Exercising Skeletal Muscle Blood Flow is Diminished in a Rat Model of Pulmonary Arterial Hypertension

Abstract

PURPOSE: Skeletal muscle dysfunction including a shift toward glycolytic metabolism has been suggested to contribute to exercise intolerance in pulmonary arterial hypertension (PAH) but an exercise perfusion limitation of skeletal muscle has not been identified. Therefore, we performed novel characterization of skeletal muscle blood flow response to exercise in a rat model of PAH. METHODS: Treadmill running at 50% VO2max was performed by male Sprague-Dawley rats (368±13g) injected with monocrotaline (MCT, 60mg/kg) to elicit a severe PAH phenotype (MCT, n=7), or vehicle control (saline) (CON, n=7). Fluorescent microspheres injected during run and rest bouts were utilized to determine blood flow via photo spectroscopy of harvested skeletal muscles. VO2max was measured prior to terminal blood flow studies to characterize exercise capacity of each rat and determine relative exercise intensity for flow analysis. Echocardiographic determination of right ventricular (RV) morphometry and function was also performed. Values are mean ± SE. RESULTS: As expected, MCT exhibited RV hypertrophy (as elevated ratio of RV to LV+S mass, p=0.002, and RV wall thickness in echocardiography, p=0.004), higher RV systolic pressure (p=0.02) and lower VO2max (p=0.03) vs. CON. During exercise, blood flow (expressed as as ml/min per 100g tissue) of the vastus lateralis, semitendinosus, gastrocnemius and biceps femoris was significantly reduced (p=0.02) in MCT (0.187±0.07) compared to CON (0.662±0.17) concomitant with higher (p=0.008) whole blood lactate in MCT (10.44±1.65 mmol/L) vs. CON (4.33±0.72 mmol/L). Further, exercising blood flow was inversely related to blood lactate at exercise (r=-0.603, p=0.03), and positively related to cardiac output (r=0.61, p<0.05). At rest, there was a tendency for both blood flow reduction (p=0.06) and higher lactates (p=0.09) in MCT (0.053±0.01, 5.98±2.48 mmol/L) vs. CON (0.148±0.04, 1.82±0.19 mmol/L). CONCLUSIONS: Exercising blood flow is reduced in a rat model of PAH and may contribute to metabolic limits to exercise capacity. Future studies will explore ways to augment skeletal muscle exercising blood flow in PAH, with the hope of improving tolerance for exercise in patients. Funding: NIH-NHLBI R-15 (MB Brown)