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Isoproterenol Causes cAMP-Independent Vasorelaxation in Pulmonary Veins: Roles of Nitric Oxide and ATP-Sensitive K+ Channels
Woonseok Roh, M.D., Paul A. Murray, Ph.D.
Center for Anesthesiology Research, Cleveland Clinic Foundation, Cleveland, Ohio.
Introduction: Our laboratory is systematically investigating fundamental mechanisms that regulate pulmonary venous tone. Changes in pulmonary venous tone can have profound effects on pulmonary capillary pressure, transcapillary fluid flux and pulmonary edema. In the present study, we investigated the mechanisms by which the classic β adrenoreceptor agonist, isoproterenol, alters pulmonary venous tone.

Methods: All procedures were approved by the Institutional Animal Care and Use Committee. Endothelium intact (E+) and endothelium denuded (E-) canine pulmonary venous rings were suspended for isometric tension recording. The thromboxane analog, U46619, was used to precontract each ring prior to the administration of isoproterenol (10-9-10-5 M). Isoproterenol concentration-response relationships were assessed in the intact condition and following nitric oxide synthase inhibition (L-NAME; 10-4 M), cyclooxygenase inhibition (indomethacin; 10-5 M), K+ATP channel inhibition (glybenclamide; 10-5 M), adenylyl cyclase inhibition (SQ22536; 10-4 M) and guanylyl cyclase inhibition (ODQ; 10-5 M). Statistical analysis utilized analysis of variance and Student's t-test. Values are means ± SEM.

Results: The maximal relaxation response (Rmax) to isoproterenol was decreased from 57 ± 4% to 32 ± 4% by removing the endothelium. In E+ pulmonary venous rings, L-NAME decreased the Rmax for isoproterenol from 54 ± 3% to 35 ± 2%, and ODQ decreased the Rmax from 51 ± 3% to 39 ± 2%. Glybenclamide also decreased the Rmax for isoproterenol from 53 ± 3% to 39 ± 2%. Indomethacin and SQ22536 had no effect on isoproterenol vasorelaxation in E+ pulmonary venous rings. Moreover, ODQ and SQ22536 had no effect on isoproterenol vasorelaxation in E- pulmonary venous rings. In contrast, glybenclamide decreased isoproterenol vasorelaxation from 37 ± 3% to 15 ± 2% in E- pulmonary venous rings precontracted with 20 mM KCl.

Discussion: Isoproterenol vasorelaxation in pulmonary veins involves both endothelium-dependent and vascular smooth muscle components. The endothelium-dependent component of isoproterenol vasorelaxation is mediated by the nitric oxide-cGMP signaling pathway, whereas the smooth muscle component involves activation of K+ATP channels. Surprisingly, the adenylyl cyclase-cAMP signaling pathway is not involved in the pulmonary venous relaxation response to isoproterenol.

Anesthesiology 2004; 101: A1589