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.
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.
Previous studies have shown that angiotensin II (Ang II) can activate cardiovascular neurons within the medulla oblongata via an action on specific receptors. The purpose of this study was to determine the distribution of neurons within the medulla activated by infusion of Ang II into the fourth ventricle of conscious rabbits, using the expression of Fos, the protein product of the immediate early gene c-fos as a marker of neuronal activation. Experiments were done in both intact and barodenervated animals. In comparison with a control group infused with Ringer's solution alone, in both intact and barodenervated animals, fourth ventricular infusion of Ang II (4 to 8 pmol/min) induced a significant increase in the number of Fos-positive neurons in the nucleus of the solitary tract and in the rostral, intermediate, and caudal parts of the ventrolateral medulla. Double-labeling for Fos and tyrosine hydroxylase immunoreactivity showed that 50% to 75% of Fos-positive cells in the rostral, intermediate, and caudal ventrolateral medulla and 30% to 40% of Fos-positive cells in the nucleus of the solitary tract were also positive for tyrosine hydroxylase in both intact and barodenervated animals. The distribution of Fos-positive neurons corresponded very closely to the location of Ang II receptor binding sites as previously determined in the rabbit. The results indicate that medullary neurons activated by Ang II are located in discrete regions within the nucleus of the solitary tract and ventrolateral medulla and include, in all of these regions, both catecholamine and noncatecholamine neurons.
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