Chronic Electric Activation Research Articles

Prolonged Baroreflex Activation Abolishes Salt-Induced Hypertension After Reductions in Kidney Mass.

Chronic electric activation of the carotid baroreflex produces sustained reductions in sympathetic activity and arterial pressure and is currently being evaluated for therapy in patients with resistant hypertension. However, patients with significant impairment of renal function have been largely excluded from clinical trials. Thus, there is little information on blood pressure and renal responses to baroreflex activation in subjects with advanced chronic kidney disease, which is common in resistant hypertension. Changes in arterial pressure and glomerular filtration rate were determined in 5 dogs after combined unilateral nephrectomy and surgical excision of the poles of the remaining kidney to produce ≈70% reduction in renal mass. After control measurements, sodium intake was increased from ≈45 to 450 mol/d. While maintained on high salt, animals experienced increases in mean arterial pressure from 102±4 to 121±6 mm Hg and glomerular filtration rate from 40±2 to 45±2 mL/min. During 7 days of baroreflex activation, the hypertension induced by high salt was abolished (103±6 mm Hg) along with striking suppression of plasma norepinephrine concentration from 139±21 to 81±9 pg/mL, but despite pronounced blood pressure lowering, there were no significant changes in glomerular filtration rate (43±2 mL/min). All variables returned to prestimulation values during a recovery period. These findings indicate that after appreciable nephron loss, chronic suppression of central sympathetic outflow by baroreflex activation abolishes hypertension induced by high salt intake. The sustained antihypertensive effects of baroreflex activation occur without significantly compromising glomerular filtration rate in remnant nephrons.

Regulation of renin secretion and arterial pressure during prolonged baroreflex activation: influence of salt intake.

Chronic electric activation of the carotid baroreflex produces sustained reductions in sympathetic activity and arterial pressure and is currently being evaluated as antihypertensive therapy for patients with resistant hypertension. However, the influence of variations in salt intake on blood pressure lowering during baroreflex activation (BA) has not yet been determined. As the sensitivity of arterial pressure to salt intake is linked to the responsiveness of renin secretion, we determined steady-state levels of arterial pressure and neurohormonal responses in 6 dogs on low, normal, and high salt intakes (5, 40, 450 mmol/d, respectively) under control conditions and during a 7-day constant level of BA. Under control conditions, there was no difference in mean arterial pressure at low (92±1) and normal (92±2 mm Hg) sodium intakes, but pressure increased 9±2 mm Hg during high salt. Plasma renin activity (2.01±0.23, 0.93±0.20, 0.01±0.01 ng angiotensin I/mL/h) and plasma aldosterone (10.3±1.9, 3.5±0.5, 1.7±0.1 ng/dL) were inversely related to salt intake, whereas there were no changes in plasma norepinephrine. Although mean arterial pressure (19-22 mm Hg) and norepinephrine (20%-40%) were lower at all salt intakes during BA, neither the changes in pressure nor the absolute values for plasma renin activity or aldosterone in response to salt were different from control conditions. These findings demonstrate that suppression of sympathetic activity by BA lowers arterial pressure without increasing renin release and indicate that changes in sympathetic activity are not primary mediators of the effect of salt on renin secretion. Consequently, blood pressure lowering during BA is independent of salt intake.

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Abstract 354: Cardiovascular Responses to Chronic Baroreflex Activation in Aldosterone Hypertension

Both suppression of sympathetic activity (SA) by chronic electrical activation of the carotid baroreflex (BA) and renal denervation (RDX) abolish obesity-induced hypertension (HT), which is mediated by increased SA. Evidence in support of a sympathetic component to aldosterone (Aldo) HT is equivocal. Therefore, at the same stimulation parameters in each dog, cardiovascular responses to 7 days of BA were determined in 9 dogs before (no HT) and after induction of HT by infusion of Aldo for 14 days (12μg/kg/day), which increased plasma levels ~ 10-fold (control= 4.3±0.4 ng/dL). 3 dogs with Aldo HT were subjected to RDX. Aldo HT was associated with increases in plasma osmolality (293±1 to 297±1 mOsm/kg) and [vasopressin] (AVP, Table), marked polydipsia (241± 90 to 2,380 ± 382 mL/day), hypokalemia (4.2±0.1 to 2.3±0.1 mmol/L), and suppression of plasma renin activity, but no significant changes in plasma [norepinephrine] (NE, Table). MAP (mmHg), NE (pg/mL), and AVP (pg/mL) responses to BA: *P&lt;0.05 vs Control Plasma [NE] decreased with BA during both no HT and Aldo HT, indicating suppression of SA, but MAP lowering was appreciably diminished during Aldo HT. In contrast, there was no lowering of MAP after RDX. There were no significant changes in plasma osmolality, drinking, or [AVP] during BA. These findings indicate that classic renal mineralocorticoid mechanisms, not increased SA, account for the initial progression of HT produced by pathophysiological circulating levels of Aldo. Further, they show that chronic stimulation of baroreceptors afferents has differential central effects to suppress SA without altering control of plasma osmolality by suppressing thirst or AVP secretion.

Renal Responses to Chronic Suppression of Central Sympathetic Outflow

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.

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.

Acute and chronic electrical activation of baroreceptor afferents in awake and anesthetized subjects

Electrical stimulation of baroreceptor afferents was used in the 1960's in several species, including human beings, for the treatment of refractory hypertension. This approach bypasses the site of baroreceptor mechanosensory transduction. Chronic electrical stimulation of arterial baroreceptors, particularly of the carotid sinus nerve (Hering's nerve), was proposed as an ultimate effort to treat refractory hypertension and angina pectoris due to the limited nature of pharmacological therapy available at that time. Nevertheless, this approach was abandoned in the early 1970's due to technical limitations of implantable devices and to the development of better-tolerated antihypertensive medications. More recently, our laboratory developed the technique of electrical stimulation of the aortic depressor nerve in conscious rats, enabling access to hemodynamic responses without the undesirable effect of anesthesia. In addition, electrical stimulation of the aortic depressor nerve allows assessment of the hemodynamic responses and the sympathovagal balance of the heart in hypertensive rats, which exhibit a well-known decrease in baroreflex sensitivity, usually attributed to baroreceptor ending dysfunction. Recently, there has been renewed interest in using electrical stimulation of the carotid sinus, but not the carotid sinus nerve, to lower blood pressure in conscious hypertensive dogs as well as in hypertensive patients. Notably, previous undesirable technical outcomes associated with electrical stimulation of the carotid sinus nerve observed in the 1960's and 1970's have been overcome. Furthermore, promising data have been recently reported from clinical trials that evaluated the efficacy of carotid sinus stimulation in hypertensive patients with drug resistant hypertension.

Baroreflex activation for the treatment of hypertension: principles and practice

This article reviews the history and current status of an innovative nonpharmacological approach for the treatment of resistant hypertension – chronic electrical activation of the afferent limb of the carotid baroreflex. Recent studies in both normotensive and hypertensive canine models have unambiguously demonstrated sustained and clinically relevant reductions in arterial pressure and sympathetic activity in the course of prolonged baroreflex activation. Clinical trials designed to evaluate the efficacy and safety of this therapy in patients with resistant hypertension are now underway in both Europe and the USA.

Prolonged activation of the baroreflex: A viable approach for the treatment of hypertension?

In most patients with hypertension, arterial pressure is above the target level for control, even in those individuals taking multiple antihypertensive drugs. In this article, we review the history and current status of a nonpharmacologic approach for the treatment of hypertension--chronic electrical activation of the afferent limb of the carotid baroreflex. Recent studies in normotensive and hypertensive dogs have clearly demonstrated impressive and sustained reductions in arterial pressure and sympathetic activity during prolonged baroreflex activation. Clinical trials are now underway in Europe, and clinical investigation in the United States will begin this year to evaluate the efficacy of this therapy in patients with resistant hypertension.

Asymmetric thickness of the left ventricular wall resulting from asynchronous electric activation: A study in dogs with ventricular pacing and in patients with left bundle branch block

Various kinds of abnormal, asynchronous electric activation of the left ventricle (LV) decrease mechanical load in early versus late activated regions of the ventricular wall. Because myocardium usually adapts its mass to changes in workload, we investigated by echocardiography whether regional differences in wall thickness are present in two kinds of asynchronous electric activation of different origin and conduction pathway: epicardial ventricular pacing in dogs and left bundle branch block (LBBB) in patients. In six dogs, 3 months of epicardial LV pacing at physiologic heart rates decreased the thickness of the early activated anterior wall by 20.5 ± 8.1% without significantly changing LV cavity area and septal thickness. In a retrospective study of 228 LBBB patients, the early activated septum was significantly thinner than the late activated posterior wall. The asymmetry most pronounced was as large as 10% in 28 patients with LBBB and paradoxic septal motion. No difference in regional wall thickness was present in 154 control patients. In conclusion, chronic asynchronous electric activation in the heart induces redistribution of cardiac mass. This redistribution occurs in hearts, which differ in impulse conduction pathway, disease, and species and is characterized by thinning of early versus late activated myocardium.

Changes in left ventricular diastolic wall thickness induced by chronic asynchronous electrical activation

Changes in left ventricular diastolic wall thickness induced by chronic asynchronous electrical activation

Chronic low frequency electrical activation for one week corrects nerve conduction velocity deficits in rats with diabetes of three months duration.

This study examined the effect of chronic electrical activation on conduction velocity deficits after three months of streptozotocin-induced diabetes. There were 30% and 20% reductions in conduction velocity in diabetic animals for tibialis anterior and saphenous nerves, respectively (p less than 0.01). Unilateral electrical stimulation of the common peroneal nerve, which contains axons supplying tibialis anterior but not saphenous nerve, was carried out in a group of diabetic and a group of normal control rats. Stimulation was given over seven days, at 10 Hz for 8 h/day. Final experiments were carried out at least 17 h after the last stimulation session. In normal rats stimulation had no effect on conduction velocity in either nerve. In diabetic animals, however, tibialis anterior conduction was within the normal control range for the stimulated nerve. In contrast, the contralateral unstimulated nerve had reduced conduction velocity (p less than 0.001), which was within the unoperated diabetic control range. There were no effects on saphenous nerve conduction, comparing stimulated and unstimulated legs. We conclude that chronic increases in nerve electrical activation promote mechanisms that reverse conduction deficits in diabetic rats.