Hypertension is the most important risk factor for the development of cardiovascular disease, the leading cause of death in the U.S. Despite therapeutic advancements, nearly 20-30% of hypertensive patients have uncontrolled high blood pressure. This resistant hypertension is associated with elevated sympathetic activity and abnormal baroreflex reflex control and thus is termed neurogenic hypertension. Animal models of neurogenic hypertension consistently implicate augmented release of GABA within the intermediate nucleus of the solitary tract (intNTS) as a contributing pathophysiological mechanism. Correcting this pathophysiological mechanism is a logical step towards decreasing high blood pressure of neurogenic origin. However, GABA and its receptors are poor therapeutic targets because GABA is the predominant inhibitory neurotransmitter in the CNS. To circumvent this impediment we began investigating whether neurons in the intNTS that express angiotensin type 2 receptors (AT2R) may serve as an access point for therapeutic interventions that relieve neurogenic hypertension. Using a novel transgenic mouse model (AT2R-eGFP reporter mouse) we discovered that GABA neurons in the intNTS robustly express AT2R and optogenetic excitation of these neurons significantly increases blood pressure. Intriguingly, DOCA-salt hypertension in mice increased indices of GABA synthesis in the intNTS but central delivery of the AT2R agonist, Compound 21 (C21), abrogated this hypertension and downregulated indices of GABA synthesis in the intNTS. Relevant to the proposed research, the antihypertensive effects of brain AT2R activation were abolished by deleting AT2R from GABA neurons. Based on these results we hypothesize that GABA neurons in the intNTS that express AT2R may be manipulated to reverse the onset of neurogenic hypertension.
Two Specific Aims are proposed to substantiate or refute this hypothesis.
Aim 1 combines genetic and pharmacological approaches to evaluate the consequences of deleting or stimulating AT2R on GABAergic neurons in the intNTS.
Aim 1 tests the hypothesis that activation of AT2R expressed on GABAergic neurons in the intNTS alleviates DOCA-salt hypertension in mice by decreasing GABA synthetic enzymes within these neurons, which consequently decreases sympatho- excitation and improves baroreflex function.
Aim 2 utilizes in vitro optogenetic and in vivo chemogenetic approaches to evaluate how DOCA-salt hypertension with or without C21 affects GABA neurotransmission within baroreflex circuits mediating cardiovascular function.
Aim 2 tests the hypothesis that the activity of neurons within the intNTS that express AT2R control baroreflex sensitivity and sympathetic outflow and their selective inhibition mediates the reversal of hypertension. Execution of the proposed experiments will identify a discrete population of neurons that can be targeted to control blood pressure and provide preclinical evidence for the development of novel approaches for alleviating resistant hypertension.
Hypertension is the leading risk factor for cardiovascular disease, diabetes, obesity, metabolic syndrome and stroke. Despite changes in lifestyle and the availability of multi-drug based therapies, 20-30% of hypertensive patients still have uncontrolled high blood pressure. These resistant patients have what is known as ?neurogenic hypertension?, where continual increases in the activity of brain areas that control the cardiovascular system lead to sustained activation of the sympathetic nerves that ultimately tell blood vessels to constrict and raise blood pressure. Therefore it is critical that new therapies for this disease are uncovered. In this project we aim to determine whether proteins that occur naturally within the brain (angiotensin type-2 receptors; AT2R) can lower blood pressure by stopping the activity of cells in the brainstem (gamma-aminobutyric acid [GABA] neurons) that drive increases in blood pressure and hypertension. We will do this by utilizing state of the art genetic approaches to activate or inhibit these AT2R-GABA neurons, combined with a drug that selectively activates AT2R. Based on our preliminary work we predict that this approach, activating AT2R and stopping GABA neurons from working, will have an immediate impact in developing innovative strategies for the treatment of currently uncontrollable resistant hypertension.
| Wang, Lei A; de Kloet, Annette D; Smeltzer, Michael D et al. (2018) Coupling corticotropin-releasing-hormone and angiotensin converting enzyme 2 dampens stress responsiveness in male mice. Neuropharmacology 133:85-93 |
