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

J Hypertens. 2015 Jan;33(1):161-9. doi: 10.1097/HJH.0000000000000357.


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.

Method: 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animal Feed
  • Animals
  • Antihypertensive Agents / chemistry
  • Atrasentan
  • Blood Pressure / physiology
  • Calcium / chemistry
  • Calcium / metabolism*
  • Calcium Channels, L-Type / metabolism
  • Captopril / chemistry
  • Endothelin A Receptor Antagonists / chemistry*
  • Hypertension / physiopathology*
  • Male
  • NG-Nitroarginine Methyl Ester / chemistry
  • Nifedipine / chemistry*
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase / metabolism
  • Pentolinium Tartrate / chemistry
  • Pyrrolidines / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Transgenic
  • Renin / genetics
  • Renin-Angiotensin System / drug effects
  • Sodium Chloride, Dietary / pharmacology
  • Sympathetic Nervous System / physiopathology
  • Vasoconstriction / drug effects
  • Vasodilation / drug effects


  • Antihypertensive Agents
  • Calcium Channels, L-Type
  • Endothelin A Receptor Antagonists
  • Pyrrolidines
  • Ren2 protein, rat
  • Sodium Chloride, Dietary
  • Nitric Oxide
  • Pentolinium Tartrate
  • Captopril
  • Nitric Oxide Synthase
  • Renin
  • Nifedipine
  • Calcium
  • NG-Nitroarginine Methyl Ester
  • Atrasentan