A localized brain renin-angiotensin system exists and generates angiotensin II, which may act as a neuromodulator or neurotransmitter along central pathways. Studies have shown that angiotensin II exerts a tonic inhibitory action on the high pressure baroreflex control of heart rate (HR) and renal sympathetic nerve activity (RSNA). However, the situation regarding the suppression of RSNA following activation of low pressure cardiopulmonary receptors and the role of brain angiotensin II is unclear. This study investigated the contribution of central angiotensin II in this cardiorenal reflex elicited by stimulation of cardiopulmonary receptors using the 5-HT3 agonist phenyl biguanide (PBG).
Male Wistar rats (300-400 g) were anaesthetized with chloralose/urethane (12/180 mg ml-1, 0.7-0.9 ml I.V.). Cannulae were inserted into a femoral artery and vein for measurement of blood pressure (BP) and HR and the infusion of saline (150 mM NaCl at 3 ml h-1) and drugs, respectively. Animals were placed in a sterotaxic frame and a guide cannula was positioned into the right lateral cerebroventricle. The kidney was exposed and bipolar electrodes sealed in place on the renal sympathetic nerves. After 2 h stabilization, BP, HR and RSNA were recorded at baseline, 20 min after saline or losartan I.C.V. and after 20 min infusion of PBG I.V. (0.64 mg ml-1, 6.4 mg kg-1 h-1). The protocol was performed in two groups of animals, receiving either I.C.V. vehicle (150 mM NaCl, 2 µl over 2 min bolus followed by 0.1 µl min-1), or losartan (7.5 mg ml-1, 2 µl over 2 min bolus followed by 0.1 µl min-1). The blood pressure and RSNA recordings were later subjected to fast Fourier transformation to generate a power spectrum from 0 to 10 Hz. Experiments accorded with UK legislation. The animals were killed humanely at the end of the experiment. Data (means ± S.E.M.) were subjected to Student’s paired t test with significance taken at P < 0.05.
In the vehicle group (n = 6), BP (100 ± 6 mmHg), HR (6.5 ± 0.3 Hz), integrated RSNA (2.6 ± 0.6 µV s-1), percentage power at HR frequency (19.7 ± 3.5 %) and total power (1.1 ± 0.4 W) were unchanged by the infusion of saline I.C.V. Infusion of PBG had no effect on either BP (98 ± 2 vs. 93 ± 3 mmHg) or HR (6.6 ± 0.2 vs. 6.8 ± 0.3 Hz), but did cause a 25 % reduction in integrated RSNA (2.7 ± 0.6 vs. 2.0 ± 0.4 µV s-1, P < 0.05) and a 67 % reduction in percentage power at HR frequency (18.6 ± 1.4 vs. 6.2 ± 1.0 %, P < 0.01). Total power remained constant (1.1 ± 0.5 vs. 0.2 ± 0.1 W). Losartan (n = 6) had no effect on BP, HR, integrated RSNA or total power but caused a 72 % reduction in % power at HR frequency (20.4 ± 3.4 vs. 5.5 ± 1.9 %, P < 0.01). Under these conditions, infusion of PBG had no effect on BP (96 ± 5 vs. 91 ± 3 mmHg), HR (6.0 ± 0.6 vs. 6.5 ± 0.6 Hz) or total power (0.9 ± 0.5 vs. 0.9 ± 0.3 W), while integrated RSNA (2.6 ± 0.6 vs. 2.3 ± 0.6 µV s-1) and percentage power at HR frequency (5.5 ± 1.9 vs. 6.9 ± 2.0 %) were unchanged. These RSNA responses were significantly different from those obtained in the rats given saline I.C.V.
These data show that the ability of PBG to suppress RSNA was prevented by blockade of brain angiotensin AT1 receptors. They suggest that an intact brain renin-angiotensin system is required for the reflex reduction of RSNA caused by stimulation of the cardiopulmonary receptors.