Objective: Recently, it was reported in a meta-analysis that exaggerated acute stress-induced pressor responses predict future cardiovascular disease risk. We previously demonstrated that acute stress-induced elevations in plasma endothelin (ET-1) correlated with stress-induced increases in blood pressure in adolescents and young adults. These studies in humans are suggestive that the stress-induced release of ET-1 may be involved in the acute stress-induced pressor response. Our laboratory is interested in elucidating the mechanisms that define the blood pressure response to acute behavioral stress in an animal model of cardiovascular disease risk. The Dahl salt-sensitive (DS) rat is susceptible to hypertension when placed on a high salt diet and is used extensively to evaluate genetically defined risk for salt-sensitive hypertension. We hypothesized that the ET-1 pathway contributes to the pressor response induced by acute air jet stress (AJS) in DS rats on a normal salt diet (pre-hypertensive). Since reactive oxygen species (ROS) have also been implicated in the pressor response to acute AJS, we further hypothesized that acute stress induced increase in ROS is downstream of ET-1 receptor activation.
Methods: Adult (9 to 12 week old), male DS rats were utilized in this study. Mean arterial pressure (MAP) was monitored by telemetry before and after 3-day treatment with the free radical scavenger, 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (tempol) in drinking water. In addition, rats were treated with ETA selective or combined ETA/B receptor antagonists, ABT-627 and A-182086, respectively, in ground food. Rats were restrained in plexiglas tubes and subjected to pulsatile air jet stress (AJS) for 3 minutes followed by 20 minutes of post-stress recovery. AJS-induced responses were evaluated by the area under the curve (AUC) for the stress and post-stress recovery periods. Additional rats were fitted with chronic venous catheters for blood sampling at baseline (non-AJS) and during AJS. Plasma samples were analyzed for ET-1 and 8-isoprostane (measure of ROS production).
Results: Neither tempol nor ET-1 receptor antagonist treatments had an effect on baseline MAP or plasma 8-isoprostane levels. Tempol significantly reduced the AUC during the stress period and increased the post-stress recovery period. The pressor response to acute AJS was accompanied by significant increases in plasma 8-isoprostane and ET-1. Tempol blunted the stress-mediated increase in plasma 8-isoprostane; conversely, tempol had no effect on the stress-induced increase in plasma ET-1. Combined ETA/B antagonism, but not selective ETA receptor blockade, similarly suppressed the pressor response to stress and increased the post-stress recovery. ETA/B antagonism also blocked the stress-mediated rise in 8-isoprostane.
Conclusions: These results indicate that reactive oxygen species contribute to the pressor response to acute air jet stress. Furthermore, the increase in ROS is dependent upon ET receptor activation. We reasoned that the pre-hypertensive DS rat is a model of young adults with family histories of cardiovascular disease; thus we predict that behavioral stress in pre-hypertensive young adults activates an ET-dependent ROS pathway. Future translational studies will explore whether the ET-dependent ROS activation is a dysfunctional, disease-promoting pathway or an adaptive response in genetically predisposed hypertensive individuals.