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. Issue 1 (January 2015)

• Record Type: Journal Article
• Authors: Vaněčková, Ivana; Dobešová, Zdenka; Kuneš, Jaroslav; Vernerová, Zdenka; Zicha, Josef
• Is Part Of: Journal of hypertension. Volume 33:Issue 1(2015:Jan.)
• Publication Date: 2015-01
• Subjects: Hypertension -- Periodicals; Hypertension -- Periodicals; 616.132005
• DOI: 10.1097/HJH.0000000000000357
• Languages: English
• ISSNs: 1473-5598

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background:</title> <p>Our previous experiments demonstrated that selective endothelin A (ET<sub>A</sub>) 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.</p> </sec> <sec> <title>Method:</title> <p>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 ET<sub>A</sub> 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<sup>ω</sup>-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<sup>2+</sup>-activated K<sup>+</sup> channels (inhibited by tetraethylammonium) – was also analyzed.</p> </sec> <sec> <title>Results:</title> <p>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<sup>2+</sup>-activated K<sup>+</sup> channels was reduced in atrasentan-treated TGRs, indicating the absence of compensatory augmentation of endothelin B receptor-mediated vasodilation in these animals.</p> </sec> <sec> <title>Conclusion:</title> <p>BP-lowering effect of chronic atrasentan treatment in TGRs was mainly caused by reduced Ca<sup>2+</sup> influx through L-type voltage-dependent calcium channels due to missing ET<sub>A</sub> receptor-dependent vasoconstriction and attenuated angiotensin II-dependent vasoconstriction.</p> </sec> </abstract>