J Kunes

Academy of Sciences of the Czech Republic, Praha, Praha, Czech Republic

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Publications (203)609.98 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Aims: Human genome-wide association studies (GWAS) of hypertension identified only few susceptibility loci with large effect that were replicated across populations. The vast majority of genes detected by GWAS has small effect and the regulatory mechanisms through which these genetic variants cause disease remain mostly unclear. Here, we used comparative genomics between human and an established rat model of hypertension to explore the transcriptional mechanisms mediating the effect of genes identified in 15 hypertension GWAS. Methods and results: Time series analysis of radiotelemetric blood pressure (BP) was performed to assess 11 parameters of BP variation in recombinant inbred strains derived from the spontaneously hypertensive rat. BP data were integrated with ∼27 000 expression quantative trait loci (eQTLs) mapped across seven tissues, detecting >8000 significant associations between eQTL genes and BP variation in the rat. We then compiled a large catalogue of human genes from GWAS of hypertension and identified a subset of 2292 rat-human orthologous genes. Expression levels for 795 (34%) of these genes correlated with BP variation across rat tissues: 51 genes were cis-regulated, whereas 459 were trans-regulated and enriched for 'calcium signalling pathway' (P = 9.6 × 10(-6)) and 'ion channel' genes (P = 3.5 × 10(-7)), which are important determinants of hypertension. We identified 158 clusters of trans-eQTLs, annotated the underlying 'master regulator' genes and found significant over-representation in the human hypertension gene set (enrichment P = 5 × 10(-4)). Conclusion: We showed extensive conservation of trans-regulated genes and their master regulators between rat and human hypertension. These findings reveal that small-effect genes associated with hypertension by human GWAS are likely to exert their action through coordinate regulation of pathogenic pathways.
    Cardiovascular Research 10/2012; 97(4). DOI:10.1093/cvr/cvs329 · 5.94 Impact Factor
  • Michal Behuliak · Jaroslav Kunes · Josef Zicha
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    ABSTRACT: Background: Spontaneously hypertensive rats (SHR) are characterized by augmented Ca2+ influx through L-type voltage-dependent calcium channels (L-VDCC), which is one of the most important factors responsible for increased blood pressure (BP). The altered BP regulation in hypertension also includes RhoA/Rho-kinase pathway playing pivotal role in Ca2+ sensitization. The ontogenetic development of Ca2+ influx and Ca2+ sensitization has not been fully examined. Our study was aimed to determine the contribution of these two mechanisms to BP maintenance in conscious normotensive Wistar-Kyoto rats (WKY) and SHR at different ages. Design and methods: BP response to acute intravenous administration of cumulative doses of L-VDCC blocker (nifedipine) or Rho kinase inhibitor (fasudil) was determined in 3-, 5-, 7-, 13-, and 26-week-old WKY and SHR. Results: There were no significant differences in BP response to nifedipine induced L-VDCC blockade in all age groups of WKY rats, while in SHR BP response increased with age and/or hypertension level. The same was true for Rho kinase inhibition. In 3-week-old rats nifedipine-sensitive BP components were identical in both strains, whereas BP response to fasudil was greater in 3-week-old WKY than in prehypertensive SHR. Finally, the fasudil-sensitive BP component was greater in 13- and 26-week-old SHR than WKY. Conclusions: Ca2+ influx through L-VDCC and Ca2+ sensitization mediated by RhoA/Rho-kinase pathway are involved in the regulation of vascular tone in both strains. Both mechanisms are augmented in rats with developed hypertension, but RhoA/Rho-kinase pathway seems to be diminished in prehypertensive SHR. Partially supported by grant 304/12/0259 (GA CR).
    Journal of Hypertension 09/2012; 30:e239. DOI:10.1097/01.hjh.0000420432.44060.a7 · 4.72 Impact Factor
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    Jirí Sedý · Josef Zicha · Jara Nedvídková · Jaroslav Kunes
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    ABSTRACT: The pronounced activation of sympathetic nervous system is a necessary prerequisite for the development of neurogenic pulmonary edema (NPE) in rats with balloon compression of spinal cord. In this study we examined whether this is a consequence of rapid activation of spinal pathways leading to sympathetic venoconstriction, blood pressure rise, and reflex bradycardia. We found that NPE development can be prevented by epidural upper thoracic anesthesia or by transection of the upper spinal cord. This indicates an important role of spinal pathways activation. NPE development can also be prevented by moderate blood loss, supporting the role of blood redistribution to pulmonary circulation. In rats developing NPE the catecholamine surge following spinal cord compression involved not only a dramatic increase of circulating norepinephrine but also of epinephrine levels. The pretreatment of rats with α-1 adrenoceptor blocker prazosin, α-2 adrenoceptor blocker yohimbine, or calcium channel blocker nifedipine prevented NPE development, whereas the effect of β-adrenoceptor blockade with propranolol was less convincing. In conclusion, considerable activation of thoracic spinal pathways, followed by marked catecholamine secretion, play a major role in the development of NPE in spinal cord-injured rats. Enhanced α-adrenergic nifedipine-sensitive vasoconstriction is responsible for observed blood pressure changes, subsequent baroreflex bradycardia, and blood volume redistribution, which represent major pathogenetic mechanisms of NPE development.
    Journal of Applied Physiology 09/2011; 112(1):1-8. DOI:10.1152/japplphysiol.00574.2011 · 3.06 Impact Factor
  • Jaroslav Kunes · Michaela Kadlecova · Josef Zicha
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    ABSTRACT: Essential hypertension is a major risk factor for several cardiovascular diseases, the etiology of which is not yet completely understood. The problem is that blood pressure (BP) is a typical quantitative trait with multifactorial determination. The interactions of multiple genetic and environmental factors as well as gene–gene interactions cause modifications of various systems that adjust blood pressure to actual living conditions. Numerous environmental factors surrounding the organism could modify its development not only by the influence on the expression of genetic information but mainly by epigenetic mechanisms. However, despite considerable research effort, it is still difficult to identify all genes and/or other genetic determinants leading to essential hypertension and other cardiovascular diseases. This is mainly because these diseases usually become a medical problem in adulthood, although their roots might be traced back to earlier stages of ontogeny. The link between distinct developmental periods (e.g., birth and adulthood) should involve the changes in gene expression involving epigenetic phenomena. The purpose of the present paper is to bring some light on gene–environmental interactions potentially implicated in the pathogenesis of hypertension, with special attention to epigenetic inheritance. KeywordsCardiovascular system-critical developmental periods-dietary intervention-epigenetics-gene-environment interactions-hypertension-metabolic syndrome-rat
    12/2010: pages 177-184;
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    ABSTRACT: Melatonin is suggested to be beneficial in several pathological conditions including arterial hypertension. One of the mechanisms proposed for its antihypertensive action is the protection against endothelial dysfunction. We investigated whether melatonin can accelerate the recovery from N(G)-nitro-L-arginine-methyl ester (L-NAME)-induced hypertension after the cessation of L-NAME administration. Male adult Wistar rats (n=40) were randomized into 3 treated groups: 5-week L-NAME, 5-week L-NAME + 3-week vehicle, 5-week L-NAME + 3-week melatonin and into 2 age-matched control groups. The blood pressure was measured in the carotid artery. The NO-signalling was represented by NO-synthase activity and expression in the aorta and NO-mediated relaxations of femoral and mesenteric arteries. The endothelium-derived-constricting factor (EDCF)-signalling was represented by aortic cyclooxygenase-2 expression and femoral EDCF-mediated contractions. Oxidative load was determined in the aorta based on conjugated dienes concentration and inner diameter was measured in femoral arteries. L-NAME caused hypertension, reduced NO-signalling and arterial diameter and increased oxidative load and EDCF-signalling. While the NO-signalling was restored spontaneously 3 weeks after L-NAME cessation, the EDCF-signalling, oxidative load and arterial remodeling were completely restored only when melatonin treatment was administered during the recovery period. The blood pressure regression was comparable between spontaneous and melatonin recovery. Although melatonin did not accelerate blood pressure reduction, it attenuated EDCF-contractions and oxidative load and enlarged arterial diameter. These effects may be beneficial for cardiovascular protection.
    Journal of Hypertension 09/2010; 28 Suppl 1(Suppl 1):S19-24. DOI:10.1097/01.hjh.0000388490.28213.de · 4.72 Impact Factor
  • I Vaneckova · Z Dobesova · J Kunes · J Zicha
    Journal of Hypertension 06/2010; 28. DOI:10.1097/01.hjh.0000379678.94578.76 · 4.72 Impact Factor
  • Journal of Hypertension 06/2010; 28. DOI:10.1097/01.hjh.0000379683.17449.b9 · 4.72 Impact Factor
  • Journal of Hypertension 06/2010; 28. DOI:10.1097/01.hjh.0000378812.21669.bb · 4.72 Impact Factor
  • M Pinterova · Z Dobesova · J Kunes · J Zicha
    Journal of Hypertension 06/2010; 28. DOI:10.1097/01.hjh.0000379686.09826.2a · 4.72 Impact Factor
  • Journal of Hypertension 06/2010; 28. DOI:10.1097/01.hjh.0000379680.71707.f1 · 4.72 Impact Factor
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    ABSTRACT: The activation of Ca(2+)-dependent K(+) channels (BK(Ca)) leads to the attenuation of vascular contraction. Our study aimed to evaluate BK(Ca) influence on norepinephrine (NE)-induced femoral artery contraction in two forms of genetic hypertension. NE dose-response curves were studied before and after BK(Ca) blockade or after combined blockade of BK(Ca) and NO synthase (NOS) in femoral arteries with intact endothelium from normotensive Wistar (WIS), hypertensive hereditary hypertriglyceridemic (HTG), or spontaneously hypertensive rats (SHR). NE-induced contractions of femoral arteries were augmented in both hypertensive strains compared with Wistar rats, but acetylcholine-induced relaxation was impaired in HTG only. The increase of basal vascular tone of isolated arteries after BK(Ca) blockade was similar in all rat strains, but subsequent NOS inhibition increased basal vascular tone more in vessels from both hypertensive rat strains. NOS inhibition increased sensitivity to NE in all strains, but BK(Ca) blockade in SHR only. Neither treatment enhanced maximal NE-induced contraction. NO-dependent attenuation of NE-induced contractions was greater in SHR than HTG or Wistar vessels, whereas large conductance Ca(2+)-dependent K(+) channels may play a greater role in modulating vascular contraction in the severe form of hypertension.
    Journal of the American Society of Hypertension 05/2010; 4(3):128-34. DOI:10.1016/j.jash.2010.02.006 · 2.61 Impact Factor
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    ABSTRACT: The mechanisms responsible for the antihypertensive effect of melatonin are not completely understood. To elucidate the possible role of the nitric oxide (NO) pathway in the hemodynamic actions of melatonin, the effects of this indolamine on vascular function during hypertension induced by the NO-synthase (NOS) inhibitor, N(omega)-nitro-L-arginine-methyl ester (L-NAME) were investigated. Four groups of male adult Wistar rats were employed: control, L-NAME (40 mg/kg), melatonin (10 mg/kg) and L-NAME + melatonin for 5 wks. Systolic and diastolic blood pressure were measured invasively in the carotid artery. Conjugated dienes concentration (an oxidative load marker), NOS RNA expression and its activity and RNA expression of cyclooxygenase-(COX)-1 and COX-2 were determined in the aorta. Acetylcholine-induced responses and their NO-mediated component were evaluated in femoral and mesenteric artery. Moreover, endothelium-derived constricting factor (EDCF)-dependent vasoconstriction and inner diameter were determined in the femoral artery. Chronic L-NAME treatment induced hypertension, elevated the oxidative load and inhibited NOS activity. Moreover, impaired NO-dependent relaxation, augmented EDCF-constriction, increased COX-2 expression and reduced arterial inner diameter were observed. Melatonin added to L-NAME treatment completely prevented elevation of the oxidative load in the aorta. However, melatonin was not able to prevent NOS activity decline, elevation of COX-2 expression or the impairment of vascular responses (except moderate improvement in relaxation of small mesenteric arteries) and it exerted only slight antihypertensive effect. In conclusion, in addition to the reduction of the oxidative load, the restoration of the NO pathway seems to play an important role in the antihypertensive effect of melatonin.
    Journal of Pineal Research 03/2010; 48(2):102-8. DOI:10.1111/j.1600-079X.2009.00732.x · 9.60 Impact Factor
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    Mária Pintérová · Petr Karen · Jaroslav Kunes · Josef Zicha
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    ABSTRACT: High blood pressure (BP) in spontaneously hypertensive rats (SHRs) is attributed to excessive activity of sympathetic nervous system (SNS) and relative nitric oxide deficiency. An important part of SNS hypertensive action is exerted by calcium influx through L-type of voltage-dependent calcium channels (L-VDCC). The overexpression of pertussis toxin (PTX)-sensitive inhibitory G-proteins (Gi) participating in the development and maintenance of high BP in SHRs suggested us to study Gi-protein involvement in the pathway through which noradrenergic vasoconstriction and calcium influx can be coupled. The participation of main vasoactive systems (angiotensin II, norepinephrine, nitric oxide) in BP maintenance was investigated in conscious SHR and WKY rats (half of them being pretreated with PTX, 10 microg/kg i.v., 48 h before the experiment). To evaluate the contribution of Gi-proteins and L-VDCC to vasoconstriction induced by exogenous norepinephrine, dose-response curves were determined before and after acute nifedipine administration. PTX pretreatment of SHRs significantly decreased BP and reduced sympathetic vasoconstriction, which was partially substituted by enhanced angiotensin II-dependent vasoconstriction. PTX pretreatment also reduced nitric oxide-dependent vasodilation in both rat strains. PTX pretreatment of SHRs decreased BP component sensitive to acute blockade of calcium entry by nifedipine. In both strains, PTX pretreatment as well as acute nifedipine administration caused substantial rightward shift of norepinephrine dose-response curves (without additive effects of both treatments). The enhanced contribution of SNS to hypertension maintenance in SHRs is mediated by Gi-protein-coupled pathway controlling calcium influx through L-VDCC.
    Journal of Hypertension 03/2010; 28(5):969-78. DOI:10.1097/HJH.0b013e328335dd49 · 4.72 Impact Factor
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    ABSTRACT: The goal of our study was to determine a contribution of nNOS to the increase of brain NO synthase activity induced by chronic N-acetylcysteine (NAC) treatment. Young 4-week-old male Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were subjected to treatment with NAC (1.5 g/kg/day) for 8 weeks. At the end of experiment total NOS activity was determined in the brainstem and cerebellum with and without specific nNOS inhibitor S-methyl-L-thiocitrulline (SMTC, 10(-6) mol/l) by measuring the formation of L-[(3)H] citrulline from L-[(3)H] arginine. Chronic NAC treatment had no effect on blood pressure (BP) of WKY, while it attenuated BP increase in young SHR. Total NOS activity was increased in the brainstem of SHR compared to WKY, but this strain difference was abolished by SMTC. Chronic NAC treatment of SHR increased total NOS activity by 32% in the brainstem and by 67% in the cerebellum. After the incubation of brainstem and cerebellum with SMTC there were no significant differences in NOS activity of NAC-treated rats compared to strain-matched controls. Taken together, nNOS seems to be responsible for the increase of total NOS activity in the brain of SHR. SMTC inhibited 86% and 70% of NAC-induced increase of total NOS activity in the brainstem and cerebellum, respectively. Thus, nNOS is responsible not only for strain differences but also for NAC-induced increase of total NOS activity in the brain.
    Journal of physiology and pharmacology: an official journal of the Polish Physiological Society 12/2009; 60(4):21-5. · 2.39 Impact Factor
  • M. Behuliak · M. Pinterova · J. Kunes · J. Zicha
    14th Annual Meeting of the European-Council-for-Cardiovascular-Research; 11/2009
  • M. Pinterova · M. Behuliak · J. Kunes · J. Zicha
    14th Annual Meeting of the European-Council-for-Cardiovascular-Research; 11/2009
  • S. Liskova · J. Kunes · J. Zicha
    14th Annual Meeting of the European-Council-for-Cardiovascular-Research; 11/2009
  • J. Zicha · Z. Dobesova · M. Pinterova · J. Kunes
    14th Annual Meeting of the European-Council-for-Cardiovascular-Research; 11/2009
  • Source
    Jirí Sedy · Josef Zicha · Jaroslav Kunes · Ales Hejcl · Eva Syková
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    ABSTRACT: Neurogenic pulmonary edema (NPE) is an acute life-threatening complication following an injury of the spinal cord or brain, which is associated with sympathetic hyperactivity. The role of nitric oxide (NO) in NPE development in rats subjected to balloon compression of the spinal cord has not yet been examined. We, therefore, pretreated Wistar rats with the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) either acutely (just before the injury) or chronically (for 4 wk prior to the injury). Acute (but not chronic) L-NAME administration enhanced NPE severity in rats anesthetized with 1.5% isoflurane, leading to the death of 83% of the animals within 10 min after injury. Pretreatment with either the ganglionic blocker pentolinium (to reduce blood pressure rise) or the muscarinic receptor blocker atropine (to lessen heart rate decrease) prevented or attenuated NPE development in these rats. We did not observe any therapeutic effects of atropine administered 2 min after spinal cord compression. Our data indicate that NPE development is dependent upon a marked decrease of heart rate under the conditions of high blood pressure elicited by the activation of the sympathetic nervous system. These hemodynamic alterations are especially pronounced in rats subjected to acute NO synthase inhibition. In conclusion, nitric oxide has a partial protective effect on NPE development because it attenuates sympathetic vasoconstriction and consequent baroreflex-induced bradycardia following spinal cord injury.
    AJP Regulatory Integrative and Comparative Physiology 09/2009; 297(4):R1111-7. DOI:10.1152/ajpregu.00251.2009 · 3.11 Impact Factor
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    Jirí Sedý · Josef Zicha · Jaroslav Kunes · Eva Syková
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    ABSTRACT: Neurogenic pulmonary edema is an acute life-threatening complication of central nervous system injury. We introduce a hypothesis that early i.v. administration of high-dose atropine can prevent neurogenic pulmonary edema development on the basis of the prevention of baroreflex-induced bradycardia, which was recognized as a major factor in neurogenic pulmonary edema formation. To validate this hypothesis, a clinical trial in patients suffering from subarachnoid haemorrhage should be performed, with atropine administered i.v. immediately after the maintenance of the living functions, intubation and ability to monitor patient.
    Medical Hypotheses 04/2009; 73(1):42-4. DOI:10.1016/j.mehy.2008.12.051 · 1.07 Impact Factor

Publication Stats

2k Citations
609.98 Total Impact Points


  • 1994–2012
    • Academy of Sciences of the Czech Republic
      • • Institute of Physiology
      • • Centrum výzkumu chorob srdce a cév
      • • Institute of Molecular Genetics
      Praha, Praha, Czech Republic
  • 2009
    • University of Texas Health Science Center at San Antonio
      San Antonio, Texas, United States
  • 1993–2009
    • The Police Academy of the Czech Republic in Prague
      Praha, Praha, Czech Republic
  • 1991–2009
    • Charles University in Prague
      • • Faculty of Science
      • • Ústav fyziologie (Plzeň)
      Praha, Praha, Czech Republic
    • Hotel Dieu Hospital
      Kingston, Ontario, Canada
  • 1995–2008
    • Slovak Academy of Sciences
      • • Institute of Normal and Pathological Physiology
      • • Institute of Experimental Endocrinology
      Presburg, Bratislavský, Slovakia
  • 2007
    • Comenius University in Bratislava
      • Institute of Pharmacology
      Presburg, Bratislavský, Slovakia
  • 2003
    • Université du Québec à Montréal
      Montréal, Quebec, Canada
  • 1999
    • Centre hospitalier de l'Université de Montréal (CHUM)
      Montréal, Quebec, Canada
  • 1998
    • Université René Descartes - Paris 5
      Lutetia Parisorum, Île-de-France, France
  • 1996
    • Hebrew University of Jerusalem
      Yerushalayim, Jerusalem, Israel