The role played by oxidative stress in evoking the exercise pressor reflex in health and simulated peripheral artery disease.

Abstract

Ligating the femoral artery of a rat for 72h, a model for peripheral artery disease, causes an exaggerated exercise pressor reflex in response to muscle contraction. Likewise, the hindlimb muscles of rats with ligated femoral arteries show increased levels of reactive oxygen species. Infusion of tiron, a superoxide scavenger, attenuated the exaggerated pressor reflex and reduced reactive oxygen species production in rats with ligated femoral arteries. Conversely, we found no effect of tiron infusion on the pressor reflex in rats with patent femoral arteries. These results suggest a role of reactive oxygen species with respect to causing the exaggerated pressor response to contraction seen in rats with ligated arteries and peripheral artery disease. Contraction of muscle evokes the exercise pressor reflex (EPR), which is expressed partly by increases in heart rate and arterial pressure. Patients with peripheral artery disease (PAD) show an exaggerated EPR, sometimes report pain when walking and are at risk for cardiac arrthymias. Previous research suggested that reactive oxygen species (ROS) mediate the exaggerated EPR associated with PAD. To examine the effects of ROS on the EPR, we infused a superoxide scavenger, tiron, into the superficial epigastric artery of decerebrated rats. In some, we simulated PAD by ligating a femoral artery for 72h before the experiment. The peak EPR in 'ligated' rats during saline infusion averaged 31±4mmHg, whereas the peak EPR in these rats during tiron infusion averaged 13±2mmHg (n=12; P<0.001); the attenuating effect of tiron on the EPR was partly reversed when saline was reinfused into the superficial epigastric artery (21±2 mmHg; P<0.01 vs. tiron). The peak EPR in 'ligated' rats was also attenuated (n=7; P<0.01) by infusion of gp91ds-tat, a peptide that blocks the activity of NAD(P)H oxidase. Tiron infusion had no effect on the EPR in rats with patent femoral arteries (n=9). Western blots showed that the triceps surae muscles of 'ligated' rats expressed more Nox2 and p67phox, which are components of NADPH oxidase, compared to triceps surae muscles of 'freely perfused' rats. Tiron added to muscle homogenates reduced ROS production in vitro. The results of the present study provide further evidence indicating that ROS mediates the exaggeration of EPR in rats with simulated PAD.