Abstract-␤ 2 -Adrenoceptors are important modulators of vascular tone, particularly in the pulmonary circulation. Because neurohormonal activation occurs in pulmonary arterial hypertension, we have investigated the effect of different adrenergic vasoactive substances on tone regulation in large and small pulmonary arteries, as well as in systemic vessels of mice. We found that the ␤ 2 -adrenoceptor antagonist ICI 118,551 (ICI) evoked a decrease of vascular tone in large pulmonary arteries and reduced the sensitivity of pulmonary arteries toward different contracting agents, eg, norepinephrine, serotonin, or endothelin. ICI proved to act specifically on pulmonary vessels, because it shifted the dose-response curve of norepinephrine to the right in pulmonary arteries, whereas there was no effect in the aorta. Pharmacological experiments proved that the right shift of the norepinephrine dose-response curve by ICI was mediated via a ␤ 2 -adrenoceptor/G i/o protein-dependent pathway enhancing NO production in the endothelium; these results were corroborated in ␤-adrenoceptor and endothelial NO synthase knockout mice where ICI had no effect. ICI increased vascular lumen diameter in lung sections and reduced pulmonary arterial pressure under normoxia and under hypoxia in the isolated perfused lung model. These effects were found to be physiologically relevant, because ICI specifically decreased pulmonary but not systemic blood pressure in vivo. Thus, the ␤ 2 -adrenoceptor antagonist ICI is a pulmonary arterial-specific vasorelaxant and, therefore, a potentially interesting novel therapeutic agent for the treatment of pulmonary arterial hypertension. proteins and have an important vasorelaxing function in the systemic and pulmonary circuits. All of the isoforms that are known so far (␤ 1 -, ␤ 2 -, ␤ 3 , and low-affinity-state ␤ 1 -AR) have been identified in pulmonary vessels, 1-3 with the ␤ 2 -AR being the most potent for vasorelaxation. 4 The pulmonary arteries (PAs) are important therapeutic targets, because pulmonary arterial hypertension often occurs after cardiac surgery in children 5 but also in adults and can result in life-threatening right heart failure. Therefore, specific and fast-acting vasodilators for PAs are urgently needed. However, most drug treatment regimens also strongly decrease vascular tone in the systemic circuit, leading to hypotension.Other than ␤-AR agonists, ␤-blockers were also reported to show promising results in the treatment of pulmonary arterial hypertension, which was not caused by left ventricular disorders. 6 In systemic arteries, it has been demonstrated that thirdgeneration ␤-blockers can directly induce vasodilation via NO release from the endothelium 7 and thereby positively affect the afterload. The aim of our study was to identify pulmonary specific vasorelaxants, and we have, therefore, investigated the impact of different ␤-adrenergic mediators on vascular tone in the pulmonary and systemic circulations of mouse. We have identified ICI 118,551 (ICI), a ␤-blocker with antago...

Novel relaxants of pulmonary arteries and airways are of special interest to obtain insights into pulmonary signaling pathways and to develop treatment strategies for lung diseases. Herein, we demonstrate that Arg-Gly-Asp (RGD) peptides induce a dose-dependent relaxation of pulmonary arteries and airways in mouse. The relaxing effect was specific because it was strongly reduced using the control peptides RGE or RAD (P<0.001). Longer peptide sequences containing RGD and its flanking amino acids found in fibronectin showed a similar effect even at a 10-fold lower concentration. The relevance of RGD-induced pulmonary vasorelaxation was demonstrated in isometric force measurements, lung slices, and the isolated perfused lung model under normoxia and hypoxia and in vivo. As cell surface receptor we identified β3- but not β1-integrin subunits. Moreover, vasorelaxation by RGD peptides was strongly diminished after removal of the endothelium in endothelial nitric oxide synthase-deficient (eNOS(-/-) mice; P<0.01) and after pharmacological inhibition of the NO/sGC pathway (P<0.05). Additionally, several potassium channels like Kv, Kir, and KATP played a role. In airways the response was mediated by Kv and KCa channels. Thus, RGD peptides are relaxants of pulmonary arteries and airways. These findings may help to establish novel therapeutic approaches for pulmonary hypertension and obstructive lung disease.

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