A Role for Benzamil‐sensitive Proteins of the Central Nervous System in the Pathogenesis of Salt‐dependent Hypertension

Abstract

SUMMARY1. While increasing evidence suggests that salt-sensitive hypertension is a disorder of the central nervous system, little is known about the critical proteins (e.g., ion channels or exchangers) that play a role in the pathogenesis of the disease. 2.Central pathways involved in the regulation of arterial pressure have been investigated. In addition, systems such as the renin-angiotensin-aldosterone axis, initially characterized in the periphery, are present in the central nervous system, and seem to play a role in the regulation of arterial pressure. 3.Central administration of amiloride, or its analogue benzamil hydrochloride, has been shown to attenuate several forms of salt-sensitive hypertension. In addition, intracerebroventricular (ICV) benzamil effectively blocks pressor responses to acute osmotic stimuli, such as ICV hypertonic saline. Amiloride or its analogues have been shown to interact with the brain renin-angiotensin-aldosterone system (RAAS) and to effect the expression of endogenous ouabain-like compounds; both could play a role in the interaction between amiloride compounds and arterial pressure. Peripheral treatments with benzamil, even at higher doses than those given centrally, have little or no effect on arterial pressure. These data provide strong evidence that benzamil-sensitive proteins (BSPs) of the central nervous system play a role in cardiovascular responsiveness to sodium. 4.Mineralocorticoids have been linked to human hypertension; many patients with essential hypertension respond well to pharmacological agents antagonizing the mineralocorticoid receptor (MR), and certain genetic forms of hypertension are due to chronically elevated levels of aldosterone. The deoxycorticosterone acetate (DOCA) -salt model of hypertension is a benzamil-sensitive model that incorporates several factors implicated in the etiology of human disease, including mineralocorticoid action and increased dietary sodium. The DOCA-salt model is ideal for investigating the role of BSPs in the pathogenesis of hypertension, because mineralocorticoid action has been shown to modulate the activity of at least one benzamil-sensitive protein, the epithelial sodium channel (ENaC). 5.Characterizing the BSPs involved in the pathogenesis of hypertension may provide a novel clinical target. Further studies are necessary to determine which BSPs are involved, and where in the nervous system they are located.

Activation of mineralocorticoid receptors in the rostral ventrolateral medulla is involved in hypertensive mechanisms in stroke-prone spontaneously hypertensive rats

“…It has been reported that acute ICV infusion 44 or microinjection into the paraventricular nucleus of Na + -rich aCSF 27 causes sympathetic hyperactivity and hypertension in normotensive rats, and pressor responses are enhanced in salt-sensitive rats compared with salt-resistant rats. 44 Abrams et al 45 hypothesized that when MRs bind ligand, there is a subsequent upregulation of ENaCs, which would increase the membrane permeability to sodium in the brain. This response, in the face of transient increases in sodium levels, would lead to membrane depolarization and an increase in neural activity, driving sympathetic outflow and increasing MAP.…”

Aldosterone in the brain

“…Aldosterone and deoxycorticosterone decrease the CSF potassium and increase CSF sodium concentration (10,102,140), whereas spironolactone reduces CSF sodium concentration (33). These ionic changes are significant, because increasing CSF sodium concentration independently produces hypertension (19,86,87,99), at least in part by stimulating osmo-and sodium-sensory neurons in the AV3V region of the hypothalamus (133), an effect that can be blocked by central infusion of benzamil, a sodium channel blocker (1). Conversely, restoration of CSF potassium by intracerebroventricular infusion attenuates the pressor effects of chronic mineralocorticoid treatment (102).…”

Effect of intracerebroventricular benzamil on cardiovascular and central autonomic responses to DOCA-salt treatment

“…These data suggest an interaction between dietary salt, benzamil-sensitive proteins (BSPs) in the brain, and SNA; however, it remains to be shown where within autonomic pathways these BSPs are located (1). While it is still unknown which BSPs in the brain are involved in DOCA-salt hypertension, ion channels permeable to sodium, such as the epithelial sodium channel (ENaC) or the acidsensitive ion channel (ASIC) are likely candidates (1,27). Both the ENaC and the ASIC are members of the degenerin/epithelial sodium channel (Deg/ENaC) superfamily of ion channels.…”