The effect of chronic activation or inhibition of central ANG II receptors on cardiac baroreflex function in conscious normotensive rabbits was examined. Animals received a fourth ventricular (4V) infusion of ANG II (30 and 100 ng/h), losartan (3 and 30 microg/h), or Ringer solution (2 microl/h) for 2 wk. After 1 and 2 wk, ANG II (100 ng/h) decreased cardiac baroreflex gain by 20 and 37%, respectively (P = 0.015), whereas losartan (30 microg/h) increased baroreflex gain by 24 and 58%, respectively (P = 0.02). Within 1 wk of the end of the infusions, cardiac baroreflex gain had returned to control. Ringer solution or the lower doses of ANG II or losartan did not modify the cardiac baroreflex function. Blood pressure and heart rate were not altered by any treatment, nor was their variability affected. These data demonstrate a novel long-term modulation of cardiac baroreflexes by endogenous ANG II that is independent of blood pressure level.
1 The aim of this study was to investigate, by use of spectral analysis, (1) the blood pressure (BP) variability changes in the conscious rat during blockade of nitric oxide (NO) synthesis by the L-arginine analogue N0-nitro-L-arginine methyl ester (L-NAME); (2) the involvement of the renin-angiotensin system in these modifications, by use of the angiotensin II AT,-receptor antagonist losartan.2 Blockade of NO synthesis was achieved by infusion for 1 h of a low-dose (10 jug kg-' min-', i.v., n= 10) and high-dose (100 pg kg-' min-', i.v., n= 10) of L-NAME. The same treatment was applied in two further groups (2 x n = 10) after a bolus dose of losartan (10 mg kg-', i.v.). 3 Thirty minutes after the start of the infusion of low-dose L-NAME, systolic BP (SBP) increased (+ 10 + 3 mmHg, P< 0.01), with the effect being more pronounced 5 min after the end of L-NAME administration (+ 20 + 4 mmHg, P< 0.001). With high-dose L-NAME, SBP increased immediately (5 min: + 8+2 mmHg, P<0.05) and reached a maximum after 40 min (+ 53+4 mmHg, P<0.001); a bradycardia was observed (60 min: -44+ 13 beats min'-, P<0.01). 4 Low-dose L-NAME increased the low-frequency component (LF: 0.02-0.2 Hz) of SBP variability (50 min: 6.7+ 1.7 mmHg2 vs 3.4+0.5 mmHg2, P<0.05), whereas the high dose of L-NAME not only increased the LF component (40 min: 11.7 + 2 mmHg2 vs 2.7 + 0.5 mmHg2, P<0.001) but also decreased the mid frequency (MF: 0.2-0.6 Hz) component (60 min: 1.14+0.3 mmHg2 vs 1.7+0.1 mmHg2, P<0.05) of SBP. 5 Losartan did not modify BP levels but had a tachycardic effect (+45 beats min-'). Moreover, losartan increased MF oscillations of SBP (4.26 + 0.49 mmHg2 vs 2.43 + 0.25 mmHg2, P< 0.001), prevented the BP rise provoked by the low-dose of L-NAME and delayed the BP rise provoked by the high-dose of L-NAME. Losartan also prevented the amplification of the LF oscillations of SBP induced by L-NAME; the decrease of the MF oscillations of SBP induced by L-NAME was reinforced after losartan. 6 We conclude that the renin-angiotensin system is involved in the increase in variability of SBP in the LF range which resulted from the withdrawal of the vasodilating influence of NO. We propose that NO may counterbalance LF oscillations provoked by the activity of the renin-angiotensin system.
In the present study, we examined the effect of blockade of the brain stem renin-angiotensin system on renal sympathetic baroreflexes and chemoreflexes in conscious rabbits and examined the role of central catecholaminergic pathways in these responses. Eleven rabbits underwent preliminary surgical instrumentation and pretreatment with central 6-hydroxydopamine (6-OHDA, 500 μg/kg) or ascorbic acid 6 wk before the commencement of the experiments. Baroreflex curves were determined under conditions of normoxia and hypoxia (10% O2 + 3% CO2) before and after central administration of either Ringer solution, the ANG II receptor antagonist losartan (10 μg), or the angiotensin-converting enzyme inhibitor enalaprilat (500 ng) on separate days. Losartan increased the upper plateau and the range of the mean arterial pressure (MAP)-renal sympathetic nerve activity (RSNA) curve (79 and 78%, respectively) in intact rabbits, whereas this effect was not observed in 6-OHDA-pretreated rabbits. Hypoxia elicited an increase in resting RSNA (111% in intact rabbits and 74% in 6-OHDA-injected rabbits) and elevated the upper plateau of the RSNA-MAP curve in both groups (89% in intact rabbits and 114% in 6-OHDA-injected rabbits). During hypoxia, losartan and enalaprilat increased the RSNA upper plateau in intact rabbits but had no effect in 6-OHDA-pretreated rabbits. No effects on the MAP-heart rate baroreflex curves were observed. Thus the effect of losartan to increase RSNA, particularly during hypoxia and baroreceptor unloading, being abolished by central noradrenergic depletion suggests that the endogenous ANG II which normally causes an inhibition of renal sympathetic motoneurons is dependent on the integrity of central catecholaminergic pathways.
The contribution of the renin-angiotensin system (RAS) and the sympathetic nervous system (SNS) to blood pressure (BP) and heart rate (HR) variability responses to air-jet stress was assessed in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. Activity of the encogenous RAS was suppressed by chronic treatment by a nonpeptide angiotensin II receptor antagonist (Iosartan). The role of alpha 1-adrenoceptor activity was evaluated in rats by acute administration of prazosin. In untreated animals, an air jet induced an increase in systolic BP (SBP; 9 +/- 2 mmHg for WKY and 8 +/- 2 mmHg for SHR) and in HR (56 +/- 19 beats/min for WKY and 76 +/- 8 beats/min for SHR), followed by an increase of the midfrequency (MF; 0.2-0.6 Hz) component of HR in WKY (183%) and by an increase of the MF component of SBP and diastolic BP in SHR (65%). Prazosin prevented BP rises as well as the MF component of BP and HR increases associated with air-jet stress. Chronic suppression of the RAS by losartan did not alter the BP response to the air jet in WKY and slightly reduced it in SHR but abolished all the BP and HR variability changes in both strains. These results indicate that the SNS but not RAS is essential for the BP rise induced by stress and demonstrate that RAS in conjunction with SNS is involved in BP and HR variability changes associated with stress.
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