Thomas E. Lohmeier

Prolonged Activation of the Baroreflex Produces Sustained Hypotension

Abstract—The role of baroreflexes in long-term control of arterial pressure is unresolved. To determine whether chronic activation of the baroreflex produces sustained hypotension, we developed a method for prolonged activation of the carotid baroreflex in conscious dogs. This was achieved by chronically implanting electrodes around both carotid sinuses and using an externally adjustable pulse generator to electrically activate the carotid baroreflex. Control values for mean arterial pressure (MAP) and heart rate were 93±3 mm Hg and 64±4 bpm, respectively. After control measurements, the carotid baroreflex was activated bilaterally for 7 days at a level that produced a prompt and substantial reduction in MAP, and for day 1 MAP was reduced to 75±4 mm Hg. Moreover, this hypotensive response was sustained throughout the entire 7 days of baroreflex activation (day 7, MAP=72±5 mm Hg). During prolonged baroreflex activation, heart rate decreased in parallel with MAP, although the changes were not as pronounced (day 7, heart rate=51±3 bpm). Prolonged baroreflex activation was also associated with ≈35% reduction in plasma norepinephrine concentration (control=87±15 pg/mL). After baroreflex activation, hemodynamic measures and plasma levels of norepinephrine returned to control levels. Interestingly, despite the pronounced fall in MAP, plasma renin activity did not increase during prolonged baroreflex activation. These data indicate that prolonged baroreflex activation can lead to substantial reductions in MAP by suppressing the sympathetic nervous system. Furthermore, sustained sympathoinhibitory effects on renin secretion may play an important role in mediating the long-term hypotensive response.

The sympathetic nervous system and long-term blood pressure regulation

There is considerable evidence that activation of the sympathetic nervous system plays an important role in the pathogenesis of several cardiovascular diseases, including hypertension. However, the mechanisms that account for sympathetic activation and the precise mechanisms that mediate neurally induced hypertension are unclear. In large part, this is due to the difficulty in assessing sympathetic function under chronic conditions. Consequently, acute observations are often extrapolated to infer that similar neural mechanisms are operative under more longterm conditions, an unwarrantable assumption. Nonetheless, considerable theoretical and experimental evidence points to the renal sympathetic nerves as the critical link between the sympathetic nervous system and long-term arterial pressure control. Both chronic increases and decreases in renal adrenergic activity alter renal excretory function and produce sustained elevations and reductions in arterial pressure, respectively. Recent observations, including those in dogs with hemibladders and one denervated kidney, indicate that chronic suppression of renal sympathetic nerve activity and attendant natriuresis are long-term compensatory responses to excess body fluid volumes and hypertension. Furthermore, studies combining deafferentation of cardiac receptors and sinoaortic baroreceptors with the split-bladder preparation suggest that chronic renal sympathoinhibition is mediated by baroreflex mechanisms, an especially important finding given the technical limitations in determining whether baroreflexes completely reset and impact sympathetic activity in chronic hypertension. In contrast to the chronic inhibitory effects of baroreflexes on sympathetic activity, other studies indicate that angiotensin II (Ang II) has sustained renal sympathoexcitatory effects. The opposing long-term effects of baroreflexes and Ang II on renal sympathetic nerve activity support two major hypotheses for sympathetic activation in hypertension: baroreflex dysfunction and activation of the renin-angiotensin system, abnormalities often associated with clinical hypertension.

Prolonged Activation of the Baroreflex Abolishes Obesity-Induced Hypertension

Prolonged electrical activation of the carotid baroreflex produces sustained reductions in sympathetic activity and arterial pressure in normotensive dogs. The main goal of this study was to assess the influence of prolonged baroreflex activation on arterial pressure and neurohormonal responses in 6 dogs with obesity-induced hypertension. After control measurements, the diet was supplemented with cooked beef fat for 6 weeks, whereas sodium intake was held constant. After 4 weeks of the high-fat diet, there were increments in body weight from 25.8±0.7 to 38.6±1.0 kg, mean arterial pressure from 97±2 to 110±3 mm Hg, heart rate from 67±3 to 91±4 bpm, and plasma norepinephrine concentration from 141±35 to 280±52 pg/mL. Plasma glucose and insulin concentrations were elevated, but increases in plasma renin activity during the initial weeks of the high-fat diet were not sustained. During week 5, baroreflex activation resulted in sustained reductions in mean arterial pressure, heart rate, and plasma norepinephrine concentration; at the end of week 5, these values were 87±2 mm Hg, 77±4 bpm, and 166±45 pg/mL, respectively. These suppressed values returned to week 4 levels during a 7-day recovery period after baroreflex activation. There were no changes in plasma glucose or insulin concentrations, or plasma renin activity during prolonged baroreflex activation. These findings indicate that baroreflex activation can chronically suppress the sympathoexcitation associated with obesity and abolish the attendant hypertension while having no effect on hyperinsulinemia or hyperglycemia.

Renal Nerves Promote Sodium Excretion During Long-Term Increases in Salt Intake

To determine whether the renal nerves contribute to sodium homeostasis during long-term increments in sodium intake, studies were conducted in conscious dogs subjected to unilateral renal denervation and surgical division of the urinary bladder into hemibladders to allow separate 24-hour urine collection from denervated and innervated kidneys. They were fed a low sodium diet and continuously infused with isotonic saline (350 mL/d) to provide a daily sodium intake of approximately 60 mmol. After control measurements, sodium intake was increased to 470 mmol/d by increasing the rate of isotonic saline infusion to 3000 mL/d for 5 days; this was followed by a 5-day recovery period. Twenty-four-hour control values for mean arterial pressure and ratios for urinary sodium, potassium, and creatinine excretion from denervated and innervated kidneys (DEN/INN) were 96+/-3, 1.06+/-0.04, 1.00+/-0.04, and 1.01+/-0.02 mm Hg, respectively. During the approximately 8-fold increase in sodium intake, there was no long-term change in mean arterial pressure, and daily sodium balance was achieved within 48 hours. Moreover, during the first day of high salt intake, there were significant reductions in the DEN/INN for sodium and potassium excretion, which persisted for the entire 5-day period of increased sodium intake; on day 5, the DEN/INN for sodium and potassium excretion was 0.86+/-0.03 and 0.86+/-0.04, respectively. In contrast, the DEN/INN for creatinine excretion remained at control levels during high salt intake. Furthermore, similar long-term reductions in the DEN/INN for sodium and potassium excretion occurred in a second group of dogs administered adrenergic receptor-blocking agents for 5 days to interrupt the functional effects of the renal nerves. These data indicate that sustained renal sympathoinhibition promotes sodium and potassium excretion during long-term increments in sodium intake by inhibiting tubular reabsorption of these electrolytes.

Influence of Prolonged Baroreflex Activation on Arterial Pressure in Angiotensin Hypertension

Despite recent evidence indicating sustained activation of the baroreflex during chronic infusion of angiotensin II (Ang II), sinoaortic denervation does not exacerbate the severity of the hypertension. Therefore, to determine whether Ang II hypertension is relatively resistant to the blood pressure-lowering effects of the baroreflex, the carotid baroreflex was electrically activated bilaterally for 7 days in 5 dogs both in the presence and absence of a continuous infusion of Ang II (5 ng/kg per minute) producing high physiological plasma levels of the peptide. Under control conditions, basal values for mean arterial pressure (MAP) and plasma norepinephrine concentration (NE) were 93±1 mm Hg and 99±25 pg/mL, respectively. By day 7 of baroreflex activation, MAP and NE were reduced to 72±4 mm Hg (−21±3 mm Hg) and 56±15 pg/mL, respectively, but PRA was unchanged (control=0.41±0.06 ng ANG I/mL per hour). All values returned to basal levels by the end of a 7-day recovery period. After 7 days of Ang II infusion, MAP increased from 93±3 to 129±3 mm Hg, whereas NE fell from 117±15 to 86±23 pg/mL. During the next 7 days of baroreflex activation/Ang II infusion, further reductions in NE were not statistically significant, and on the final day of baroreflex activation, the reduction in MAP was only 5±1 mm Hg, compared with 21±3 mm Hg in the control normotensive state. These findings indicate that long-term baroreflex-mediated reductions in arterial pressure are markedly diminished, but not totally eliminated, in the presence of hypertension produced by chronic infusion of Ang II.

Sustained Activation of the Central Baroreceptor Pathway in Obesity Hypertension

Abstract—The major goal of this study was to determine whether there is increased activation of medullary neurons that participate in the central baroreceptor reflex pathway in dogs with obesity-induced hypertension, a model of hypertension that is associated with increased sympathetic activity. We used Fos-like (Fos-Li) protein immunohistochemical methods to determine activation of neurons in the nucleus tractus solitarius (NTS), caudal ventrolateral medulla (CVLM), and rostral ventrolateral medulla (RVLM). Dogs were fed either a regular diet or an identical diet with the addition of 0.5 to 0.9 kg of cooked beef fat. After ≈6 weeks of the high fat diet, body weight (36.3±0.4 vs 21.5±0.5 kg), mean arterial pressure (105±4 vs 91±3 mm Hg), and heart rate (97±4 vs 70±3 bpm) were significantly greater in obese than in control dogs, respectively. There was little Fos-Li immunoreactivity in medullary neurons of control dogs but marked reactivity in obese dogs. Specifically, the number of Fos-Li–positive cells in the NTS and CVLM was 3 to 5 times greater in obese than in control dogs. Furthermore, despite sustained activation of these baroreceptor-sensitive neurons, there was a significantly greater number of Fos-Li positive cells in the RVLM of dogs fed the high fat diet. As baroreceptor suppression of sympathoexcitatory cells in the RVLM is mediated by activation of neurons in the NTS and CVLM, these results support recent findings indicating that baroreflex suppression of sympathetic activity is a long-term compensatory response in hypertension. However, sympathoexcitatory inputs onto RVLM neurons would appear to predominate over the inhibitory effects of the baroreflex in obesity hypertension.

Renal Denervation Does Not Abolish Sustained Baroreflex-Mediated Reductions in Arterial Pressure

Recent studies indicate that suppression of renal sympathetic nerve activity and attendant increments in renal excretory function are sustained baroreflex-mediated responses in hypertensive animals. Given the central role of the kidneys in long-term regulation of arterial pressure, we hypothesized that the chronic blood pressure–lowering effects of the baroreflex are critically dependent on intact renal innervation. This hypothesis was tested in 6 dogs by bilaterally activating the carotid baroreflex electrically for 7 days before and after bilateral renal denervation. Before renal denervation, control values for mean arterial pressure and plasma norepinephrine concentration were 95±2 mm Hg and 96±12 pg/mL, respectively. During day 1 of baroreflex activation, mean arterial pressure decreased 13±1 mm Hg, and there was modest sodium retention. Daily sodium balance was subsequently restored, but reductions in mean arterial pressure were sustained throughout the 7 days of baroreflex activation. Activation of the baroreflex was associated with sustained decreases in plasma norepinephrine concentration (≈50%) and plasma renin activity (30% to 40%). All of the values returned to control levels during a 7-day recovery period. Two weeks after renal denervation, control values for mean arterial pressure, plasma norepinephrine concentration, plasma renin activity, and sodium excretion were comparable to those measured when the renal nerves were intact. Moreover, after renal denervation, all of the responses to activation of the baroreflex were similar to those observed before renal denervation. These findings demonstrate that the presence of the renal nerves is not an obligate requirement for achieving long-term reductions in arterial pressure during prolonged activation of the baroreflex.

Systemic and Renal-Specific Sympathoinhibition in Obesity Hypertension

Chronic pressure-mediated baroreflex activation suppresses renal sympathetic nerve activity. Recent observations indicate that chronic electric activation of the carotid baroreflex produces sustained reductions in global sympathetic activity and arterial pressure. Thus, we investigated the effects of global and renal specific suppression of sympathetic activity in dogs with sympathetically mediated, obesity-induced hypertension by comparing the cardiovascular, renal, and neurohormonal responses to chronic baroreflex activation and bilateral surgical renal denervation. After control measurements, the diet was supplemented with beef fat, whereas sodium intake was held constant. After 4 weeks on the high-fat diet, when body weight had increased ≈50%, fat intake was reduced to a level that maintained this body weight. This weight increase was associated with an increase in mean arterial pressure from 100±2 to 117±3 mm Hg and heart rate from 86±3 to 130±4 bpm. The hypertension was associated with a marked increase in cumulative sodium balance despite an approximately 35% increase in glomerular filtration rate. The importance of increased tubular reabsorption to sodium retention was further reflected by ≈35% decrease in fractional sodium excretion. Subsequently, both chronic baroreflex activation (7 days) and renal denervation decreased plasma renin activity and abolished the hypertension. However, baroreflex activation also suppressed systemic sympathetic activity and tachycardia and reduced glomerular hyperfiltration while increasing fractional sodium excretion. In contrast, glomerular filtration rate increased further after renal denervation. Thus, by improving autonomic control of cardiac function and diminishing glomerular hyperfiltration, suppression of global sympathetic activity by baroreflex activation may have beneficial effects in obesity beyond simply attenuating hypertension.

Renal Nerves Promote Sodium Excretion in Angiotensin-Induced Hypertension

To determine whether the sympathetic nervous system contributes to the hypertension induced by pathophysiological increments in plasma angiotensin II (Ang II) concentration, we determined the neurally induced changes in renal excretory function during chronic intravenous infusion of Ang II. Studies were carried out in five conscious chronically instrumented dogs subjected to unilateral renal denervation and surgical division of the urinary bladder into hemibladders to allow separate 24-hour urine collection from the denervated and innervated kidneys. After control measurements, Ang II was infused for 5 days at a rate of 4.8 pmol/kg per minute (5 ng/kg per minute); this was followed by a 5-day recovery period. Twenty-four-hour control values for mean arterial pressure (MAP) and for the ratio of denervated to innervated kidneys (DEN/INN) for urinary sodium, potassium, and creatinine excretion were 93+/-5 mm Hg, 1.17+/-0.09, 1.10+/-0.10, and 1.00+/-0.02, respectively. As expected, Ang II infusion caused sodium retention for several days before sodium balance was achieved at an elevated MAP (day 5=124+/-4 mm Hg). Moreover, by day 2 of Ang II-induced hypertension, there were significant reductions in the DEN/INN for sodium and potassium, which persisted for the 5 days of Ang II infusion; on day 5, the DEN/INN values for sodium and potassium were 0.71+/-0.10 and 0.91+/-0.12, respectively. In contrast, the DEN/INN for creatinine was unchanged from control levels during Ang II infusion, and measurements of renal hemodynamics indicated comparable reductions in glomerular filtration rate (approximately 13%) and renal plasma flow (approximately 25%) during Ang II infusion. This indicates that the renal nerves promoted sodium and potassium excretion during Ang II-induced hypertension by inhibiting tubular reabsorption of these electrolytes. Thus, this study provides no support for the hypothesis that increased renal sympathetic nerve activity impairs sodium excretion and contributes to Ang II-induced hypertension.

Chronic Lowering of Blood Pressure by Carotid Baroreflex Activation: Mechanisms and Potential for Hypertension Therapy

Recent technical advances have renewed interest in device-based therapy for the treatment of drug-resistant hypertension. Findings from recent clinical trials regarding the efficacy of electric stimulation of the carotid sinus for the treatment of resistant hypertension are reviewed here. The main goal of this article, however, is to summarize the preclinical studies that have provided insight into the mechanisms that account for the chronic blood pressure–lowering effects of carotid baroreflex activation. Some of the mechanisms identified were predictable and confirmed by experimentation. Others have been surprising and controversial, and resolution will require further investigation. Although feasibility studies have been promising, firm conclusions regarding the value of this device-based therapy for the treatment of resistant hypertension awaits the results of current multicenter trials.