Endothelial defect mediates attenuated vasorelaxant response to isoproterenol after lung transplantation
Yoshida, K.; Flavahan, N.A.; Horibe, M.; Smedira, N.G.; Murray, P.A.
American Journal of Physiology 276(1): H159-H166
1999
ISSN/ISBN: 0002-9513 PMID: 9887029 Document Number: 500536
We have previously demonstrated that pulmonary vasodilation in response to isoproterenol is attenuated in conscious dogs after left lung autotransplantation (LLA). Our present goal was to identify the cellular mechanism responsible for this dysfunction. Size- and position-matched pulmonary arterial rings were isolated from the right (control) and left (LLA) lungs of 23 dogs 1-14 mo post-LLA. The rings were suspended for isometric tension recording and precontracted, and the vasorelaxant responses to activators of the b-adrenoreceptor signaling pathway were examined. With the endothelium intact the maximal pulmonary vasorelaxant response to isoproterenol was reduced (P < 0.02) to 57 ± 9% in LLA rings, compared with 87 ± 3% in control rings. Responses to the Gs protein activator cholera toxin were also attenuated post-LLA, with the concentration-effect curve shifted to the right (P < 0.01) and no change in the maximal response. In contrast, the vasorelaxant responses to forskolin (adenylyl cyclase activator) or dibutyryl cAMP were similar in endothelium-intact control and LLA rings. In endothelium-denuded rings the maximal vasorelaxant responses to isoproterenol were reduced (P < 0.01) to 50% in LLA rings compared with control. Oxypurinol (endothelial xanthine oxidase inhibitor) restored the pulmonary vasorelaxant response to isoproterenol in endothelium-intact LLA rings. Our results provide the first evidence that activation of the b-adrenoreceptor signaling pathway in endothelium-intact pulmonary arterial rings results in an increase in cGMP. Moreover, the attenuation in b-adrenoreceptor-mediated pulmonary vasorelaxation post-LLA is due to inactivation of nitric oxide by endothelium-derived superoxide anion. Reprinted by permission of the publisher.