Background: Aberrant sympathetic nerve activity exacerbates cardiovascular risk in hypertension and diabetes, which are common comorbidities, yet clinically sympathetic nerve activity remains poorly controlled. The hypertensive diabetic state is associated with increased reflex sensitivity and tonic drive from the peripheral chemoreceptors, the cause of which is unknown. We have previously shown hypertension to be critically dependent on the carotid body (CB) input in spontaneously hypertensive rat, a model that also exhibits a number of diabetic traits. CB overstimulation by insulin and leptin has been similarly implicated in the development of increased sympathetic nerve activity in metabolic syndrome and obesity. Thus, we hypothesized that in hypertensive diabetic state (spontaneously hypertensive rat), the CB is sensitized by altered metabolic signaling causing excessive sympathetic activity levels and dysfunctional reflex regulation. Methods: Using a hypothesis-free RNA-seq approach, we investigated potential molecular targets implicated in energy metabolism mediating CB sensitization and its regulation of sympathetic outflow in experimental hypertension. Identified targets were characterized using molecular and functional techniques assessing peripheral chemoreflex sensitivity in situ and in vivo. Results: We discovered GLP1R (glucagon-like peptide-1 receptor) expression in the CBs of rat and human and showed that its decreased expression is linked to sympathetic hyperactivity in rats with cardiometabolic disease. We demonstrate GLP1R to be localized to CB chemosensory cells, while targeted administration of GLP1R agonist to the CB lowered its basal discharge and attenuated chemoreflex-evoked blood pressure and sympathetic responses. Importantly, hyperglycemia-induced peripheral chemoreflex sensitization and associated basal sympathetic overactivity were abolished by GLP1R activation in the CB suggesting a role in a homeostatic response to high blood glucose. Conclusions: We show that GLP1 (glucagon-like peptide-1) modulates the peripheral chemoreflex acting on the CB, supporting this organ as a multimodal receptor. Our findings pinpoint CBs as potential targets for ameliorating excessive sympathetic activity using GLP1R agonists in the hypertensive-diabetic condition.

The paraventricular nucleus (PVN) is a highly organized structure of the hypothalamus that has a key role in regulating cardiovascular and osmotic homeostasis. Functionally, the PVN is divided into autonomic and neuroendocrine (neurosecretory) compartments, both equally important for maintaining blood pressure (BP) and body fluids in the physiological range. Neurosecretory magnocellular neurons (MCNs) of the PVN are the main source of the hormones vasopressin (VP), responsible for water conservation and hydromineral balance, and oxytocin (OT), involved in parturition and milk ejection during lactation. Further, neurosecretory parvocellular neurons (PCNs) take part in modulation of the hypothalamic–pituitary–adrenal axis and stress responses. Additionally, the PVN takes central place in autonomic adjustment of BP to environmental challenges and contributes to its variability (BPV), underpinning the PVN as an autonomic master controller of cardiovascular function. Autonomic PCNs of the PVN modulate sympathetic outflow toward heart, blood vessels and kidneys. These pre-autonomic neurons send projections to the vasomotor nucleus of rostral ventrolateral medulla and to intermediolateral column of the spinal cord, where postganglionic fibers toward target organs arise. Also, PVN PCNs synapse with NTS neurons which are the end-point of baroreceptor primary afferents, thus, enabling the PVN to modify the function of baroreflex. Neuroendocrine and autonomic parts of the PVN are segregated morphologically but they work in concert when the organism is exposed to environmental challenges via somatodendritically released VP and OT by MCNs. The purpose of this overview is to address both neuroendocrine and autonomic PVN roles in BP and BPV regulation.

Vasopressin (VP) and oxytocin (OT) are mainly synthesized in the magnocellular neurons of the paraventricular (PVN) and supraoptic nucleus (SON) of the hypothalamus. Axons from the magnocellular part of the PVN and SON project to neurohypophysis where VP and OT are released in blood to act like hormones. Axons from the parvocellular part of PVN project to extra-hypothalamic brain areas (median eminence, limbic system, brainstem and spinal cord) where VP and OT act like neurotransmitters/modulators. VP and OT act in complementary manner in cardiovascular control, both as hormones and neurotransmitters. While VP conserves water and increases circulating blood volume, OT eliminates sodium. Hyperactivity of VP neurons and quiescence of OT neurons in PVN underlie osmotic adjustment to pregnancy. In most vascular beds VP is a potent vasoconstrictor, more potent than OT, except in the umbilical artery at term. The vasoconstriction by VP and OT is mediated via V1aR. In some vascular beds, i.e. the lungs and the brain, VP and OT produce NO dependent vasodilatation. Peripherally, VP has been found to enhance the sensitivity of the baro-receptor while centrally, VP and OT increase sympathetic outflow, suppresse baro-receptor reflex and enhance respiration. Whilst VP is an important mediator of stress that triggers ACTH release, OT exhibits anti-stress properties. Moreover, VP has been found to contribute considerably to progression of hypertension and heart failure while OT has been found to decrease blood pressure and promote cardiac healing.

Since the discovery of vasopressin (VP) and oxytocin (OT) in 1953, considerable knowledge has been gathered about their roles in cardiovascular homeostasis. Unraveling VP vasoconstrictor properties and V1a receptors in blood vessels generated powerful hemostatic drugs and drugs effective in the treatment of certain forms of circulatory collapse (shock). Recognition of the key role of VP in water balance via renal V2 receptors gave birth to aquaretic drugs found to be useful in advanced stages of congestive heart failure. There are still unexplored actions of VP and OT on the cardiovascular system, both at the periphery and in the brain that may open new venues in treatment of cardiovascular diseases. After a brief overview on VP, OT and their peripheral action on the cardiovascular system, this review focuses on newly discovered hypothalamic mechanisms involved in neurogenic control of the circulation in stress and disease.

Sudden death is a major health problem all over the world. The most common causes of sudden death are cardiac but there are also other causes such as neurological conditions (stroke, epileptic attacks and brain trauma), drugs, catecholamine toxicity, etc. A common feature of all these diverse pathologies underlying sudden death is the imbalance of the autonomic nervous system control of the cardiovascular system. This paper reviews different pathologies underlying sudden death with emphasis on the autonomic nervous system contribution, possibilities of early diagnosis and prognosis of sudden death using various clinical markers including autonomic markers (heart rate variability and baroreflex sensitivity), present possibilities of management and promising prevention by electrical neuromodulation.