Impaired pulmonary vasomotor control in exercising swine with multiple comorbidities

Wouw, Jens van de; Steenhorst, Jarno J.; Sorop, Oana; Drie, Ruben W. A. van; Wielopolski, Piotr A.; Kleinjan, Alex; Hirsch, Alexander; Duncker, Dirk J. und Merkus, Daphne (2021): Impaired pulmonary vasomotor control in exercising swine with multiple comorbidities. In: Basic Research in Cardiology, Bd. 116, Nr. 1, 51

Abstract

Pulmonary hypertension is common in heart failure with preserved ejection fraction (HFpEF). 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 + HC + CKD swine model. 6 months after induction of DM + HC + CKD, pulmonary arterial pressure was similar in chronically instrumented female DM + HC + CKD (n = 19) and Healthy swine (n = 18). However, cardiac output was lower both at rest and during exercise, implying an elevated pulmonary vascular resistance (PVR) in DM + HC + CKD swine (153 +/- 10 vs. 122 +/- 9 mmHg center dot L-1 center dot min center dot kg). Phosphodiesterase 5 inhibition and endothelin receptor antagonism decreased PVR in DM + HC + CKD (- 12 +/- 12 and - 22 +/- 7 mmHg center dot L-1 center dot min center dot kg) but not in Healthy swine (- 1 +/- 12 and 2 +/- 14 mmHg center dot L-1 center dot min center dot kg), indicating increased vasoconstrictor influences of phosphodiesterase 5 and endothelin. Inhibition of nitric oxide synthase produced pulmonary vasoconstriction that was similar in Healthy and DM + HC + CKD swine, but unmasked a pulmonary vasodilator effect of endothelin receptor antagonism in Healthy (- 56 +/- 26 mmHg center dot L-1 center dot min center dot kg), whereas it failed to significantly decrease PVR in DM + HC + CKD, indicating loss of nitric oxide mediated inhibition of endothelin in DM + HC + CKD. Scavenging of reactive oxygen species (ROS) had no effect on PVR in either Healthy or DM + HC + CKD swine. 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 was higher in DM + HC + CKD compared to Healthy swine (824 +/- 41 vs. 698 +/- 35 mmHg center dot L-1 center dot min center dot kg). ROS scavenging induced systemic vasodilation in DM + HC + CKD, 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0300-8428
• Sprache: Englisch