Clinical management of hypertension (HTN) presents a persistent and problematic issue for primary care physicians. Under half of patients receiving anti-hypertensive drug therapy reach therapeutic goals meaning most treated patients still carry considerable risk for developing further cardiovascular complications. Sympathetic activation is known to be an important factor in the pathophysiology of many forms of hypertension, and has been a rationale for using the adrenergic system as a therapeutic target for lowering blood pressure (BP). Sympathetic activity to the kidney in particular has been of great interest as renal sympathetic nerves activate many physiological pathways that can impact blood pressure: renin release, sodium reabsorption, and direct renovascular vasoconstriction. Sensory nerves supplying the kidneys have also been demonstrated to modulate BP perhaps through alterations in central sympathetic outflow. Recently, catheter-based renal nerve ablation (CBRNA) was developed as a non-pharmacological treatment modality for managing difficult-to-treat HTN. Clinical studies have shown that in patients not reaching goal blood pressure during pharmacological interventions, ablation of the renal nerves significantly and chronically lowers blood pressure. Responses to CBRNA in humans have been quite variable in magnitude, which has prompted investigators to ask important questions such as 1) For which hypertensive patients should this treatment option be indicated? 2) What patient characteristics predict a good response to the new therapy? and 3) How do concomitant antihypertensive medication regimens affect the fall in BP seen after CBRNA? These questions all derive from the fact that we do not yet understand the mechanisms that mediate the BP response to CBRNA. Technical and ethical considerations limit our ability to investigate questions of mechanism in human subjects, thus highlighting the importance of studying this problem in a pre-clinical setting. The studies performed in the following dissertation use an animal model of human hypertension in an attempt to identify the mechanisms responsible for the long-term reduction in blood pressure after CBRNA. The central hypotheses of this dissertation are that 1) renal denervation in the spontaneously hypertensive rat (SHR) will decrease BP to a degree similar to the effect of CBRNA in human patients with drug-resistant hypertension, and 2) that the BP response to renal denervation in the SHR is due to suppression of both renal sympathetic nerve activity (RSNA) and non-renal sympathetic nerve activity) (NRSNA). The ultimate goals of this work were to 1) understand the relevant physiological and pharmacological mechanisms that influence the blood pressure lowering effect of renal denervation, and 2) provide pre-clinical evidence to help guide more effective selection of patients likely to response to CBRNA with a clinically significant fall in blood pressure.
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