Blunted pulmonary dilation during exercise in familial hypercholesterolemic swine does not involve endothelin‐1

Abstract

Pulmonary dilation during exercise aids in effective gas exchange; however, the effect of hypercholesterolemia on this dilation is unclear. Hypercholesterolemia likely causes endothelial dysfunction and may hamper pulmonary dilation during exercise. We investigated pulmonary hemodynamics during exercise using chronically instrumented control (n=5) and familial hypercholesterolemic (FH; n=4) swine. Cholesterol levels were elevated in FH compared to control swine (651±13 v 59±4 mg/dl). Resting pulmonary vascular conductance (PVC) was similar between FH and control swine (8±1 v 9±1 ml/min/kg/mmHg) and pulmonary artery pressure was elevated in FH swine (28±2 v 12±1 mmHg). Graded treadmill exercise resulted in increased PVC in control swine (12.2±0.8 ml/min/kg/mmHg at 3mph) which was blunted in FH swine (10.0±0.8 ml/min/kg/mmHg). We further examined whether increased pulmonary constriction via endothelin-1 (ET-1) accounted for blunted pulmonary dilation in FH swine. Pulmonary responses to exercise were determined after treatment with the mixed ET-1 receptor antagonist tezosentan. Blockade of ET receptors significantly reduced resting PVC in both groups; however, responses to exercise were principally unchanged. Thus, chronic hypercholesterolemia attenuates pulmonary dilation during exercise, but not via enhanced pulmonary constriction to ET-1. Supported by NIH HL52490 and NHF 2000T042.