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
Abstrakt
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 reninangiotensin system (captopril), sympathetic nervous system (pentolinium) and nitric oxide synthase [ N-omega -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 Ca2+-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 systemdependent 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 Ca2+-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 Ca2+ influx through L-type voltage-dependent calcium channels due to missing ETA receptor-dependent vasoconstriction and attenuated angiotensin II-dependent vasoconstriction.