Neural mechanisms of angiotensin II-salt hypertension: implications for therapies targeting neural control of the splanchnic circulation

Abstract

Chronically elevated plasma angiotensin II (AngII) causes a salt-sensitive form of hypertension that is associated with a differential pattern of peripheral sympathetic outflow. This "AngII-salt sympathetic signature" is characterized by a transient reduction in sympathetic nervous system activity (SNA) to the kidneys, no change in SNA to skeletal muscle, and a delayed activation of SNA to the splanchnic circulation. Studies suggest that the augmented sympathetic influence on the splanchnic vascular bed increases vascular resistance and decreases vascular capacitance, leading to hypertension via translocation of blood volume from the venous to the arterial circulation. This unique sympathetic signature is hypothesized to be generated by a balance of central excitatory inputs and differential baroreceptor inhibitory inputs to sympathetic premotor neurons in the rostral ventrolateral medulla. The relevance of these findings to human hypertension and the future development of targeted sympatholytic therapies are discussed.

Fig. 1

Central modulation of sympathetic outflow by circulating angiotensin II (AngII) and salt (NaCl). Circulating AngII and salt stimulates neurons in the forebrain circumventricular organs (subfornical organ, SFO; organum vasculosum of the lamina terminalis, OVLT), which leads to activation of neurons in the hypothalamic paraventricular nucleus (PVN) through direct or indirect projections via the median preoptic nucleus (MnPO). Benzamil-sensitive sodium channels are thought to be involved in transducing this salt signal. PVN activation leads to enhanced central drive to sympathetic premotor neurons in the rostral ventrolateral medulla (RVLM). The degree of enhanced central drive is hypothesized to be specific to different vascular beds, depicted as specific sets of RVLM neurons targeting the splanchnic, renal, or lumbar vascular regions. During the initial stage of hypertension, when direct vascular actions of AngII are the main contributor to the increase in mean arterial pressure, feedback inhibitory input from peripheral baroreceptors relayed through the nucleus of the solitary tract (NTS) counteracts the central drive in the RVLM. This inhibitory drive is thought to be strongest to RVLM neurons that modulate renal sympathetic nerve activity (RSNA), and the level of inhibition is coupled to the temporal pattern and degree of baroreceptor adaptation during the course of hypertension. The different level of excitatory and inhibitory input to specific populations of RVLM neurons results in a gradual rise in splanchnic SNA (SSNA), an initial decrease and gradual recovery of RSNA, and no change in lumbar SNA (LSNA). The gradual rise in SSNA and its influence on the splanchnic vascular bed, which stores a large proportion of total blood volume and receives a significant percentage of cardiac output, is thought to be the main contributor to the gradual rise in mean arterial pressure (MAP) during AngII-salt hypertension. A high SSNA causes vasoconstriction in arterioles, small veins, and venules, which contributes to an increase in total peripheral resistance and leads to reduced vascular capacitance. The combined effect mobilizes unstressed blood volume from the venous compartment into the arterial compartment, ultimately reflected as a rise in MAP