title: Endothelin A receptor blocker atrasentan lowers blood pressure by the reduction of nifedipine-sensitive calcium influx in Ren-2 transgenic rats fed a high-salt diet.
abstract: BACKGROUND
  Our previous experiments demonstrated that selective endothelin A (ETA) receptor blockade had antihypertensive effects in Ren-2 transgenic rats (TGRs), but the mechanisms responsible for this change of blood pressure (BP) have not been explored yet.
  
  
  METHODS
  Four-week-old male heterozygous TGRs and their normotensive controls--Hannover Sprague-Dawley (HanSD) rats--were fed high-salt diet (2% NaCl) and were treated with selective ETA receptor blocker atrasentan (5 mg/kg per day) for 8 weeks. At the end of the study, the contribution of principle vasoactive systems was evaluated by the sequential blockade of the renin-angiotensin system (captopril), sympathetic nervous system (pentolinium) and nitric oxide synthase [N-nitro-L-arginine methyl ester (L-NAME)]. The role of calcium influx through L-type voltage-dependent calcium channels in BP maintenance was evaluated using nifedipine. In a separate group of animals, the efficiency of distinct vasodilator systems--prostanoids (blocked by nonselective cyclooxygenase inhibitor indomethacin) and Ca-activated K channels (inhibited by tetraethylammonium)--was also analyzed.
  
  
  RESULTS
  Atrasentan attenuated the development of hypertension in heterozygous TGRs, but had no effects in Hannover Sprague-Dawley rats. Moreover, atrasentan moderately attenuated renin-angiotensin system-dependent vasoconstriction, whereas it had no effect on sympathetic vasoconstriction. The nifedipine-sensitive BP component was markedly decreased by atrasentan treatment. In contrast, vasodilatation mediated by nitric oxide, endogenous prostanoids or Ca-activated K channels was reduced in atrasentan-treated TGRs, indicating the absence of compensatory augmentation of endothelin B receptor-mediated vasodilation in these animals.
  
  
  CONCLUSIONS
  BP-lowering effect of chronic atrasentan treatment in TGRs was mainly caused by reduced Ca influx through L-type voltage-dependent calcium channels due to missing ETA receptor-dependent vasoconstriction and attenuated angiotensin II-dependent vasoconstriction.
authors.affiliation: aInstitute of Physiology, Academy of Sciences of the Czech Republic bDepartment of Pathology, 3rd Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Ivana
authors.initials: I
authors.lastname: Vaněčková
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Dobešová
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Kuneš
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Vernerová
authors.forename: Josef
authors.initials: J
authors.lastname: Zicha
mesh_terms: D000821:Animal Feed; D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry; D000077868:Atrasentan; D001794:Blood Pressure / Q000502:physiology; D002118:Calcium / Q000737:chemistry / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002216:Captopril / Q000737:chemistry; D065130:Endothelin A Receptor Antagonists / Q000737:chemistry*; D006973:Hypertension / Q000503:physiopathology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000737:chemistry; D009543:Nifedipine / Q000737:chemistry*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010425:Pentolinium Tartrate / Q000737:chemistry; D011759:Pyrrolidines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D012083:Renin / Q000235:genetics; D012084:Renin-Angiotensin System / Q000187:drug effects; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D013564:Sympathetic Nervous System / Q000503:physiopathology; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D020746:Calcium Channels, L-Type; D065130:Endothelin A Receptor Antagonists; D011759:Pyrrolidines; C535029:Ren2 protein, rat; D017673:Sodium Chloride, Dietary; D009569:Nitric Oxide; D010425:Pentolinium Tartrate; D002216:Captopril; D019001:Nitric Oxide Synthase; D012083:Renin; D009543:Nifedipine; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester; D000077868:Atrasentan