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Renal responses to chronic suppression of central sympathetic outflow.

ABSTRACT: Chronic electric activation of the carotid baroreflex produces sustained reductions in sympathetic activity and arterial pressure and is currently being evaluated as hypertension therapy for patients with resistant hypertension. However, the chronic changes in renal function associated with natural suppression of sympathetic activity are largely unknown. In normotensive dogs, we investigated the integrative cardiovascular effects of chronic baroreflex activation (2 weeks) alone and in combination with the calcium channel blocker amlodipine, which is commonly used in the treatment of resistant hypertension. During baroreflex activation alone, there were sustained decreases in mean arterial pressure (17±1 mmHg) and plasma (norepinephrine; ?35%), with no change in plasma renin activity. Despite low pressure, sodium balance was achieved because of decreased tubular reabsorption, because glomerular filtration rate and renal blood flow decreased 10% to 20%. After 2 weeks of amlodipine, arterial pressure was also reduced 17 mmHg, but with substantial increases in norepinephrine and plasma renin activity and no change in glomerular filtration rate. In the presence of amlodipine, baroreflex activation greatly attenuated neurohormonal activation, and pressure decreased even further (by 11±2 mmHg). Moreover, during amlodipine administration, the fall in glomerular filtration rate with baroreflex activation was abolished. These findings suggest that the chronic blood pressure-lowering effects of baroreflex activation are attributed, at least in part, to sustained inhibition of renal sympathetic nerve activity and attendant decreases in sodium reabsorption before the macula densa. Tubuloglomerular feedback constriction of the afferent arterioles may account for reduced glomerular filtration rate, a response abolished by amlodipine, which dilates the preglomerular vasculature.

SUBMITTER: Iliescu R

PROVIDER: S-EPMC3501271 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Renal responses to chronic suppression of central sympathetic outflow.

Iliescu Radu R Irwin Eric D ED Georgakopoulos Dimitrios D Lohmeier Thomas E TE

Hypertension (Dallas, Tex. : 1979) 20120702 3

Chronic electric activation of the carotid baroreflex produces sustained reductions in sympathetic activity and arterial pressure and is currently being evaluated as hypertension therapy for patients with resistant hypertension. However, the chronic changes in renal function associated with natural suppression of sympathetic activity are largely unknown. In normotensive dogs, we investigated the integrative cardiovascular effects of chronic baroreflex activation (2 weeks) alone and in combinatio ...[more]

PMID: 22753216

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Project description:1. Chronic electrical stimulation of the carotid sinuses has provided unique insight into the mechanisms that cause sustained reductions in blood pressure during chronic suppression of central sympathetic outflow. 2. Because renal denervation does not abolish the sustained fall in arterial pressure in response to baroreflex activation, this observation has seemingly challenged the concept that the kidneys play a critical role in the long-term control of arterial pressure during chronic changes in sympathetic activity. The aim of the present study was to use computer simulations to provide a more comprehensive understanding of physiological mechanisms that mediate sustained reductions in arterial pressure during prolonged baroreflex-mediated suppression of central sympathetic outflow. 3. Physiological responses to baroreflex activation under different conditions were simulated by an established mathematical model of human physiology (QHP2008; see Supporting Information (Appendix S1) provided in the online version of this article and/or http://groups.google.com/group/modelingworkshop). The model closely reproduced empirical data, providing important validation of its accuracy. 4. The simulations indicated that baroreflex-mediated suppression of renal sympathetic nerve activity does chronically increase renal excretory function but that, in addition, hormonal and haemodynamic mechanisms also contribute to this natriuretic response. The contribution of these redundant natriuretic mechanisms to the chronic lowering of blood pressure is of increased importance when suppression of renal adrenergic activity is prevented, such as after renal denervation. Activation of these redundant natriuretic mechanisms occurs at the expense of excessive fluid retention. 5. More broadly, the present study illustrates the value of numerical simulations in elucidating physiological mechanisms that are not obvious intuitively and, in some cases, not readily testable in experimental studies.

Project description:1. This study examined the role of histamine H(3) receptors in vagal and sympathetic autonomic reflexes in the conscious rabbit, and in rabbit and guinea-pig isolated right atria. 2. The baroreceptor-heart rate reflex (baroreflex), Bezold-Jarisch-like and nasopharyngeal reflexes were assessed after these treatments (i.v.; with H(1) and H(2) receptor block): (i) vehicle (saline; n=11); (ii) H(3) receptor agonist, (R)-alpha-methylhistamine (R-alpha-MH) 100 micro g kg(-1)+100 micro g kg(-1) h(-1) (n=9); (iii) H(3) receptor antagonist, thioperamide 1 mg kg(-1)+1 mg kg(-1) h(-1) (n=11); (iv) R-alpha-MH and thioperamide (n=6); and (v) H(2) and H(3) antagonist, burimamide 6.3 mg kg(-1)+6.3 mg kg(-1) h(-1) (n=4). 3. R-alpha-MH caused a thioperamide-sensitive fall in mean arterial pressure (MAP) of 8+/-1 mmHg and tachycardia of 18+/-2 bpm (P<0.0005). Burimamide was without effect, however thioperamide elicited an increase in MAP of 4+/-1 mmHg (P<0.01), but no change in heart rate (HR). 4. R-alpha-MH caused a 44% decrease in the average gain of the baroreflex (P=0.0001); this effect was antagonised by thioperamide. Thioperamide caused a parallel rightward shift in the barocurve with an increase in MAP of 5 mmHg (P<0.05). Burimamide had no effect on the baroreflex. The vagally mediated bradycardia elicited by the Bezold-Jarisch and nasopharyngeal reflexes was unaffected by H(3) receptor ligand administration. 5. R-alpha-MH (<or=10 micro M) caused a thioperamide-sensitive depression of both sympathetic and vagal responses in guinea-pig atria, but had no effect in rabbit atria. 6. As H(3) receptor activation caused a significant decrease in baroreflex gain without affecting HR range, the former is unlikely to be simply due to peripheral sympatholysis (supported by the lack of effect in isolated atria). Central H(3) receptors may have a tonic role in the baroreflex as thioperamide caused a rightward resetting of the barocurve. In contrast, the peripherally acting H(3) antagonist burimamide was without effect. These findings suggest a role for central histamine H(3) receptors in cardiovascular homeostasis in the rabbit.

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Renal responses to chronic suppression of central sympathetic outflow.

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Renal responses to chronic suppression of central sympathetic outflow.

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