Prolonged blood pressure elevation following continuous infusion of angiotensin II—a baroreflex study in healthy humans

Abstract

ANG II interacts with the sympathetic nervous system at central nervous blood pressure-regulating structures, including the baroreflex. It is unknown whether prolonged BP elevation mediated by high ANG II plasma levels could induce a persistent shift of the central nervous baroreflex setpoint, lasting beyond the short ANG II plasmatic half time of a few seconds, thereby consolidating elevated BP and/or increased SNA in healthy humans. In a blinded crossover design, ANG II or placebo (saline) was infused for a 6-h period in 12 resting normotensive students (6 males, 6 females) raising BP to borderline hypertensive levels. Between 60 and 120 min after the infusion period, muscle sympathetic nerve activity (MSNA) was assessed microneurographically and correlated with oscillometric BP measurements and heart rate at supine rest (baseline) and during pharmacologic baroreceptor challenge. Infusion of ANG II increased BP to borderline-hypertensive levels, as intended, whereas heart rate remained unaltered. At baroreflex assessment (i.e., 60-120 min after end of infusion period), systolic BP was significantly higher compared with placebo (Δ8.4 ± 3.1 mmHg; P < 0.05), whereas diastolic values were nearly equal between conditions. Baseline MSNA was neither decreased nor increased, and baroreflex sensitivity to vasoactive drug challenge was not altered. Our results show that elevation of ANG II plasma levels over 6 h was able to increase systolic, but not diastolic, BP far beyond blood-mediated ANG II effects. MSNA or heart rate did not counter-regulate this BP elevation, indicating that ANG II had sustainably reset the central nervous BP threshold of sympathetic baroreflex function to accept elevated BP input signals without counter-regulatory response.

The renin–angiotensin system in cardiovascular autonomic control: recent developments and clinical implications

“…The evidence for RAS: autonomic interactions in humans is more tenuous with acute Ang II administration producing inconsistent effects on sympathetic neural outflow and adrenal medullary catecholamine secretion in healthy subjects and patients with essential hypertension [35,21,36,37]. This may reflect a reflexive decrease in sympathetic activity in response to the pressor response produced by peripheral Ang II administration, regional differences in changes in sympathetic outflow, limitations in the route and duration of administration in humans, and difficulties with quantitatively assessing cardiovascular autonomic activity in humans.…”

“…This may reflect a reflexive decrease in sympathetic activity in response to the pressor response produced by peripheral Ang II administration, regional differences in changes in sympathetic outflow, limitations in the route and duration of administration in humans, and difficulties with quantitatively assessing cardiovascular autonomic activity in humans. Despite conflicting findings for sympathetic tone, Ang II alters the operating point and sensitivity of the arterial baroreceptor reflex in clinical populations [35,38,39,36]. There is currently no information on the role of other components of Ang II pathways, such as Ang- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) or Ang III, in cardiovascular control in humans.…”

Differential Effects of Angiotensin-II Compared to Phenylephrine on Arterial Stiffness and Hemodynamics: A Placebo-Controlled Study in Healthy Humans

“…The threshold of the baroreflex feedback-loop can be readjusted to a new BP level via superordinate feed-forward signals to instantaneously address altered needs—a process called “resetting”. Our findings indicate that circulating Ang II resets the central nervous baroreflex threshold to accept higher BP with prolonged aftereffects beyond the immediate effects of the circulating hormone [ 9 , 18 ].…”

“…PE has purely peripheral action and, therefore, the PE-mediated BP increase is answered by reflex-bradycardia and decreased cardiac output. In contrast, Ang II permeates across the blood–brain barrier into hypothalamic and brain stem structures and adjusts the BP setpoint of the sympathetic baroreflex loop to accept higher BP—a process termed resetting [ 9 ]. Thus, BP elevation mediated by Ang II is accompanied by a largely attenuated baroreflex-response as compared to the strong counter-regulatory sympathoinhibition induced by equipotent peripherally acting vasoconstrictors such as PE [ 10 , 11 , 12 , 13 ].…”

Parental Renovascular Hypertension-Induced Autonomic Dysfunction in Male Offspring Is Improved by Prenatal or Postnatal Treatment With Hydrogen Sulfide

“…The NTS and RVLM, two important cardiovascular centers, are involved in the regulation of BP and autonomic function (Vasquez et al, 1992; Braga et al, 2011; Sayk et al, 2015). The NLR family, pyrin domain-containing 3 (NLRP3) inflammasome is increased in several diseases (An et al, 2019; Li et al, 2019).…”