang JK, Gohil K, Packer L (1986) Simultaneous determination of tocopherols, ubiquinols, and ubiquinones in blood, plasma, tissue homogenates, and subcellular fractions. Anal Biochem 157:106–116
Lenaz G, Bovina C, Castelluccio C, Fato R, Formiggini G, Genova ML, Marchetti M, Pich MM, Pallotti F, Parenti Castelli G, Biagini G (1997) Mitochondrial complex I defects in aging. Mol Cell Biochem 174:329–333
Li Z, Bains JS, Ferguson AV (1993) Functional evidence that the angiotensin antagonist Losartan crosses blood-brain barrier in the rat. Brain Res Bull 30:33–39
Liu D, Gao L, Roy SK, Cornish KG, Zucker IH (2008) Role of oxidant stress on AT1 receptor expression in neurons of rabbits with heart failure and in cultured neurons. Circ Res 103:186–193
Lopez-Campistrous A, Hao L, Xiang W, Ton D, Semchuk P, Sander J, Ellison MJ, Fernandez-Patron C (2008) Mitochondrial dysfunction in the hypertensive rat brain: respiratory complexes exhibit assembly defects in hypertension. Hypertension 51:412–419
Lowry DH, Rosenbrough NY, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–276
Lu D, Yu K, Paddy MR, Rowland NE, Raizada MK (1996) Regulation of norepinephrine transport system by angiotensin II in neuronal cultures of normotensive and spontaneously hypertensive rat brains. Endocrinology 137:763–772
Mahajan AS, Babbar R, Kansal N, Agarwal SK, Ray PC (2007) Antihypertensive and antioxidant action of amlodipine and vitamin C in patients of essential hypertension. J Clin Biochem Nutr 40:141–147
Manning RD Jr, Tian N, Meng S (2005) Oxidative stress and antioxidant treatment in hypertension and the associated renal damage. Am J Nephrol 25:311–317
Muscatello U, Carafoli E (1969) The oxidation of exogenous and endogenous cytochrome C in mitochondria. A biochemical and ultrastructural study. J Cell Biol 40:602–621
Naini A, Lewis VJ, Hirano M, DiMauro S (2003) Primary coenzyme Q10 deficiency and the brain. Biofactors 18:145–152
Newaz MA, Yousefipour Z, Nawal NN (2005) Modulation of nitric oxide synthase activity in brain, liver, and blood vessels of spontaneously hypertensive rats by ascorbic acid: protection from free radical injury. Clin Exp Hypertens 27:497–508
Noguchi T, Ikeda K, Sasaki Y, Yamamoto J, Yamori Y (2004) Effects of vitamin E and sesamin on hypertension and cerebral thrombogenesis in stroke-prone spontaneously hypertensive rats. Clin Exp Pharmacol Physiol 31(Suppl 2):S24–S26
Panov AV, Dikalov S, Shalbueva N, Taylor G, Sherer T, Greenamyre JT (2005) Rotenone model of Parkinson disease: multiple brain mitochondria dysfunctions after short term systemic rotenone intoxication. J Biol Chem 280:42026–42035
Pecháňová O, Šimko F (2009) Chronic antioxidant therapy fails to ameliorate hypertension: potential mechanism behind. J Hypertens Suppl 6:S32–S36
Pecháňová O, Zicha J, Kojšová S, Dobešová Z, Jendeková L, Kuneš J (2006) Effect of chronic N-acetylcysteine treatment on the development of spontaneous hypertension. Clin Sci (Lond) 110:235–242
Pecháňová O, Zicha J, Paulis L, Zenebe W, Dobešová Z, Kojšová S, Jendeková L, Sládková M, Dovinová I, Šimko F, Kuneš J (2007) The effect of N-acetylcysteine and melatonin in adult spontaneously hypertensive rats with established hypertension. Eur J Pharmacol 561:129–136
Pediconi D, Martarelli D, Fontanazza A, Pompei P (2005) Effects of Losartan and Irbesartan administration on brain angiotensinogen mRNA levels. Eur J Pharmacol 528:79–87
Polizio AH, Peña C (2005) Effects of angiotensin II type 1 receptor blockade on the oxidative stress in spontaneously hypertensive rat tissues. Regul Pept 128:1–5
Polizio AH, Balastrasse KB, Gornalusse GG, Gorzalczany SB, Santa-Cruz DM, Yannarelli GG, Peña C, Tomaro ML (2009) Losartan exerst renoprotection through NADP(H) oxidase downregulation in a renovascular model of hypertension. Regul Pept 156:28–33
Postnov YV, Orlov SN, Budnikov YY, Doroschuk AD, Postnov AY (2007) Mitochondrial energy conversion disturbance with decrease in ATP production as a source of systemic arterial hypertension. Pathophysiology 14:195–204
Puddu P, Puddu GM, Cravero E, De Pascalis S, Muscari A (2007) The putative role of mitochondrial dysfunction in hypertension. Clin Exp Hypertens 29:427–434
Seccia TM, Atlante A, Vulpis V, Marra E, Passarella S, Pirrelli A (1998) Mitochondrial energy metabolism in the left ventricular tissue of spontaneously hypertensive rats: abnormalities in both adeninenucleotide and phosphate translocators and enzyme adenylate-kinase and creatine-phosphokinase activities. Clin Exp Hypertension 20:345–358
Studneva IM, Postnov AIu, Pisarenko OI (1999) Changes in the energy state of tissues in spontaneously hypertensive rats. Ross Fiziol Zh Im I M Sechenova 85:813–818
Sumbalová Z, Kucharská J, Gvozdjáková A, Bernátová I, Pecháňová O (2001) Could red wine polyphenolic compounds affect function of skeletal muscle mitochondria in hypertension. Physiol Res 50:P40
Sun C, Sellers KW, Sumners C, Raizada MK (2005) NAD(P)H oxidase inhibition attenuates neuronal chronotropic actions of angiotensin II. Circ Res 96:659–666
Sun L, Gao YH, Tian DK, Zheng JP, Zhu CY, Ke Y, Bian K (2006) Inflammation of different tissues in spontaneously hypertensive rats. Sheng Li Xue Bao. 58:318–323
Tajima A, Hans FJ, Livingstone D, Wei L, Finnegan W, DeMaro J, Fenstermacher J (1993) Smaller local brain volumes and cerebral atrophy in spontaneously hypertensive rats. Hypertension 21:105–111
Vasdev S, Gill V, Parai S, Longerich L, Gadag V (2002) Dietary vitamin E supplementation lowers blood pressure in spontaneously hypertensive rats. Mol Cell Biochem 238:111–117
Veerasingham SJ, Raizada MK (2003) Brain renin-angiotensin system dysfunction in hypertension: recent advances and perspectives. Br J Pharmacol 139:191–202
Wilms H, Rosenstiel P, Unger T, Deuschl G, Lucius R (2005) Neuroprotection with angiotensin receptor antagonists: a review of the evidence and potential mechanisms. Am J Cardiovasc Drugs 5:245–253
Yamakawa H, Jezova M, Ando H, Saavedra JM (2003) Normalization of endothelial and inducible nitric oxide synthase expression in brain microvessels of spontaneously hypertensive rats by angiotensin II AT1 receptor inhibition. J Cereb Blood Flow Metab 23:371–380
Yang H, Raizada MK (1998) MAP kinase-independent signaling in angiotensin II regulation of neuromodulation in SHR neurons. Hypertension 32:473–481
Zalba G, San José G, Moreno MU, Fortuño MA, Fortuño A, Beaumont FJ, Díez J (2001) Oxidative stress in arterial hypertension: role of NAD(P)H oxidase. Hypertension 38:1395–1399
Zhen J, Lu H, Wang XQ, Vaziri ND, Zhou XJ (2008) Upregulation of endothelial and inducible nitric oxide synthase expression by reactive oxygen species. Am J Hypertension 21:28–34
Zimmerman MC, Dunlay RP, Lazartigues E, Zhang Y, Sharma RV, Engelhardt JF, Davisson RL (2004a) Requirement for Rac1-dependent NADPH oxidase in the cardiovascular and dipsogenic actions of angiotensin II in the brain. Circ Res 95:532–539
Zimmerman MC, Lazartigues E, Sharma RV, Davisson RL (2004b) Hypertension caused by angiotensin II infusion involves increased superoxide production in the central nervous system. Circ Res 95:210–216
Zimmerman MC, Sharma RV, Davisson RL (2005) Superoxide mediates angiotensin II-induced influx of extracellular calcium in neural cells. Hypertension 45:717–723
Acknowledgments
This study was supported by grants VEGA No 1/3442/06, 2/6139/26, 2/0083/09, and 1/0328/10. Technical assistance of Anna Štetková, Ľudmila Butašová, and Ľubica Kosnáčová is highly appreciated. We would like to thank Dr. Peter Kvasnička for the help with statistical evaluation of the results, and Dr. Charles F. Merbitz for language corrections.
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Sumbalová, Z., Kucharská, J. & Kristek, F. Losartan improved respiratory function and coenzyme Q content in brain mitochondria of young spontaneously hypertensive rats. Cell Mol Neurobiol 30, 751–758 (2010). https://doi.org/10.1007/s10571-010-9501-4
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DOI: https://doi.org/10.1007/s10571-010-9501-4