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
Language English Country Netherlands Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Endothelin A Receptor Antagonists chemistry MeSH
- Antihypertensive Agents chemistry MeSH
- Atrasentan MeSH
- Hypertension physiopathology MeSH
- Captopril chemistry MeSH
- Blood Pressure physiology MeSH
- Animal Feed MeSH
- Rats MeSH
- Sodium Chloride, Dietary pharmacology MeSH
- NG-Nitroarginine Methyl Ester chemistry MeSH
- Nifedipine chemistry MeSH
- Nitric Oxide metabolism MeSH
- Pentolinium Tartrate chemistry MeSH
- Rats, Sprague-Dawley MeSH
- Rats, Transgenic MeSH
- Pyrrolidines therapeutic use MeSH
- Renin-Angiotensin System drug effects MeSH
- Renin genetics MeSH
- Sympathetic Nervous System physiopathology MeSH
- Nitric Oxide Synthase metabolism MeSH
- Calcium chemistry metabolism MeSH
- Calcium Channels, L-Type metabolism MeSH
- Vasodilation drug effects MeSH
- Vasoconstriction drug effects MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Endothelin A Receptor Antagonists MeSH
- Antihypertensive Agents MeSH
- Atrasentan MeSH
- Captopril MeSH
- Sodium Chloride, Dietary MeSH
- NG-Nitroarginine Methyl Ester MeSH
- Nifedipine MeSH
- Nitric Oxide MeSH
- Pentolinium Tartrate MeSH
- Pyrrolidines MeSH
- Ren2 protein, rat MeSH Browser
- Renin MeSH
- Nitric Oxide Synthase MeSH
- Calcium MeSH
- Calcium Channels, L-Type MeSH
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.
References provided by Crossref.org
Altered Balance between Vasoconstrictor and Vasodilator Systems in Experimental Hypertension
