Up4A has been identified as a novel, endothelium- derived vasoconstrictive factor (Jankowski et al., 2005). However, in conscious rodents, infusion of Up4A decreased blood pressure (Bie et al., 2007). Therefore, we investigated the vasoactive effect of Up4A in vitro. Experiments were performed with mouse aorta segments suspended and normalised in a Mulvany- Halpern myograph. After viability testing of smooth muscle and endothelium with phenylephrine (PE, 10^­5 M) and acetylcholine (ACh, 10­6 M), respectively, Up4A was added to PE-constricted blood vessels. Cumulative addition of Up4A in 10 min intervals initially elicited vasoconstriction (+18 ±2 % and +76 ±16 % of PE- contraction at10–7M and 10–6 M, respectively). However, at 10^­5 M of Up4A, predominant vasodilatation (­46 ±6%) was evident. Vasoconstriction returned at higher Up4A concentrations. In contrast, one-step exposure of PE-preconstricted aortae to 10^­5 M of Up4A caused a predominant vasoconstriction (+80 ±2%). Up4A (10^­7– 10^­5 M) added cumulatively to PE-untreated vessels induced a transient constriction at all concentrations. The constriction on 10^­5 M was smaller than at 10–6 ^M, showing parallels with the PE pre-treated rings. In conclusion, Up4A has a biphasic effect on vascular tone. Vasoconstriction is the dominant effect at low concentrations, while vasodilatation dominates at higher concentrations. The latter is potentiated by prior exposure to Up4A. This is compatible with activation of P2X and P2Y receptors by UP4A with different affinities. References: Jankowski V. et al.: Nature Med. 11:223, 2005 Bie P. et al.: 2007Experimental Biology meeting abstracts [on CD-ROM], Abstract #597.7.