Recent studies demonstrate that ET-1 constricts human pulmonary vessels. although the mechanism of this response is not completely understood. In this study, we examined possible mechanisms by which ET-1 might constrict human PA. Rings of human intrapulmonary artery (6-14 mm) with and without endothelium (E+ and F-) were suspended in tissue baths containing Kreb's bicarbonate solution (16%O2, 5% CO2; 37°C) for isometric tension recording. Contraction to ET-1 was greater in F- than E+ rings, with maximal response at 10-8M. BQ-123 (10-6 M), an endothelin A (ETA) receptor antagonist, abolished ET-1-induced constriction in both E+ and F- rings. In additional experiments, smooth muscle cells freshly isolated from these arteries were superfused with modified Tyrode's solution and dialyzed with standard high K+ pipette solution. Using whole-cell patch-clamp techniques, outward K+ currents were activated by depolarizing cells from a holding potential of -60 mV to test potentials of -30 to +40 mV. KDR currents were examined in the presence of 100 nM charybdotoxin and were identified by current characteristics and inhibition by 4-aminopyridine (10 mM). ET-1 (10-8 M) caused significant inhibition of KDR current. Staurosporine (1 nM). a protein kinase C (PKC) inhibitor, abolished the effect of ET-1. These data suggest ET-1 constricts human PA via activation of ETA receptors, possibly due to myocyte depolarization via PKC-dependent inhibition of KDR. Furthermore, endothelium-derived relaxing factors modulate this response. Our results are consistent with data we reported previously in the rat. suggesting similar mechanisms may be operative in both species.
|Original language||English (US)|
|State||Published - Dec 1 1997|
ASJC Scopus subject areas
- Molecular Biology