In the United States and other developed countries, 1 in 3 (33 percent) adults has arterial hypertension or high blood pressure. In the US, only ~50 percent of people with hypertension are undergoing antihypertensive treatment, despite the fact that hypertension is the leading cause of death and disability among men and post-menopausal women worldwide. Of those being treated, nearly 50% are designated “treatment resistant” because they remain clinically hypertensive despite taking 3 or more antihypertensive medications.
The massive prevalence of treatment resistance indicates that unidentified mechanisms support persistent hypertension in a large fraction of patients and underscores the need for basic research to uncover these unknown causes of disease. Dr. Glenn Toney’s research findings indicate that neurological dysfunction is a major unrecognized cause of treatment resistant hypertension. Indeed, studies show that specific populations of neurons in the brainstem and hypothalamus generate exaggerated motor neuron output trafficked through sympathetic nerves.
This exaggerated nerve activity causes excessive cardiac contraction and constriction of peripheral blood vessels. Sympathetic activity to the kidneys and adrenal glands activate hormonal systems that promulgate neurological dysfunction through positive feedback to the brain. Dr. Toney’s research focuses on understanding the maladaptive neural mechanisms that result in exaggerated sympathetic network output to cardiovascular tissues.
Techniques in routine use include brain slice and whole animal single neuron electrophysiology aided by viral manipulation of gene/protein expression and coupled with excitatory and inhibitory opto- and chemogenetic approaches. Other featured techniques include immunofluorescence histochemistry, tract tracing, mRNA/protein expression techniques, confocal/fluorescence microscopy, sympathetic nerve recordings and telemetry-based hemodynamic measures in conscious freely behaving rats and mice. Projects are funded by the National Heart, Lung and Blood Institute of the NIH and seek to restore normal function of cardiovascular regulatory neurons and thereby lower sympathetic nerve activity to improve treatment of resistant hypertension. Current efforts focus on neuromodulation by pro-inflammatory cytokines, which modulate specific neurotransmitter and chloride transporters to disrupt the normal balance between excitatory and inhibitory synaptic transmission among identified populations of sympathetic control neurons in the hypothalamus.
Blackburn MB, Andrade MA and Toney GM. The Hypothalamic PVN Contributes to Acute Intermittent Hypoxia-Induced Sympathetic but not Phrenic Long-Term Facilitation. J Appl Physiol 2018. In Press
Holbein WW, Blackburn MB, Andrade MA and Toney GM. Burst Patterning of Hypothalamic Paraventricular Nucleus-Driven Sympathetic Nerve Activity in Angiotensin II-Salt Hypertension. Am J Physiol, Heart & Circ Physiol. Am J Physiol Heart Circ Physiol. 2017 Nov 22: PMID: 29167122
Bardgett ME, Chen QH, Guo Q, Calderon AS, Andrade MA, and Toney GM. Coping with Dehydration: Sympathetic Activation and Regulation of Glutamatergic Transmission in the Hypothalamic PVN. AJP: Regul., Integ. Comp. Physiol. 306(11): R804-13, 2014. PMC4042205
Bardgett ME, Holbein WW, Herrera-Rosales M and Toney GM. Ang II-Salt Hypertension Depends on Neuronal Activity in the Hypothalamic PVN, but not on Local Actions of TNF-α. Hypertension. 63(3):527-34, 2014. PMCID: PMC394517
Mifflin SW, Cunningham JT and Toney GM. Neurogenic Mechanisms Underlying the Rapid Onset of Sympathetic Responses to Intermittent Hypoxia. J Appl Physiol 119(12):1441-8, 2015. PMC4683347