Acute baroreflex resetting and its control of blood pressure in an open loop model

Summary Acute baroreflex resetting has been quantitatively studied in anesthetized dogs. Carotid sinuses were isolated bilaterally and carotid sinus conditioning pressure (CP_csp) was set at nine different levels for 20 min over a range of from 40 to 200 mm Hg. Over this range of 160 mm Hg in CP_csp, the magnitude of baroreflex resetting of set point pressure (Psp), threshold pressure (Pth) and BP50 was 32.0±5, 43.3±6 and 39.6±6 mm Hg, respectively. The extent of resetting was a non-linear function of the level of CP_csp. There is less resetting at high CP_csp. The average extent of resetting is only about 25%. In contrast to this small degree of resetting, a profound inverse relationship between the baseline pressure and the conditioning pressure was observed at the end of the conditioning period for each CP_csp. In addition, we also observed an attenuation in the buffering capacity of the baroreflex at very high or very low CP_csp. Vagotomy and aortic section did not alter baroreflex resetting. This data indicates that the baroreflex in capable of monitoring the absolute level of blood pressure during acute resetting in addition to buffering transient disturbances in arterial pressure. Based upon the results of the present experiments, the concept that acute baroreflex resetting results in an inability of the baroreflex to monitor the absolute level of arterial pressure does not appear to be valid. Supported by NIH Grant NoO. HL 33359 Supported by NIH Postdoctoral Fellowship No. HC 07241     

Rapid baroreceptor resetting in chronic hypertension. Implications for normalization of arterial pressure

The purpose of this study was to examine the ability of baroreceptors of renal hypertensive rabbits to reset rapidly during acute changes in arterial pressure. The carotid sinus (CS) was vascularly isolated and baroreceptor activity was recorded during slow ramp increases in CS pressure in hypertensive (one-kidney, one wrap; 127 +/- 3 mm Hg) and normotensive (one-kidney, no wrap; 85 +/- 3 mm Hg) rabbits anesthetized with chloralose. Control measurements were made after holding pressure for 10-15 minutes at the level of arterial pressure recorded before each experiment. Baroreceptor threshold pressure (Pth) was higher in hypertensives (78 +/- 4 mm Hg) compared with normotensives (55 +/- 3 mm Hg, p less than 0.05), and nerve activity was less in hypertensives over a wide range of pressure. CS distensibility (sonomicrometers) was not significantly different in the two groups. After increasing holding pressure from control by 30 and 60 mm Hg for 10-15 minutes, the extent of baroreceptor resetting (delta Pth/delta holding pressure x 100%) in normotensives was 39 +/- 6% and 33 +/- 2%, respectively, but only 14 +/- 5% and 9 +/- 3% in hypertensives (p less than 0.05). After decreasing holding pressure by 30 and 60 mm Hg, resetting was similar in normotensives (32 +/- 6% and 28 +/- 3%) and hypertensives (34 +/- 3% and 30 +/- 4%). In hypertensive rabbits, acute (10-15 minutes) exposure of baroreceptors to normotension (71 +/- 4 mm Hg) decreased Pth to 62 +/- 4 mm Hg and increased nerve activity to levels not significantly different from those of normotensive animals without altering CS distensibility.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dynamic effects of carotid sinus baroreflex on ventriculoarterial coupling studied in anesthetized dogs.

We evaluated dynamic effects of the carotid sinus baroreflex on ventriculoarterial coupling. In seven anesthetized, vagotomized dogs, we bilaterally isolated carotid sinuses and randomly changed carotid sinus pressure while measuring aortic pressure, aortic flow, and left ventricular pressure. Estimating left ventricular end-systolic elastance (Ees) and effective arterial elastance (Ea) on a beat-to-beat basis, we determined transfer functions from the carotid sinus pressure to Ees (HEes) and from the carotid sinus pressure to Ea (HEa) over the frequency range spanning 0.002-0.25 Hz. Both HEes and HEa exhibited characteristics of a second-order low-pass filter. The gains of HEes and HEa were 0.085 +/- 0.065 (mean +/- SD) and 0.081 +/- 0.049 mm Hg/ml/mm Hg, respectively. There were no significant differences in natural frequencies (0.039 +/- 0.013 versus 0.039 +/- 0.007 Hz) or damping ratios (0.65 +/- 0.11 versus 0.64 +/- 0.24). The results indicated that the carotid sinus baroreflex dynamically altered Ees and Ea to the same extent in the process of stabilizing arterial pressure. Because the arterial system extracts maximal external work from a given heart when Ea equals Ees, the carotid sinus baroreflex appeared to be designed to regulate the ventricular and arterial properties to optimize the energy transmission from the left ventricle to the arterial system in anesthetized, vagotomized dogs.     

Carotid sinus compliance and baroreflex responses in hypertensive dogs

The hypothesis that changes in baroreflex function seen in hypertension could be explained by a decreased vascular compliance in the carotid sinus region itself was tested. Six dogs were made chronically hypertensive (MAP = 146.0 +/- 3.3 mm Hg) using a bilateral renal wrap technique, while six other dogs were sham operated and served as normotensive controls (MAP = 125.8 +/- 4.7 mm Hg). Six weeks after the procedure, compliance of the carotid sinus region was measured, and carotid baroreflex control of arterial pressure and heart rate was assessed acutely. Dogs were anesthetized with sodium pentobarbital and the carotid sinus was isolated and perfused at controlled pressures. Vagotomy was performed to eliminate aortic and cardiopulmonary reflex buffering. The carotid sinus pressure (CSP) was changed from 25 to 250 mm Hg in a stepwise fashion, and the corresponding arterial pressure, heart rate and volume changes were recorded. Compliance was determined as the change in volume infused divided by the changes in pressure achieved. Significant differences between the normotensive and hypertensive groups were found in the reflex responses of arterial pressure and heart rate to changes in CSP. Carotid sinus compliance decreased with increasing CSP, but was not different in the two groups. Changes in baroreflex responses seen in mild hypertension occur without significant changes in carotid sinus compliance, and cannot be explained solely by a decreased compliance in the receptor wall.     

Analysis of the action of angiotensin II on the baroreflex control of heart rate in conscious rabbits

There is considerable evidence that angiotensin II (Ang II) attenuates the baroreflex control of heart rate (HR), but the mechanism and site of this action have not been precisely defined. In the present study the effects of systemically and centrally administered Ang II on the baroreflex control of HR were investigated in conscious, chronically prepared rabbits. Baroreflex curves (HR vs. mean arterial pressure) were generated with iv infusions of phenylephrine or nitroprusside. Background infusion of Ang II at 10 ng/kg.min increased mean arterial pressure from 77.3 +/- 3.0 to 94.3 +/- 4.1 mm Hg (P less than 0.001) without changing HR [212.1 +/- 7.2 to 218.0 +/- 9.8 beats/min (bpm)] and shifted (reset) the baroreflex curve with phenylephrine to a higher pressure level (P less than 0.001) without changing its slope (-1.40 +/- 0.40 to -1.65 +/- 0.46 bpm/mm Hg; P = 0.4). Background infusion of an equipressor dose of phenylephrine did not shift the baroreflex curve or change its slope. Ang II also shifted the baroreflex curve with nitroprusside to a higher pressure level (P less than 0.01), but again the slope was not significantly changed (-2.30 +/- 1.25 to -1.51 +/- 0.52 bpm/mm Hg; P = 0.2). Background intraventricular infusion of Ang II at 1 ng/kg.min had the same effects as iv infusion of Ang II at 10 ng/kg.min; the curve was shifted to a higher pressure level (P less than 0.001), but the slope was not changed (-0.76 +/- 0.47 to -1.143 +/- 0.48 bpm/mm Hg). Intravenous infusion of Ang II at 1 ng/kg.min had no effect on the baroreflex. The resetting of the baroreflex with phenylephrine by iv Ang II (10 ng/kg.min) was not blocked by propranolol: atropine markedly reduced the baroreflex response to phenylephrine in both the absence and presence of Ang II. These results indicate that in conscious rabbits, Ang II resets the baroreflex control of HR, but does not change its sensitivity. This effect apparently results from an action of Ang II on the brain that is mediated by withdrawal of vagal tone to the heart. The resetting of the baroreflex by Ang II can explain the ability of the peptide to increase arterial pressure without decreasing HR.     

Effects of calcium channel antagonists on carotid sinus baroreflex control of arterial pressure and heart rate in anesthetized dogs

Our study was designed to determine whether the calcium channel antagonists verapamil, diltiazem, and nifedipine and the nitrate vasodilator sodium nitroprusside modulate carotid sinus (CS) baroreflex control of mean arterial pressure (MAP) and heart rate (HR). Pentobarbital-anesthetized, vagotomized dogs were surgically prepared for reversible vascular isolation of the CS regions. Open-loop performance of the CS baroreflex was determined under control conditions and after intravenous infusion of each agent for 20 minutes at four rates (nitroprusside: 0.3-10 micrograms/kg/min; verapamil and diltiazem: 1-30 micrograms/kg/min; nifedipine: 0.1-3 micrograms/kg/min). With the CS baroreflex loop closed, each vasodilator decreased MAP from control (nitroprusside: 127 +/- 3 to 69 +/- 5 mm Hg; verapamil: 137 +/- 7 to 86 +/- 5 mm Hg; diltiazem: 137 +/- 9 to 100 +/- 5 mm Hg; nifedipine: 140 +/- 6 to 109 +/- 7 mm Hg). Each compound also caused a dose-dependent downward shift in the open-loop CSP-MAP relations. The higher doses of each vasodilator also depressed the total range of control of MAP (i.e., maximum MAP minus minimum MAP) by the baroreflex and significantly attenuated the peak open-loop MAP/CSP gains (nitroprusside: 1.21 +/- 0.19 to 0.56 +/- 0.12; verapamil: 1.36 +/- 0.16 to 0.64 +/- 0.10; diltiazem: 1.52 +/- 0.34 to 0.89 +/- 0.11; nifedipine: 1.35 +/- 0.20 to 0.83 +/- 0.14) but did not alter the CSP at which the peak gain was manifest. Only verapamil and diltiazem significantly shifted downward the CSP-HR relations, whereas none of the drugs affected the total range of baroreflex control of HR (i.e., maximum HR minus minimum HR) or the peak open-loop HR/CSP gains. Our results suggest that 1) it is unlikely that calcium channel antagonists act directly on the baroreceptors or the neural components of the baroreflex loop (i.e., afferent, central and efferent nerves) because they impair CS baroreflex control of MAP but not HR and 2) the impairment of MAP control is predominantly due to a nonspecific blunting of adrenergic vasoconstriction.     

Contrasting effects of static and pulsatile pressure on carotid baroreceptor activity in dogs

The purpose of this study was to contrast the effects of static and pulsatile pressure on carotid baroreceptor activity over a wide range of mean arterial pressure. Static and pulsatile pressure were applied to the isolated carotid sinus of dogs anesthetized with chloralose. Recordings were obtained from single baroreceptor units as well as from the whole sinus nerve or a large strand of the nerve. Three observations are reported. First, in single units the pulsatile pressure threshold, which averaged 48 +/- 8 (SEM) mm Hg, was far below the static pressure threshold, which averaged 79 +/- 8 mm Hg (p less than 0.05, n = 15). Thus, pulsatility decreased the threshold by an average of 31 mm Hg in contrast to the minimal or lack of decrease in threshold reported by others in aortic baroreceptors. Second, at moderate arterial pressures a shift from static to pulsatile pressure caused a decrease in single and multiple unit activities. In single units, the decrease approximated 15% (from 42.0 +/- 2.1 to 35.5 +/- 1.9 spikes/sec, p less than 0.05, n = 25). In all units, there was no diastolic nerve activity ("silence") when diastolic pressure was 1 to 10 mm Hg above static pressure threshold; 80% of the units exhibited "diastolic silence" when diastolic pressure was 20-30 mm Hg above threshold and 40% of the units showed silence at diastolic pressures 40-50 mm Hg above threshold. In whole nerve recordings, pulsatility increased activity from 57 +/- 15 to 142 +/- 29 spikes/sec (p less than 0.05) at low mean arterial pressures (50 and 75 mm Hg), as expected from the reduction in pressure threshold noted in single units, and decreased activity by approximately 15% (from 373 +/- 69 to 320 +/- 55 spikes/sec, p less than 0.05, n = 9) at mean arterial pressures of 125 and 150 mm Hg. This decrease in activity with a shift from static to pulsatile pressure at moderate arterial pressures has not been reported previously. Third, the static pressure-activity curve was sigmoid, and its gain peaked sharply at 75-100 mm Hg; in contrast, the pulsatile pressure-activity curve was linear between 25 and 150 mm Hg, and its maximum gain was half the maximum gain during static pressure. These differences between the static pressure-activity curve and the pulsatile pressure-activity curve were noted during both increases and decreases in carotid sinus pressure; both curves exhibited some hysteresis during the decreases in pressure.     

Aggregating human platelets in carotid sinus of rabbits decrease sensitivity of baroreceptors.

Aggregating platelets release factors that act in a local paracrine manner to alter vascular tone. The purpose of the present study was to explore the possibility that factors released from aggregating platelets may alter the sensitivity of arterial baroreceptors. Baroreceptor activity was recorded from the vascularly isolated carotid sinus of rabbits anesthetized with sodium pentobarbital. The carotid sinus was filled with oxygenated Krebs-Henseleit buffer and distended with slow ramp increases in nonpulsatile pressure. Sensitivity of baroreceptors to increased pressure was determined before and during intraluminal exposure of the sinus to washed human platelets suspended in Krebs' buffer. Platelets activated with thrombin (0.4 units/ml) decreased baroreceptor activity and the slope of the pressure-activity curve significantly (n = 6). The platelet-induced decrease in baroreceptor sensitivity was related to the duration of exposure to platelets with no change in baroreceptor activity after 4 minutes and a progressive decrease in activity over the next 12 minutes. The slope of the pressure-nerve activity relation averaged 1.26 +/- 0.08 %/mm Hg during control and decreased to 0.97 +/- 0.22, 0.80 +/- 0.19, and 0.53 +/- 0.15 %/mm Hg after 12-16 minutes of exposure to 10(7), 10(8), and 3-6 x 10(8) activated platelets/ml, respectively (p less than 0.05). Baroreceptor sensitivity was restored after removal of platelets from the carotid sinus. Thrombin alone had no effect on baroreceptor sensitivity. Activated platelets did not alter the carotid pressure-diameter relation, suggesting a direct inhibitory effect on baroreceptors. The slope of the pressure-activity curve and maximum baroreceptor activity were not decreased by the stable thromboxane analogue U46619, serotonin, or ADP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prostaglandins contribute to activation of baroreceptors in rabbits. Possible paracrine influence of endothelium

The purpose of this study was to test the hypothesis that prostaglandins released from vascular endothelial cells contribute to activation of baroreceptors during increases in arterial pressure. Baroreceptor activity was recorded from the vascularly isolated carotid sinus in rabbits anesthetized with chloralose. Baroreceptor activity was measured during ramp or step increases in nonpulsatile carotid sinus pressure over a range of 0-175 mm Hg. Exposure of the isolated carotid sinus to inhibitors of prostaglandin formation (indomethacin [n = 10] or aspirin [n = 6]) decreased baroreceptor activity significantly (p less than 0.05). The slope of the pressure-activity relation averaged 0.80 +/- 0.07 %/mm Hg (mean +/- SEM) during control measurements and 0.72 +/- 0.06 and 0.63 +/- 0.05 %/mm Hg during exposure to 10 and 20 microM indomethacin, respectively. Exposure of the carotid sinus to exogenous prostacyclin (PGI2 [n = 11]) increased baroreceptor activity significantly. The slope of the pressure-activity relation averaged 0.89 +/- 0.10, 1.09 +/- 0.09, and 1.26 +/- 0.16 %/mm Hg during control and during exposure to 10 and 20 microM PGI2, respectively. Activity returned to control after removal of PGI2 (0.89 +/- 0.12 %/mm Hg). Removal of endothelium with either a balloon catheter (n = 4) or a jet of a 95% O2-5% CO2 gas mixture (n = 6) decreased the slope of the pressure-activity relation from 0.92 +/- 0.09 to 0.56 +/- 0.08 %/mm Hg (p less than 0.05). Exposure of the denuded sinus to exogenous PGI2 (20 microM [n = 4]) restored activity (slope = 1.09 +/- 0.24 %/mm Hg). Neither indomethacin (n = 5) nor PGI2 (n = 5) nor denudation (n = 5) significantly altered the pressure-diameter relation of the carotid sinus (sonomicrometers), suggesting that the effects on baroreceptor discharge are not caused by altered stretch of the carotid sinus at a given pressure. The results suggest that prostaglandins (e.g., PGI2) released from endothelium contribute in a paracrine manner to activation of baroreceptors during increases in arterial pressure.     

Aldosterone reduces baroreceptor discharge in the dog.

We have previously demonstrated that baroreceptor discharge sensitivity is depressed in dogs with experimental heart failure and that this depressed sensitivity can be reversed by the Na+,K(+)-ATPase inhibitor ouabain. This suggests that enhanced Na+,K(+)-ATPase activity in baroreceptors is responsible for the blunted baroreceptor discharge sensitivity seen in heart failure state. Because aldosterone, a known stimulator of Na+,K(+)-ATPase, is elevated in heart failure the present study was undertaken to determine the effects on baroreceptor discharge of perfusion of the carotid sinus with aldosterone in normotensive dogs. Single unit baroreceptor activity was recorded as well as carotid sinus pressure and the diameter of the carotid sinus. Perfusion of the carotid sinus with aldosterone (in Krebs-Henseleit solution) significantly elevated threshold pressure (108.5 +/- 3.1 mm Hg versus 92.7 +/- 4.6 mm Hg, p less than 0.05) and reduced peak discharge rate (40.3 +/- 3.9 spikes/sec, p less than 0.05). These effects appeared 15 minutes after aldosterone perfusion and remained constant for the next 60 minutes. There was no change in the carotid sinus pressure-diameter curve during perfusion with aldosterone. Perfusion of the carotid sinus with ouabain (0.1 microgram/ml) during aldosterone perfusion did not reverse the blunted baroreceptor discharge. The blunted baroreceptor activity induced by perfusion of the carotid sinus with aldosterone was prevented by removal of the endothelial cells in the carotid sinus area with a balloon-tipped catheter or by perfusion with saponin. Finally, perfusion of the carotid sinus with spironolactone (10 ng/ml), a mineralocorticoid receptor antagonist, prevented the inhibitory effect of aldosterone. These data suggest that aldosterone reduces maximum baroreceptor discharge.(ABSTRACT TRUNCATED AT 250 WORDS)     

Baroreflex control of muscle sympathetic nerve activity after carotid body tumor resection

Bilateral carotid body tumor resection causes a permanent attenuation of vagal baroreflex sensitivity. We retrospectively examined the effects of bilateral carotid body tumor resection on the baroreflex control of sympathetic nerve traffic. Muscle sympathetic nerve activity was recorded in 5 patients after bilateral carotid body tumor resection (1 man and 4 women, 51+/-11 years) and 6 healthy control subjects (2 men and 4 women, 50+/-7 years). Baroreflex sensitivity was calculated from changes in R-R interval and muscle sympathetic nerve activity in response to bolus injections of phenylephrine and nitroprusside. In addition, sympathetic responses to the Valsalva maneuver and cold pressor test were measured. The integrated neurogram of patients and control subjects contained a similar pattern of pulse synchronous burst of nerve activity. Baroreflex control of both heart rate and sympathetic nerve activity were attenuated in patients as compared with control subjects [heart rate baroreflex sensitivity: 3.68+/-0.93 versus 11.61+/-4.72 ms/mm Hg (phenylephrine, P=0.011) and 2.53+/-1.36 versus 5.82+/-1.94 ms/mm Hg (nitroprusside, P=0.05); sympathetic baroreflex sensitivity: 3.70+/-2.90 versus 7.53+/-4.12 activity/100 beats/mm Hg (phenylephrine, P=0.10) and 3.93+/-4.43 versus 15.27+/-10.03 activity/100 beats/mm Hg (nitroprusside, P=0.028)]. The Valsalva maneuver elicited normal reflex changes in muscle sympathetic nerve activity, whereas heart rate responses were blunted in the patients with bilateral carotid body tumor resection. Maximal sympathetic responses to the cold pressor test did not differ between the two groups. Denervation of carotid sinus baroreceptors as the result of bilateral carotid body tumor resection produces chronic impairment of baroreflex control of both heart rate and sympathetic nerve activity. During the Valsalva maneuver, loss of carotid baroreflex control of heart rate is less well compensated for by the extra carotid baroreceptors than the control of muscle sympathetic nerve activity.     

Carotid sinus baroreceptor sensitivity in experimental heart failure

Single-unit carotid sinus baroreceptor activity was recorded in normal and heart-failure (pacing-induced) dogs. The sensitivity of these units was compared between the two groups of dogs. After development of clinical heart failure, the animals were anesthetized, and the left carotid sinus was vascularly isolated and perfused with oxygenated Krebs-Henseleit solution. Single-unit baroreceptor discharge was recorded from the carotid sinus nerve in response to stepwise increases in carotid sinus pressure (CSP). In addition, the carotid sinus diameter was measured with sonomicrometer crystals. In this way, both CSP-discharge and CSP-diameter curves were constructed for both normal and heart-failure dogs. Analysis of these curves demonstrated that the heart-failure group exhibited a significant decrease in peak discharge (48.1 +/- 3.0 vs. 22.2 +/- 2.2 spikes/sec; p less than 0.001) and a significant elevation in threshold pressure compared with the normal animals (91.0 +/- 5.0 vs. 119.1 +/- 4.4 mm Hg; p less than 0.001). The peak slope of the CSP-discharge curve was also significantly lower in the heart-failure group (0.63 +/- 0.06 vs. 0.40 +/- 0.09 spikes/sec/mm Hg; p less than 0.05). In the heart-failure group, perfusion of the carotid sinus with ouabain (0.01 micrograms/ml) caused a significant decrease in threshold pressure and a significant increase in peak discharge frequency, as well as an increase in slope of the CSP-discharge curve. There were no changes in CSP-diameter relations in response to ouabain. This dose of ouabain had no effect on pressure-discharge relations or carotid sinus diameters in normal dogs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Importance of aortic baroreflex in regulation of sympathetic responses during hypotension. Evidence from direct sympathetic nerve recordings in humans

Arterial baroreceptors in the carotid sinus and aortic arch regions reflexly regulate heart rate and peripheral vascular responses during changes in arterial pressure. The relative influence of these two arterial baroreflex pathways on the control of these autonomic responses is debatable. Recent studies in our laboratory demonstrate that the aortic baroreflex produces substantial and sustained inhibition of efferent sympathetic nerve activity to muscle (MSNA) during increases in arterial pressure. The regulation of MSNA by these two baroreflexes in humans during hypotension, and particularly the role of the aortic baroreflex, remains undefined. We therefore performed a new series of studies to assess the relative influence of the aortic and carotid baroreflexes on MSNA responses during sustained decreases in arterial pressure. In eight normal male subjects, aged 23 +/- 1 years (mean +/- SEM), we directly measured mean arterial pressure, heart rate, central venous pressure, and MSNA (microneurography) during hypotension (combined aortic and carotid baroreceptor deactivation) produced by intravenous infusion of sodium nitroprusside and during nitroprusside infusion with superimposed application of external neck suction. Neck suction was applied at levels sufficient to maintain transmural carotid sinus pressure above control levels (carotid baroreceptor activation) while the aortic baroreflexes remained deactivated. Central venous pressure was maintained constant with volume infusion. We also studied responses of these same subjects to direct carotid baroreceptor deactivation with the application of external neck pressure. During neck pressure alone, there was a reflex increase in mean arterial pressure; thus, during this portion of the protocol, we achieved carotid baroreceptor deactivation with some aortic baroreceptor activation. Nitroprusside infusion (combined aortic and carotid deactivation) decreased mean arterial pressure from 90.8 +/- 3.1 to 77.8 +/- 1.1 mm Hg (p less than 0.01) with concomitant increases in heart rate from 62.6 +/- 3.0 to 89.7 +/- 6.1 beats/min (p less than 0.001) and in MSNA from 273.8 +/- 43.0 to 950.6 +/- 133.5 units (p less than 0.001). During continued nitroprusside infusion with superimposed neck suction (aortic baroreceptor deactivation and carotid baroreceptor activation), mean arterial pressure decreased to 70.3 +/- 1.9 mm Hg (p less than 0.001 vs. control), heart rate decreased to 82.5 +/- 6.5 beats/min (p less than 0.01 vs. control or vs. nitroprusside alone), but MSNA remained markedly increased at 889.7 +/- 105.1 units (p less than 0.001 vs. control; p = NS vs. nitroprusside alone).(ABSTRACT TRUNCATED AT 400 WORDS)     

Prolonged activation of the baroreflex produces sustained hypotension

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 approximately 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.     

Yohimbine attenuates baroreflex-mediated bradycardia in humans

Alpha-2 adrenoreceptor stimulation profoundly augments baroreflex-mediated bradycardia presumably through parasympathetic activation. We tested the hypothesis that endogenous alpha-2 adrenergic tone mediates a similar response. In 10 healthy men (age: 33+/-3 years; body mass index: 24+/-1.3 kg/m(2)), we determined baroreflex control of heart rate and sympathetic traffic after ingestion of the selective alpha-2 adrenoceptor antagonist yohimbine (20 mg) or placebo. Testing was conducted in a randomized, double-blind, crossover fashion. We measured heart rate, brachial and finger blood pressure, and muscle sympathetic nerve activity. Sympathetic and parasympathetic baroreflex curves were determined using incremental phenylephrine and nitroprusside infusions (0.3, 0.6, 0.9, 1.2, and 1.5 microg/kg per minute). Plasma norepinephrine increased with yohimbine (50+/-38 ng/L; P<0.05) and was unchanged with placebo (2.2+/-7.6 ng/L). Blood pressure increased 13+/-4/8+/-1 mm Hg with yohimbine and 6+/-2/3+/-1 mm Hg with placebo (P<0.01). HR increased 5+/-1 bpm with yohimbine but did not change with placebo (P<0.01). Ninety minutes after drug ingestion, resting muscle sympathetic nerve activity was similar with yohimbine and with placebo. Baroreflex control of heart rate was decreased with yohimbine (6 ms/mm Hg versus 10 ms/mm Hg; P<0.01) and reset to higher blood pressure and heart rate values. In contrast, yohimbine did not alter the sympathetic baroreflex curve. Yohimbine selectively attenuates baroreflex heart rate control in normotensive young men possibly through parasympathetic mechanisms.     

Baroreceptor-heart rate reflex function before and after surgical reversal of two-kidney, one-clip hypertension in the rat

Baroreflex function was studied in conscious early phase (less than 6 weeks) two-kidney, one-clip hypertensive rats before and 24 hours after surgical reversal of hypertension by removal of the constricting renal artery clip or after pharmacological reduction of blood pressure by an infusion of hydralazine or captopril. A normotensive sham-clipped group was included. Another group of two-kidney, one-clip rats was studied 3 weeks after unclipping. Baroreflex sensitivity, as assessed by the steady-state method using a graded phenylephrine infusion, mean arterial pressure, and heart rate were measured preoperatively and at 24 hours postoperatively. Two-kidney, one-clip rats were significantly hypertensive preoperatively compared with control (mean arterial pressure, 183 +/- 4 vs. 106 +/- 2 mm Hg, p less than 0.001), heart rate was similar (420 +/- 9 vs. 401 +/- 9 beats/min, p greater than 0.05), and baroreflex sensitivity was significantly reduced (0.76 +/- 0.07 vs. 1.50 +/- 0.20 msec/mm Hg; p less than 0.001). There was a minimal change in heart rate despite the fall in mean arterial pressure in all hypertensive groups, indicating resetting of the baroreflexes. At 24 hours after the operation, baroreflex sensitivity was unchanged in all groups compared with the preoperative value. By 3 weeks, baroreflex sensitivity was significantly greater than in the hypertensive two-kidney, one-clip rats before the operation and 24 hours after they were unclipped, but not compared with normotensive sham-clipped rats. Thus, although resetting occurs within 24 hours, whatever the method of blood pressure reduction, baroreflex sensitivity remains impaired at this time.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Baroreflex regulation of heart rate and sympathetic vasomotor tone in women and men

Gender has been reported to influence baroreflex heart rate regulation and baroreflex blood pressure buffering. We tested the hypothesis that gender influences baroreflex regulation of heart rate and sympathetic vasomotor tone. We recruited 32 normal-weight healthy subjects (17 men and 15 women). ECGs for heart rate, brachial and finger blood pressure, and muscle sympathetic nerve activity (MSNA) were measured. Baroreflex heart rate and MSNA regulation were assessed using incremental phenylephrine and nitroprusside infusions. Baseline blood pressure was similar in men and women. MSNA was 21+/-2.5 bursts/min in women and 19+/-2.8 bursts/min in men (NS). The gain of the baroreflex MSNA curves was similar in women and men (-1.9+/-0.2 bursts/min per mm Hg in men and -2.0+/-0.3 bursts/min per mm Hg in women). Baroreflex gain for heart rate regulation was 17+/-3.2 ms/mm Hg in women and 19+/-1.9 ms/mm Hg in men (NS). We conclude that baroreflex gains for heart rate and sympathetic MSNA regulation are similar in women and men. However, the probability for congruence between men and women in terms of the MSNA baroreflex curves was 0.06% for burst rate, 0.4% for burst incidence, and 0.01% for burst area. In women, the MSNA baroreflex curve may be shifted to slightly lower blood pressure such that at a given blood pressure MSNA tends to be lower.     

What sets the long-term level of renal sympathetic nerve activity: a role for angiotensin II and baroreflexes?

Increasing evidence suggests elevated sympathetic outflow may be important in the genesis of hypertension. It is thought that peripheral angiotensin II, in addition to its pressor actions, may act centrally to increase sympathetic nerve activity (SNA). Without direct long-term recordings of SNA, testing the involvement of neural mechanisms in angiotensin II-induced increases in arterial pressure is difficult. Using a novel telemetry-based implantable amplifier, we made continuous recordings of renal SNA (RSNA) before, during, and after 1 week of angiotensin II-based hypertension in rabbits living in their home cages. Angiotensin II infusion (50 ng x kg(-1) x min(-1)) caused a sustained increase in arterial pressure (18+/-3 mm Hg). There was a sustained decrease in RSNA from 18+/-2 normalized units (n.u.) before angiotensin II to 8+/-2 n.u. on day 2 and 9+/-2 n.u. on day 7 of the angiotensin II infusion (P<0.01) before recovering to 17+/-2 n.u. after ceasing angiotensin II. Analysis of the baroreflex response showed that although angiotensin II-induced hypertension led to resetting of the relationship between mean arterial pressure (MAP) and heart rate, there was no evidence of resetting of the MAP-RSNA relationship. We propose that the lack of resetting of the MAP-RSNA curve, with the resting point lying near the lower plateau, suggests the sustained decrease in RSNA during angiotensin II is baroreflex mediated. These results suggest that baroreflex control of RSNA and thus renal function is likely to play a significant role in the control of arterial pressure not only in the short term but also in the long term.     

Importance of endogenous angiotensin II in the cardiovascular responses to sympathetic stimulation in conscious rabbits

Pharmacological evidence indicates that angiotensin (Ang II) converting enzyme inhibitors attenuate cardiovascular responses to sympathetic stimulation. To investigate the physiological significance of this attenuation, the pressor and heart rate responses to bilateral carotid occlusion (BCO) were studied before and after administration of captopril and again during Ang II replacement in conscious, aortic nerve-sectioned rabbits with chronically implanted carotid occluders. In the control period, BCO produced increases (p less than 0.05) in mean arterial pressure (MAP) and heart rate (HR) of 37.3 +/- 3.0 mm Hg and 21.7 +/- 5.4 beats/min from baseline values of 79.1 +/- 2.5 mm Hg and 255.4 +/- 16.7 beats/min. Captopril (5 mg/kg i.v.) markedly reduced (p less than 0.05) both the pressor (10.2 +/- 2.6 mm Hg) and HR (5.0 +/- 4.0 beats/min) responses to BCO, in parallel with a decrease in plasma Ang II of 75%. Infusion of a subpressor dose of Ang II (5-25 ng/kg/min i.v.) increased plasma Ang II to precaptopril levels and fully restored (p less than 0.05) the pressor (33.0 +/- 5.7 mm Hg) and HR (19.8 +/- 7.7 beats/min) responses to BCO. In two additional series of experiments, the mechanism of the effects of captopril and Ang II were investigated. In the first series, cardiac baroreflex curves (pulse interval versus MAP) were generated by increasing or decreasing blood pressure with phenylephrine or nitroprusside (5-20 micrograms/kg/min i.v.). The slope of the linear region of the curve (2.9 msec/mm Hg) was not changed significantly by captopril treatment (3.1 msec/mm Hg) or Ang II replacement (3.2 msec/mm Hg), indicating that cardiac baroreflex sensitivity was not altered by blockade of the renin-angiotensin system. In the second series, the effect of captopril on the pressor response to exogenous norepinephrine (0.1-2.5 micrograms/kg/min i.v.) was tested. The response was reduced by less than 40%, indicating only a modest postsynaptic component to the action of captopril. These results provide physiological evidence for an important action of endogenous Ang II in facilitating the cardiovascular responses to sympathetic stimulation in conscious rabbits. This facilitation is not due to an action upon the baroreflex per se but results, at least in part, from a presynaptic action of Ang II.