P1402Influence of macitentan on the vascular tone and recruitment of capillaries under hypobaric hypoxia in high altitude

Abstract

Introduction: The ascent to high altitudes leads to a systemic hypobaric hypoxia. Several mediators, e.g. endothelin (ET)-1, are released by endothelial cells to regulate the vascular tone and the regional blood flow in order to maintain a sufficient oxygen supply, corresponding to the regional demand. Macitentan, a dual ET-receptor antagonist, should influence these ET effects on the peripheral vasculature and microcirculation. The purpose of this study was to measure and visualize these changes of the vascular tone and regional blood flow non-invasively in healthy volunteers. Methods: The baseline measurements were performed at 140 m altitude, the second after 24 h in high altitude (2978 m, Swiss Alpes) and the third after 48 h in high altitude and 3 h after oral intake of 10mg Macitentan. The study participants (15 males, 2 females, mean age 36.7±10.8 years) were abstinent from alcohol and caffeine, smoking and performing physical exercise. Blood pressure measurements and pulse wave acquisition were performed with photoplethysmographic sensors and the pulse wave velocity (PWV) and augmentation index (AIX) calculated. The reactive hyperaemia index (RHI) were measured with fingertipvolume- sensors after an ischemic period of five minutes. Nailfold capillaroscopy with a 200-fold magnification was performed directly before and after the ischemic period. Data are expressed as mean ± SD. Results: Compared to base line the systolic (123.5±10.0 vs. 132.9±9.2 mmHg; p=0.006) and diastolic (75.0±5.1 vs. 80.9±7.6 mmHg; p=0.044) blood pressure values, the heart rates (62.8±6.5 vs. 75.2±9.1 bpm; p=0.01) and PWV (6.81±0.54 vs. 7.81±0.91 m/s; p=0.002) were increased at high altitude, with no relevant changes of these parameters after macitentan. The AIX and RHI were measured on the same level at all time points. Exposure to hypobaric hypoxia led to a significantly reduced capillary density, measured in the finger nailfold capillaroscopy, that was antagonized by macitentan to a level, significantly higher than base line (9.25±1.48 vs. 7.82±1.19 vs. 10.75±1.65 n/mm; p<0.001). The pre-ischemic widths of the arterial limbs of the capillary loops were measured at the same level throughout all time points (9.5±.6 μm), with no relevant post-ischemic change at baseline (10.1±1.8 μm), a significant increase at height (11.5±2.2 μm; p=0.021) and an impressive post-ischemic dilatation after intake of macitentan (17.2±2.9 μm; p<0.001). Conclusions: Hypobaric hypoxia led to a reduced acral perfusion with increase of the vascular tone and reduced regional blood flow in the finger-tips. These changes could at best be measured and visualized via calculation of the PWV and capillaroscopy. A single dose of Macitentan antagonized the alterations of capillary recruitment and capillary loop diameter to values higher than at baseline. This indicates the importance of ET-1 for the regulation of the microcirculation.