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Here, we tested the hypothesis that comorbidities [diabetes mellitus (DM, streptozotocin), hypercholesterolemia (HC, high-fat diet) and chronic kidney disease (CKD, renal microembolization)] directly impair pulmonary vasomotor control in a DM\u2009+\u2009HC\u2009+\u2009CKD swine model. 6 months after induction of DM\u2009+\u2009HC\u2009+\u2009CKD, pulmonary arterial pressure was similar in chronically instrumented female DM\u2009+\u2009HC\u2009+\u2009CKD (<jats:italic>n<\/jats:italic>\u2009=\u200919) and Healthy swine (<jats:italic>n<\/jats:italic>\u2009=\u200918). However, cardiac output was lower both at rest and during exercise, implying an elevated pulmonary vascular resistance (PVR) in DM\u2009+\u2009HC\u2009+\u2009CKD swine (153\u2009\u00b1\u200910 vs. 122\u2009\u00b1\u20099\u00a0mmHg\u2219L<jats:sup>\u22121<\/jats:sup>\u2219min\u2219kg). Phosphodiesterase 5 inhibition and endothelin receptor antagonism decreased PVR in DM\u2009+\u2009HC\u2009+\u2009CKD (\u2212\u200912\u2009\u00b1\u200912 and \u2212\u200922\u2009\u00b1\u20097\u00a0mmHg\u2219L<jats:sup>\u22121<\/jats:sup>\u2219min\u2219kg) but not in Healthy swine (\u2212\u20091\u2009\u00b1\u200912 and 2\u2009\u00b1\u200914\u00a0mmHg\u2219L<jats:sup>\u22121<\/jats:sup>\u2219min\u2219kg), indicating increased vasoconstrictor influences of phosphodiesterase 5 and endothelin. Inhibition of nitric oxide synthase\u00a0produced pulmonary vasoconstriction that was similar in Healthy and DM\u2009+\u2009HC\u2009+\u2009CKD swine, but unmasked a pulmonary vasodilator effect of endothelin receptor antagonism in Healthy (\u2212\u200956\u2009\u00b1\u200926\u00a0mmHg\u2219L<jats:sup>\u22121<\/jats:sup>\u2219min\u2219kg), whereas it failed to significantly decrease PVR in DM\u2009+\u2009HC\u2009+\u2009CKD, indicating loss of nitric oxide\u00a0mediated inhibition of endothelin in DM\u2009+\u2009HC\u2009+\u2009CKD. Scavenging of reactive oxygen species (ROS) had no effect on PVR in either Healthy or DM\u2009+\u2009HC\u2009+\u2009CKD\u00a0swine. Cardiovascular magnetic resonance imaging, under anesthesia, showed no right ventricular changes. Finally, despite an increased contribution of endogenous nitric oxide to vasomotor tone regulation in the systemic vasculature, systemic vascular resistance at rest\u00a0was higher in DM\u2009+\u2009HC\u2009+\u2009CKD compared to Healthy swine (824\u2009\u00b1\u200941 vs. 698\u2009\u00b1\u200935\u00a0mmHg\u2219L<jats:sup>\u22121<\/jats:sup>\u2219min\u2219kg). ROS scavenging induced systemic vasodilation in DM\u2009+\u2009HC\u2009+\u2009CKD, but not Healthy swine. In conclusion, common comorbidities directly alter pulmonary vascular control, by enhanced PDE5 and endothelin-mediated vasoconstrictor influences, well before overt left ventricular backward failure or pulmonary hypertension develop.<\/jats:p>","DOI":"10.1007\/s00395-021-00891-7","type":"journal-article","created":{"date-parts":[[2021,9,12]],"date-time":"2021-09-12T15:02:41Z","timestamp":1631458961000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Impaired pulmonary vasomotor control in exercising swine with multiple comorbidities"],"prefix":"10.1007","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7133-3046","authenticated-orcid":false,"given":"Jens","family":"van de Wouw","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1998-181X","authenticated-orcid":false,"given":"Jarno J.","family":"Steenhorst","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3713-4136","authenticated-orcid":false,"given":"Oana","family":"Sorop","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5383-4960","authenticated-orcid":false,"given":"Ruben W. 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