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(Hypertension. 2009;54:157.)
© 2009 American Heart Association, Inc.

Original Articles

β₂-Adrenoceptor Antagonist ICI 118,551 Decreases Pulmonary Vascular Tone in Mice via a G_i/o Protein/Nitric Oxide-Coupled Pathway

Daniela Wenzel; Ralf Knies; Michaela Matthey; Alexandra M. Klein; Julia Welschoff; Vanessa Stolle; Philipp Sasse; Wilhelm Röll; Johannes Breuer; Bernd K. Fleischmann

From the Institute of Physiology I (D.W., M.M., A.M.K., J.W., P.S., W.R., B.K.F.) and Departments of Pediatric Cardiology (R.K., V.S., J.B.) and Cardiac Surgery (A.M.K., W.R.), University of Bonn, Bonn, Germany.

Correspondence to Bernd K. Fleischmann, Institute of Physiology I, University of Bonn, Sigmund-Freud-Str 25, 53127 Bonn, Germany. E-mail bernd.fleischmann{at}uni-bonn.de or Johannes Breuer, MD, Department of Pediatric Cardiology, University of Bonn, Adenauerallee 119, 53113 Bonn, Germany. E-mail johannes.breuer@ukb.uni-bonn.de

β₂-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 β₂-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 β₂-adrenoceptor/G_i/o protein-dependent pathway enhancing NO production in the endothelium; these results were corroborated in β-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 β₂-adrenoceptor antagonist ICI is a pulmonary arterial-specific vasorelaxant and, therefore, a potentially interesting novel therapeutic agent for the treatment of pulmonary arterial hypertension.

Key Words: basic science • adrenoceptors • blood flow regulation • NO • cell signaling • pulmonary hypertension