A role for benzamil-sensitive proteins of the central nervous system in the pathogenesis of salt-dependent hypertension.

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. 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. 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. 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). 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. Keywords: Sympathetic Nervous System, Epithelial Sodium Channel (ENaC), Acid Sensitive Ion Channel (ASIC), Aldosterone, DOCA, Benzamil, Salt-sensitive Hypertension INTRODUCTION Evidence suggests that in humans, hypertension is a disorder of the central nervous system; specifically, sympathetic nervous activity (SNA) is increased in the human disease state [1, 2]. Furthermore, increasing dietary sodium has been shown to affect both arterial pressure and SNA [3–9]. In addition, several animal models of salt-sensitive hypertension exhibit increased SNA, or increased levels of plasma norepinephrine (an indicator of increased sympathetic drive) [10–12]. While high sympathetic tone seems to be a hallmark of many salt-dependent models of hypertension, central administration of amiloride, or its analogue benzamil, attenuates both the level of hypertension reached and circulating levels of norepinephrine [13]. These data suggest an interaction between benzamil-sensitive proteins (BSPs) and SNA; however, it remains to be shown where within autonomic pathways the BSPs mediating this interaction are located. This review will address what is known about the neural pathways involved in the regulation of arterial pressure, as well as the characteristics of known benzamil-sensitive proteins. In addition, we will attempt to summarize possible interactions between the activity of BSPs and central neural control of cardiovascular function.