The Roles of Mineralocorticoid Receptors and Gamma-Aminobutyric Acid in the Pathogenesis of Exercise Pressor Reflex Dysfunction in Hypertension
Downey, Ryan Michael
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Hypertension is a global epidemic. Over 40% of the world population has elevated blood pressures and estimates predict this number to increase 60% in the next 10 years to over 1 billion individuals. While drug therapies are available to a large number of these patients, the treatment that consistently decreases the signs and symptoms of hypertension is exercise. However, exercise in hypertensive patients carries an elevated risk for myocardial ischemia, infarction, cardiac arrest, stroke, and possibly death during and after physical activity due to the exaggerated elevations in blood pressure and sympathetic activity that accompany the physical exertion. Understanding the mechanisms through which hypertension causes a dysregulation in blood pressure management during physical activity is paramount if we are to find safe ways for patients to benefit from exercise without dangerous complications. Our lab has strongly linked hypertension to a dysfunction in the exercise pressor reflex (EPR), a cardiovascular control system that originates within exercising muscle. However, the mechanisms underlying the pathogenesis of this dysfunction remain largely undetermined. To address this gap in knowledge studies were performed to investigate the roles of two logical candidates for the generation of EPR over-activity in hypertension: 1) aldosterone acting via mineralocorticoid receptors, and 2) gamma-aminobutyric acid (GABA) acting within the muscle reflex processing center located in the solitary tract nucleus (NTS) of the brainstem. The role of aldosterone and mineralocorticoid receptors was investigated by feeding normotensive and hypertensive rat a diet containing normal chow, or the mineralocorticoid receptor antagonists spironolactone (SPIR) or eplerenone (EPL). The role of central GABA was investigated in normotensive and hypertensive rats by microdialyzing the GABA synthesis inhibitor (3-mercaptopropionic acid), the GABAA receptor antagonist (bicuculline), or the GABAB receptor antagonist (saclofen) into the NTS. The results of the studies demonstrated that: 1) SPIR and EPL can be used as effective treatments to reduce the exaggerated cardiovascular responses to EPR activation in hypertension, and 2) GABA maintains the ability to modulate muscle mechanoreflex activity (a component of the EPR) within the NTS via activation of GABAA receptors in normotension with this ability being compromised after the development of hypertension.