Systemic angiotensin II does not increase cardiac sympathetic nerve activity in normal conscious sheep

Abstract

While it is well established that centrally injected angiotensin II (Ang II) has potent actions on sympathetic nervous activity (SNA), it is less clear whether peripheral Ang II can immediately stimulate SNA. In particular, the contribution of cardiac sympathetic nerve activity (CSNA) to the acute pressor response is unknown. We therefore examined the effect of incremental doses of intravenous Ang II (3, 6, 12, 24, and 48 ng/kg/min each for 30 min) on CSNA in eight conscious sheep. Ang II infusions progressively increased plasma Ang II up to 50 pmol/l above control levels in dose-dependent fashion (P<0.001). This was associated with the expected increases in mean arterial pressure (MAP) above control levels from <10 mmHg at lower doses up to 23 mmHg at the highest dose (P<0.001). Heart rate and cardiac output fell progressively with each incremental Ang II infusion achieving significance at higher doses (P<0.001). There was no significant change in plasma catecholamines. At no dose did Ang II increase any of the CSNA parameters measured. Rather, CSNA burst frequency (P<0.001), burst incidence, (P=0.002), and burst area (P=0.004) progressively decreased achieving significance during the three highest doses. In conclusion, Ang II infused at physiologically relevant doses increased MAP in association with a reciprocal decrease in CSNA presumably via baroreceptor-mediated pathways. The present study provides no evidence that even low-dose systemic Ang II stimulates sympathetic traffic directed to the heart, in normal conscious sheep.

Keywords: angiotensins; blood pressure; sympathetic nervous system.

Figure 1. Hexamethonium effect on CSNA.

Sample recording of effect of ganglionic blockade with hexamethonium infusion (2 mg/kg IV over 2 h) on integrated CSNA recording.

Figure 2. Angiotensin II (AngII) effect on CSNA – sample traces.

Sample recordings from a representative sheep of arterial pressure, integrated CSNA, and ECG at baseline after incremental doses of 6, 24, and 48 ng/kg/min Ang II (each infused for 30 min) and then 60 min post-cessation of Ang II infusion (recovery).

Figure 3. AngII effect on hemodynamics.

MAP, HR, and cardiac output responses to incremental dose IV infusions of Ang II (●) or vehicle control (○) in eight sheep. Values shown are mean ± S.E.M. Significant differences were observed for MAP (P<0.001), HR (P<0.001), and cardiac output (P=0.001). Individual time points significantly different from time-matched control (Fisher’s protected LSD from two-way ANOVA) are indicated by *P<0.05, ^†P<0.01, and ^‡P<0.001.

Figure 4. Effect of AngII on CSNA.

CSNA responses to incremental dose IV infusions of Ang II (●) or vehicle control (○) in eight sheep. Values shown are mean ± S.E.M. Significant differences were observed for burst frequency (P<0.001), burst area (P=0.004), burst incidence (P=0.002), and burst area incidence (P=0.037). Individual time points significantly different from time-matched control (Fisher’s protected LSD from two-way ANOVA) are indicated by *P<0.05, ^†P<0.01, and ^‡P<0.001.

Figure 5. Plasma AngII and catecholamine levels.

Plasma Ang II, norepinephrine, and epinephrine response to incremental dose IV infusions of Ang II (●) or vehicle control (○) in eight sheep. Values shown are mean ± S.E.M. Significant differences were observed for Ang II (P<0.001). Individual time points significantly different from time-matched control (Fisher’s protected LSD from two-way ANOVA) are indicated by ^†P<0.01 and ^‡P<0.001.