Endothelin-1 and serotonin are involved in activation of RhoA/Rho kinase signaling in the chronically hypoxic hypertensive rat pulmonary circulation

We have previously reported that vasoconstrictor sensitivity to KC1 (a receptor-independent and voltage-gated Ca2+ influx-mediated vasoconstrictor) is augmented in the chronically hypoxic hypertensive rat pulmonary circulation probably through increased Rho kinase-mediated Ca2+ sensitization. However, the upstream mechanism by which the RhoA/Rho kinase signaling pathway is activated is unknown. This study examined if endogenous endothelin-1 (ET-1) and serotonin (5-HT) play roles in the Rho kinase-mediated augmented vasoconstrictor response to KC1 and the activation of RhoA in chronically hypoxic hypertensive rat pulmonary arteries. The augmented KC1 vasoconstriction in hypertensive lungs was reduced by the ETA receptor antagonist BQ123, while a dual ETA/B. antagonist had no further effects. A combination of BQ123 and a 5-HT1B/1D receptor antagonist, GR127935, was more effective than either agent alone. The combined antagonists also reduced augmented contractile sensitivity to KCI in hypertensive intrapulmonary arteries. Membrane-to-cytosol ratio of RhoA expression in hypertensive arteries was greater than that in normotensive arteries and was reduced by BQ123 and GR127935. These results suggest that stimulation of ETA and 5-HT1B/1D receptors by endogenous ET-1 and 5-HT, respectively, is involved in RboA/Rho kinase-mediated increased Ca2+ sensitization in the chronically hypoxic hypertensive rat pulmonary circulation.