Nitric oxide impacts on angiotensin AT2 receptor modulation of high-pressure baroreflex control of renal sympathetic nerve activity in anaesthetized rats

Abstract

Aim: Nitric oxide (NO) interacts with the local brain renin-angiotensin system to modulate sympathetic outflow and cardiovascular homoeostasis. This study investigated whether NO influenced the ability of angiotensin AT2 receptor activation to modify the high-pressure baroreceptor regulation of renal sympathetic nerve activity (RSNA) and heart rate (HR).

Methods: Anaesthetized (chloralose/urethane) rats were prepared to allow generation of baroreflex gain curves for RSNA or HR following intracerebroventricular (I.C.V.) CGP42112 (AT2 receptor agonist), PD123319 (AT2 receptor antagonist) or losartan (AT1 receptor antagonist), and then in combination with L-NAME (NO synthase inhibitor).

Results: I.C.V. PD123319, CGP42112, and Losartan did not change baseline mean arterial pressure, HR or RSNA. Baroreflex sensitivities for RSNA and HR were increased following AT2 receptor activation with CGP42112 by 112 and 157%, respectively, but were reduced following PD123319 by 20% (all P < 0.05). L-NAME alone increased baroreflex sensitivity for both RSNA and HR, by 62 and 158%, respectively, but when co-infused with either CGP42112 or PD123319, the baroreflex sensitivity fell to values comparable to those obtained during I.C.V. saline infusion. The baroreflex sensitivities for RSNA and HR were increased by losartan by 92% and 192%, respectively, but in the presence of L-NAME were no different from those obtained during I.C.V. saline infusion.

Conclusion: There is an important facilitatory role for AT2 receptors in the high-pressure baroreflex regulation of RSNA and HR which is dependent on a functional NO/NOS system. Conversely, AT1 receptors have an inhibitory effect on the baroreflex, an action that relies on a tonic inhibition of NO.

Keywords: AT2 receptors; high-pressure baroreflex; nitric oxide.

Figure 1

Representative recording from an individual rat of systemic arterial pressure (AP), mean arterial blood pressure (MAP), heart rate (HR), integrated renal sympathetic nerve activity (RSNA) and row RSNA signal. Ramp changes in AP were established by bolus intravenous infusions of phenylephrine (50 μg kg⁻¹) to increase AP and sodium nitroprusside (50 μg kg⁻¹) to decrease AP. Data are presented at two different recording speeds.

Figure 2

The baroreflex curve for renal sympathetic nerve activity (a) and heart rate (b) following ramp changes in mean arterial blood pressure in the time control group whereby a first I.C.V. saline infusion was followed by a second I.C.V. saline infusion. RSNA, renal sympathetic nerve activity; MAP, mean arterial blood pressure; and HR, heart rate.

Figure 3

The baroreflex curve for renal sympathetic nerve activity (a) and heart rate (b) following ramp changes in mean arterial blood pressure in I.C.V. saline infused rats followed by L-NAME. *P < 0.05, baroreflex sensitivity of the second phase compared with the first phase. LNM, L-NAME; RSNA, renal sympathetic nerve activity; MAP, mean arterial blood pressure; and HR, heart rate.

Figure 4

The baroreflex curve for renal sympathetic nerve activity and heart rate following ramp changes in mean arterial blood pressure in I.C.V. saline infused rats followed by CGP (a, b) or PD (c, d). *P < 0.05, baroreflex sensitivity of the second phase compared with the first phase. PD, PD123319; RSNA, renal sympathetic nerve activity; MAP, mean arterial blood pressure; and HR, heart rate.

Figure 5

The baroreflex curve for renal sympathetic nerve activity (a) and heart rate (b) following ramp changes in mean arterial blood pressure in I.C.V. saline infused rats followed by losartan. *P < 0.05, baroreflex sensitivity of the second phase compared with the first phase. LOS, losartan; RSNA, renal sympathetic nerve activity; MAP, mean arterial blood pressure; and HR, heart rate.

Figure 6

The baroreflex curve for renal sympathetic nerve activity and heart rate following ramp changes in mean arterial blood pressure in PD/PD+L-NAME (a, b), L-NAME/L-NAME+PD (c, d) and CGP/CGP+L-NAME (e, f). *P < 0.05, baroreflex sensitivity of the second phase compared with the first phase. LNM, L-NAME; PD, PD123319; RSNA, renal sympathetic nerve activity; MAP, mean arterial blood pressure; and HR, heart rate.

Figure 7

The baroreflex curve for renal sympathetic nerve activity (a) and heart rate (b) following ramp changes in mean arterial blood pressure in losartan/losartan+L-NAME. *P < 0.05, baroreflex sensitivity of the second phase compared with the first phase. LOS, losartan; LNM, L-NAME; RSNA, renal sympathetic nerve activity; MAP, mean arterial blood pressure; and HR, heart rate.

Figure 8

The percentage change in baroreflex sensitivity (A2) of RSNA (a) and HR (b) baroreflex gain curves from control (saline) in the presence and absence of L-NAME. The data are for the percentage difference of the slope values (A2) of the second baroreflex curves in all groups with reference to the slope of second saline phase in saline/saline group as a baseline value. *P < 0.05, with L-NAME compared to without L-NAME; #P < 0.05, PD+L-NAME compared with L-NAME. LNM, L-NAME; PD, PD123319; and LOS, losartan.