Long‐term Sympatho‐excitatory Effect of Angiotensin Ii: A Mechanism of Spontaneous and Renovascular Hypertension

Abstract

1. The peptide hormone angiotensin II (AngII) is acknowledged to be an important factor in the pathophysiology of hypertension. This is particularly the case in hypertension caused by luminal narrowing of one renal artery, (i.e. renovascular hypertension). The primary mechanism by which AngII raises blood pressure, however, is disputed. Strong arguments can be made supporting either vascular contraction, effects on renal excretion of sodium and water, or trophic actions on cardiovascular structures as the key element. In this paper I review evidence that AngII influences blood pressure by modulating autonomic nervous system activity. Modulation can occur at both the peripheral and central aspects of the autonomic system, but I focus on brain pathways involved in determining sympathetic nervous system activity. 2. Experimental and clinical investigations are cited to support the hypothesis that sympathetically mediated pressor effects are increased by both circulating and brain-derived AngII in hypertension. Recent work points specifically to sympathetic pre-motor neurons in the rostral ventrolateral medulla (RVLM) as a critical site of action of brain AngII in normotensive and hypertensive animals. 3. This same set of neurons appears to be an important relay in the sympatho-excitatory response to circulating AngII initiated at circumventricular organs, particularly the area postrema. AngII has important effects on the baroreflex. These do not mediate the sympatho-excitation elicited by circulating AngII, but rather mask its expression. 4. Substantial data support the hypothesis that increased blood concentrations of AngII in renovascular hypertension elevate blood pressure by causing neurogenic vasoconstriction mediated through the area postrema and RVLM.

Increased dietary sodium alters neural control of blood pressure during intravenous ANG II infusion

“…This treatment was selected as a sympathoexcitatory stimulus for several reasons. First, increased systemic ANG II contributes to hypertension through activation of central SNS pathways (11). Second, whereas intravenous ANG II initially produces sympathoinhibition due to baroreflex-mediated withdrawal of SNS tone, Fig.…”

“…Although the initial increase in blood pressure during peripheral administration of pressor concentrations of ANG II is due to the direct vasoconstrictor effects of the hormone on vascular smooth muscle, the chronic hypertensive response to longer-term, continuous administration (hours to days) of ANG II is mediated by progressive activation of the SNS (6,25). Indeed, a predominant mechanism through which ANG II contributes to sustained hypertension is activation of central SNS sympathoexcitatory centers (11). It is possible that increased dietary sodium contributes to hypertension by sensitizing central SNS circuits to the excitatory effects of systemic ANG II.…”

Sex differences in angiotensin II- induced hypertension

“…It has been reported that chronic low-dose ANG II-induced hypertension, which develops over a period of days, is not due to the peripheral vasoconstrictor activity of ANG II, but is most likely the result of excitation of the sympathetic nerve activity (8,17). Recent studies from our laboratory have shown in mice that decreases in blood pressure induced by ganglionic blockade are much smaller on day 1 as compared to day 7 of ANG II infusion, thus suggesting that an enhancement of sympathetic outflow contributes to the ANG II-induced progressive increase in blood pressure (21).…”

“…Central actions of ANG II increase sympathetic nerve activity and modulate reflex regulation of heart rate through actions of the peptide on sensory circumventricular organs (15) such as the area postrema, subfornical organ and organum vasculosum of the lamina terminalis (8,(16)(17)(18)(19)(20). It has been reported that chronic low-dose ANG II-induced hypertension, which develops over a period of days, is not due to the peripheral vasoconstrictor activity of ANG II, but is most likely the result of excitation of the sympathetic nerve activity (8,17).…”

Mecanismos Fisiológicos E Fisiopatológicos Determinantes Da Atividade Vasomotora Simpática

“…Na fase estável de hipertensão, há um aumento na atividade colinérgica da RVLM, sem nenhuma alteração na atividade de outros núcleos do bulbo, isto sugere, portanto, uma possível especificidade no aumento da atividade simpática e manutenção da hipertensão 18 . Uma outra explicação para o aumento da atividade simpática é a ação central da Ang II nos tecidos periventriculares da região ântero-ventral do terceiro ventrículo (AV3V) ou área postrema, regiões destituídas da barreira hemato-encefálica 19,20 . Em estudo prévio desenvolvido em nosso laboratório, demonstrou-se que na HA renovascular há um aumento da atividade vasomotora simpática em parte por uma ação tônica de receptores glutamatérgicos localizados na RVLM, o bloqueio desses receptores produz queda da PA em ratos hipertensos renovasculares sem afetar os níveis tensionais em ratos controles 21 .…”