Fifty (50) million Americans suffer from hypertension, of which 66% are not adequately controlled and at least 10% are multi-drug resistant. Stimulation of pressure sensors in blood vessels, the baroreceptors, decreases blood pressure (BP);implantable electrical stimulators have been used to provide continuous baroreceptor activation;although these devices effectively lower basal BP, because constant stimulation disables endogenous mechanisms of BP regulation, patients, using these devices, suffer compromised responses to orthostatic, and other daily cardiovascular challenges. Also, continuous stimulation consumes a large amount of energy, and frequent battery replacement is invasive and costly. We propose to test an alternative strategy: long-term potentiation of the endogenous baroreflex mechanisms by occasional, brief high frequency (tetanic) stimulation of the baroafferent pathway. The aortic depressor nerve (ADN) and carotid sinus nerve (CSN) are the major baroafferent inputs carrying BP signals from the baroreceptors to the brain. In the brainstem, the dorsal medial nucleus of the solitary tract (dmNTS) is the first relay of ADN and CSN signals. Recently, using a rat model, we showed that a brief burst of tetanic stimulation of the ADN, increased the size of subsequent ADN evoked responses in the dmNTS for 10-15 hours, which indicates that following a strong activation of the ADN, baroreflex depressor responses are enhanced;thus, a burst of baroreceptor nerve stimulation might ameliorate hypertension for many hours. In this proposal, we will systematically investigate the effects of uni- and bi-lateral CSN tetanus on basal BP in normotensive and obesity-induced hypertensive dogs. Thirteen (10 experimental + 3 control) dogs will be used;every dog will have bilateral CSN electrodes.
Aim 1 consists of 3 phases: Baseline (7 days) ->Tetanus (7 days) ->Recovery (7 days). For the experimental dogs, the tetanus phase consists of one daily bout of tetanus.
In Aim 2, obesity hypertension will be induced over several weeks by a high-fat diet;and then Aim 1 will be repeated. We hypothesize that, for the experimental dogs, the 7 successive daily tetanus applications will produce increasing BP reductions;the unilateral tetanus effects are expected to be 50-75% of the bilateral. Signal processing algorithms will be used in Aim 3 to determine whether the gain and/or threshold of the baroreflex are changed by the tetanus;this is important for anticipating the effects of tetanus on BP stability. Clinical Significance: Occasional brief tetanic stimulation offers a new and effective clinical method for controlling hypertension, especially multi-drug resistant forms. In contrast to continuous stimulation, the method proposed would produce less tissue damage;enhance, rather than diminish normal moment-to-moment baroreflex control of BP, and better preserve the normal orthostatic and exercise regulation of BP. The proposed method naturally lends itself to an extremely compact, electrically passive (no battery), implantable baroafferent stimulator, and our eventual goal is to develop such a device.

Public Health Relevance

50 million Americans suffer from high blood pressure;the proposed experiments investigate the effects of brief high frequency (tetanic) stimulation of the carotid sinus nerve on a long lasting blood pressure reduction in normotensive and hypertensive dogs. Positive results could open entirely new avenues for developing more efficient hypertension therapies;and provide an effective treatment for the many patients suffering from drug resistant hypertension.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Grants (R21)
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Hypertension and Microcirculation Study Section (HM)
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Thrasher, Terry N
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Pennsylvania State University
Schools of Medicine
United States
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Stocker, Sean D; Monahan, Kevin D; Sinoway, Lawrence I (2013) The hypothalamic paraventricular nucleus may not be at the heart of sympathetic outflow. J Physiol 591:1