ß₂-adenoceptors in pulmonary arteries were reported to be of high importance for the regulation of vascular tone. In pulmonary arterial hypertension abnormal neurohormonal stimulation occurs. We have therefore tested the impact of different adrenergic substances on the tone of large and small pulmonary arteries and compared the physiological effects with systemic arteries.

In isometric force measurements we found that the ß₂-adrenoceptor inhibitor ICI 118,551 induced vasorelaxation of norepinephrine (NE) pre-contracted pulmonary arteries (PAs). Furthermore, ICI 118,551 shifted the NE dose-response curve to the right in PAs (pEC50: 8.0930.200, n=8 (NE, PA) vs. 7.2810.075, n=6 (NE+ICI, PA), p<0.05) while there was no effect in aorta. Similarly, in PAs ICI 118,551 reduced the sensitivity towards several other contracting agonists like serotonin and endothelin. The right-shift of the NE dose-response curves induced by ICI 118,551 was mediated by a ß₂-adrenoceptor/G_i/o protein-dependent pathway as it could be abrogated by the ß₂-adrenoceptor blocker butoxamine and the G_i/o protein inhibitor pertussis toxin. The critical contribution of ß₂-adenoceptors was corroborated in ß₂-adrenoceptor KO mice where ICI 118,551 had no effect in PAs. Furthermore, removal of the endothelium or incubation with the NOS-inhibtor L-NAME attenuated the right-shift of the NE dose-response evoked by ICI 118,551 indicating that it was dependent on eNOS activation and nitric oxide production in the endothelium. In fact, Western Blot experiments revealed that ICI 118,551 induced a phosphorylation of the eNOS at Ser1177; similarly [NO]_i measurements in bovine pulmonary arterial cells with the membrane permeant dye DAF-FM DA showed an increase of NO release upon stimulation with ICI 118,551. These findings were further corroborated by experiments in PAs of eNOS KO mice where no response to ICI 118,551 could be detected.

The physiological relevance of the effect was proven in small PAs of lung slices and in the isolated perfused mouse lung under normoxic and hypoxic conditions. Also in these models ICI 118,551 induced vasorelaxation in PAs. Thus, we conclude that the ß₂-adrenoceptor inhibitor ICI 118,551 is a strong vasorelaxant in large and small PAs. This compound may provide novel options for the treatment of pulmonary arterial hypertension.