Artikel
Pharmakologische Aktivierung von endothelialen TRPV4-Kationenkanälen induziert NO-mediierte Vasodilatation
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Veröffentlicht: | 8. August 2006 |
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Ca2+-influx through Ca2+-permeable cation channels of the TRP-superfamily has been proposed to play a significant role in Ca2+-dependent production of endothelial vasodilators factors. In the present study, we characterized endothelial TRPV4 channels by in situ patch-clamp technique combined with "multiplex" single-cell-RT-PCR, and Ca2+-imaging. In pressure-myograph experiments, we investigated how TRPV4 channels contribute to endothelium-dependent vasodilatation. Endothelial cells of rat carotid artery (CA), expressed TRPV4 channels, but not the other closely related TRPV1-3.
TRPV4 mRNA-expression was also present in human microvascular ECs.Endothelial TRPV4 was activated by the selective TRPV4-opener 4alpha-phorbol-12, 13-didecanoate (4alphaPDD), low pH, moderate warmth, and mechanically by hypotonic cell swelling. Activation of TRPV4 by 4alphaPDD increased intracellular [Ca2+]i by ≈ 140 nmol/L above basal levels. In pressure-myograph experiments, intraluminal application of 4alphaPDD caused a robust vasodilatation by ≈ 80% (at 1 µmol/L; KD 0.3 µmol/L) which was strictly endothelium-dependent and was also suppressed prevented by TRPV-inhibitor ruthenium red (RuR; 1 µmol/L). In the presence of inhibitors of NO- and prostacyclin-synthesis, 4alphaPDD did not produce vasodilatation under physiological Ca2+-gradients. Wall shear stress induced vasodilatation by ≈ 15% was similarly blocked by 1 µmol/L RuR. In conclusion, Ca2+-entry through endothelial TRPV4 channels triggers NO-dependent vasodilatation in endothelium of rat CA. Since selective blockage of TRPV4 suppressed wall shear stress-induced vasodilatation, TRPV4 channel may thus play a pivotal role in endothelial mechanosensing of hemodynamic forces. Pharmacological activation of TRPV4 may represent a novel pharmacotherapeutic strategy for the treatment of hypertension