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 93Ϯ3 mm Hg and 64Ϯ4 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 75Ϯ4 mm Hg. Moreover, this hypotensive response was sustained throughout the entire 7 days of baroreflex activation (day 7, MAPϭ72Ϯ5 mm Hg). During prolonged baroreflex activation, heart rate decreased in parallel with MAP, although the changes were not as pronounced (day 7, heart rateϭ51Ϯ3 bpm). Prolonged baroreflex activation was also associated with Ϸ35% reduction in plasma norepinephrine concentration (controlϭ87Ϯ15 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. Key Words: baroreflex Ⅲ arterial pressure Ⅲ sympathetic nervous system Ⅲ renin-angiotensin system Ⅲ sodium S ince McCubbin et al 1 demonstrated a marked resetting of the arterial baroreflex in chronic hypertension, there has been considerable skepticism that baroreflexes participate in long-term control of arterial pressure. 2-5 Nonetheless, because of the importance of this neural feedback mechanism in the acute regulation of sympathetic activity and arterial pressure, there has been continued interest in the possibility that baroreflexes may play a role in the pathogenesis of hypertension. Indeed, a recurrent hypothesis to account for excessive sympathetic activation in hypertension is baroreflex dysfunction, an associated finding in some forms of experimental and clinical hypertension. 2,3,6,7 However, whether impaired baroreflex suppression of sympathetic activity plays a role in the hypertensive process would appear to depend on whether baroreflexes completely reset when exposed to chronic changes in arterial pressure. If, in fact, resetting is complete and baroreflexes do not chronically alter sympathetic activity, then they could not produce functional changes that influence the severity of hypertension.The fundamental question of whether baroreflexes completely reset and have the capacity to chronically alter sympathet...

Chronic pressure-mediated baroreflex activation suppresses renal sympathetic nerve activity. Recent observations indicate that chronic electrical 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 while sodium intake was held constant. After 4 weeks on the high-fat, when body weight had increased ~a 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 ~ a 35% increase in GFR. The importance of increased tubular reabsorption to sodium retention was further reflected by ~ a 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, GFR 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.

Abstract-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 93Ϯ1 mm Hg and 99Ϯ25 pg/mL, respectively. By day 7 of baroreflex activation, MAP and NE were reduced to 72Ϯ4 mm Hg (Ϫ21Ϯ3 mm Hg) and 56Ϯ15 pg/mL, respectively, but PRA was unchanged (controlϭ0.41Ϯ0.06 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 93Ϯ3 to 129Ϯ3 mm Hg, whereas NE fell from 117Ϯ15 to 86Ϯ23 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 5Ϯ1 mm Hg, compared with 21Ϯ3 mm Hg in the control normotensive state.

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.

Lohmeier TE, Iliescu R, Dwyer TM, Irwin ED, Cates AW, Rossing MA. Sustained suppression of sympathetic activity and arterial pressure during chronic activation of the carotid baroreflex. Am J Physiol Heart Circ Physiol 299: H402-H409, 2010. First published May 28, 2010; doi:10.1152/ajpheart.00372.2010.-Following sinoaortic denervation, which eliminates arterial baroreceptor input into the brain, there are slowly developing adaptations that abolish initial sympathetic activation and hypertension. In comparison, electrical stimulation of the carotid sinus for 1 wk produces sustained reductions in sympathetic activity and arterial pressure. However, whether compensations occur subsequently to diminish these responses is unclear. Therefore, we determined whether there are important central and/or peripheral adaptations that diminish the sympathoinhibitory and blood pressure-lowering effects of more sustained carotid sinus stimulation. To this end, we measured whole body plasma norepinephrine spillover and ␣ 1-adrenergic vascular reactivity in six dogs over a 3-wk period of baroreflex activation. During the first week of baroreflex activation, there was an ϳ45% decrease in plasma norepinephrine spillover, along with reductions in mean arterial pressure and heart rate of ϳ20 mmHg and 15 beats/min, respectively; additionally, plasma renin activity did not increase. Most importantly, these responses during week 1 were largely sustained throughout the 3 wk of baroreflex activation. Acute pressor responses to ␣-adrenergic stimulation during ganglionic blockade were similar throughout the study, indicating no compensatory increases in adrenergic vascular reactivity. These findings indicate that the sympathoinhibition and lowering of blood pressure and heart rate induced by chronic activation of the carotid baroreflex are not diminished by adaptations in the brain and peripheral circulation. Furthermore, by providing evidence that baroreflexes have long-term effects on sympathetic activity and arterial pressure, they present a perspective that is opposite from studies of sinoaortic denervation. blood pressure; sympathetic nervous system; renin-angiotensin system THE RECENT DEVELOPMENT OF technology allowing chronic electrical stimulation of the carotid sinus has provided greater insight into the mechanisms that mediate the chronic blood pressure-lowering effects of baroreflex activation. Experimental studies using chronic stimulation of the carotid sinus have demonstrated that prolonged baroreflex activation (PBA) produces sustained and controllable reductions in mean arterial pressure (MAP), concomitant with suppression of plasma norepinephrine (NE) concentration (12, 14 -16, 18). Thus these studies suggest that sustained activation of the baroreflex has the capacity to produce substantial long-term reductions in MAP by inhibiting centrally generated sympathetic outflow.One limitation of these initial findings studies of PBA is their relatively short duration, lasting only 1 wk. The potential significance of this limitatio...

Abstract-Much of the current pharmacological therapy for chronic heart failure targets neurohormonal activation. In spite of recent advances in drug therapy, the mortality rate for chronic heart failure remains high. Activation of the carotid baroreceptor (BR) reduces sympathetic outflow and augments vagal tone. We investigated the effect of chronic activation of the carotid BR on hemodynamic and neurohormonal parameters and on mortality in dogs with chronic heart failure. Fifteen dogs were instrumented to record hemodynamics. Electrodes were applied around the carotid sinuses to allow for activation of the BR. After 2 weeks of pacing (250 bpm), electrical carotid BR activation was initiated in 7 dogs and continued for the remainder of the study.

Abstract-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 95Ϯ2 mm Hg and 96Ϯ12 pg/mL, respectively. During day 1 of baroreflex activation, mean arterial pressure decreased 13Ϯ1 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 (Ϸ50%) 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. Key Words: baroreflex Ⅲ arterial pressure Ⅲ renal nerves Ⅲ sympathetic nervous system Ⅲ norepinephrine Ⅲ renin-angiotensin system Ⅲ sodium excretion N ovel experimental approaches in chronically instrumented animals have recently provided greater insight into the role of baroreflexes in long-term control of arterial pressure. 1-10 These studies, conducted over several weeks, indicate that baroreflex resetting is incomplete in experimental models of hypertension. They also indicate that during chronic increases in arterial pressure, there is sustained baroreflex-mediated suppression of renal sympathetic nerve activity and attendant increments in renal excretory function, responses expected to attenuate the severity of hypertension. However, the quantitative importance of renal sympathoinhibition in mediating the chronic blood pressure-lowering effects of sustained baroreflex activation remains unclear.We have recently developed methodology that is ideal for evaluating the time dependency and underlying mechanisms of the blood pressure-lowering effects of the baroreflex. 6,10 To activate the carotid baroreflex, an externally adjustable pulse generator is used to electrically stimulate electrodes chronically implanted around both c...

A surgically implantable device for electrical stimulation of the carotid baroreflex system can be placed safely and produces a significant acute decrease in blood pressure without significant side effects.