title: Ontogenetic changes in contribution of calcium sensitization and calcium entry to blood pressure maintenance of Wistar-Kyoto and spontaneously hypertensive rats.
abstract: BACKGROUND
  Altered calcium sensitization (mediated by RhoA/Rho-kinase pathway) and enhanced calcium entry through L-type voltage-dependent calcium channels (L-VDCCs) participate in blood pressure (BP) maintenance of adult spontaneously hypertensive rats (SHRs). This study aimed to evaluate ontogenetic changes of these two pathways in BP control of SHR and Wistar-Kyoto (WKY) aged 3, 5, 7, 13, 26 and 42 weeks.
  
  
  METHODS
  BP response to acute administration of Rho-kinase inhibitor fasudil or L-VDCC blocker nifedipine and the expression of particular components of RhoA/Rho-kinase pathway were determined in young and adult animals.
  
  
  RESULTS
  Fasudil-induced BP reduction was attenuated in young SHR compared with WKY, but was enhanced in adult SHR. In contrast, BP response to nifedipine was similar in 3-week-old SHR and WKY and it was augmented with age in SHR but not in WKY. Consequently, the ratio between fasudil-induced and nifedipine-induced BP changes was lower in all age groups of SHR compared with WKY. Fasudil effects on contractility of isolated arteries were attenuated in young but not in adult SHR. mRNA expression of selected Rho-GEFs (Arhgef1, Arhgef11 and Arhgef12) was decreased only in adult SHR, whereas p63RhoGEF and CPI-17 expression was reduced in both age groups of SHR. Active RhoA and phosphorylated CPI-17 were increased in adult but not in young SHR.
  
  
  CONCLUSIONS
  The importance of RhoA/Rho-kinase pathway for BP/vascular tone control is attenuated in SHR from prehypertensive stages. Enhanced RhoA activation and/or CPI-17 phosphorylation might be counteracted by reduced expression of upstream activators of Rho-kinase (Rho-GEFs) together with lower expression of CPI-17 (in downstream cascade of Rho-kinase).
authors.affiliation: aInstitute of Physiology, Czech Academy of Sciences bDepartment of Physiology, Faculty of Sciences, Charles University, Prague, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Behuliak
authors.forename: Anna
authors.initials: A
authors.lastname: Vavřínová
authors.forename: Michal
authors.initials: M
authors.lastname: Bencze
authors.forename: Kamila
authors.initials: K
authors.lastname: Polgárová
authors.forename: Peter
authors.initials: P
authors.lastname: Ergang
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Kuneš
authors.forename: Ivana
authors.initials: I
authors.lastname: Vaněčková
authors.forename: Josef
authors.initials: J
authors.lastname: Zicha
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D006973:Hypertension / Q000503:physiopathology; D008297:Male; D009119:Muscle Contraction; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009543:Nifedipine / Q000494:pharmacology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics; D015398:Signal Transduction; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: C577237:Arhgef11 protein, rat; C577224:Arhgef12 protein, rat; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020662:Guanine Nucleotide Exchange Factors; D009124:Muscle Proteins; D010750:Phosphoproteins; C491519:Ppp1r14a protein, rat; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D064067:Rho Guanine Nucleotide Exchange Factors; C000608318:p63RhoGEF protein, rat; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; D009543:Nifedipine; C049347:fasudil; D002118:Calcium