Baroreflex mechanisms regulating mean level of SNA differ from those regulating the timing and entrainment of the sympathetic discharges in rabbits

The arterial baroreflex pathway provides the fundamental basis for the short-term control of blood pressure via the rapid regulation of the mean level of sympathetic nerve activity (SNA) in response to changes in blood pressure. A central tenet in the generation and regulation of bursts of SNA is that input from the arterial baroreceptors also regulates the timing of the bursts of sympathetic activity. With the use of an implantable telemetry-based amplifier, renal SNA was recorded in intact and arterial baroreceptor-denervated (SAD) conscious rabbits. Data were collected continuously while animals were in their home cage. Mean levels of SNA were not different between SAD and baroreceptor-intact animals. Whereas SNA was unresponsive to changes in blood pressure in SAD rabbits, the timing of the bursts of SNA relative to the arterial pulse wave was maintained (time between the diastolic pressure and the next maximum SNA voltage averaged 107+/-12 ms SAD vs. 105+/-7 ms intact). Transfer function analysis between blood pressure and SNA indicates the average gain at the heart rate frequency was not altered by SAD, indicating strong coupling between the cardiac cycle and SNA bursts in SAD animals. Further experiments in anesthetized rabbits showed that this entrainment is lost immediately after performing baroreceptor denervation surgery and remained absent while the animal was under anesthesia but returned within 20 min of turning off the anesthesia. We propose that this finding indicates the regulation of the mean level of SNA requires the majority of input from baroreceptors to be functional; however, the regulation of the timing of the bursts in the conscious animal requires only minimal input, such as a sensitive trigger mechanism. This observation has important implications for understanding the origin and regulation of SNA.     

兔颈动脉窦和主动脉弓压力感受器反射效应的比较研究

对81只麻醉兔,在静脉注射新福林和硝普钠升降血压而改变动脉压力感受器活动的条件下,观察心率,后肢血管阻力和肾交感神经活动的反射性变化。主要结果如下:(1) 由新福林升高血压时,心率减慢、后肢血管阻力降低和肾交感神经活动抑制;硝普钠降低血压时引起相反效应。各指标的反射性变化有良好的可重复性。(2) 切断两侧减压神经或切断两侧窦神经后,静注新福林和硝普钠诱发的心率反射性变化均显著减弱(P<0.01);切断两侧减压神经较切断两侧窦神经后减弱得更为明显,其中对于新福林升压时的心率减慢反应差异显著(P<(0.05)。相反,对于新福林和硝普钠引起的后肢血管阻力反射性变化,与缓冲神经部分切断之前相比无明显差异;在对照肾交感神经活动已增高的基础上,硝普钠降压时肾交感神经活动的反射性兴奋效应降低,而新福林升压时的肾交感神经活动反射性抑制效应与神经切断前相比无明显差异。(3) 缓冲神经全部切断(SAD)后,新福林和硝普钠引起的平均动脉血压(MAP)变动幅度显著增大(P<0.05)。此时心率、后肢血管阻力和肾交感神经活动的反射调节效应均明显减弱(P<0.001)。(4) 进一步切断两侧迷走神经后,残留的反射效应即行消失。 以上结果表明,颈动脉窦和主动脉弓压力感受器传入以单纯相加的方式对心率进行反射性调节,以主     

Unloading arterial baroreceptors causes neurogenic hypertension

We developed a new model to examine the role of arterial baroreceptors in the long-term control of mean arterial pressure (MAP) in dogs. Baroreceptors in the aortic arch and one carotid sinus were denervated, and catheters were implanted in the descending aorta and common carotid arteries. MAP and carotid sinus pressure (CSP) averaged 104 +/- 2 and 102 +/- 2 mmHg (means +/- 1 SE), respectively, during a 5-day control period. Baroreceptor unloading was induced by ligation of the common carotid artery proximal to the innervated sinus (n = 6 dogs). MAP and CSP averaged 127 +/- 7 and 100 +/- 3 mmHg, respectively, during the 7-day period of baroreceptor unloading. MAP was significantly elevated (P < 0.01) compared to control, but CSP was unchanged. Heart rate and plasma renin activity increased significantly in response to baroreceptor unloading. Removal of the ligature to restore normal flow through the carotid resulted in normalization of all variables. Ligation of the carotid below a denervated sinus (n = 4) caused a significant decrease in CSP but no systemic hypertension. These results indicate that chronic unloading of carotid baroreceptors can produce neurogenic hypertension and provide strong evidence that arterial baroreceptors are involved in the long-term control of blood pressure.     

Altered baroreflex control of forearm vascular resistance during simulated microgravity

Reflex peripheral vasoconstriction induced by activation of cardiopulmonary baroreceptors in response to reduced central venous pressure (CVP) is a basic mechanism for elevating systemic vascular resistance and defending arterial blood pressure during orthostatically-induced reductions in cardiac filling and output. The sensitivity of the cardiopulmonary baroreflex response [defined as the slope of the relationship between changes in forearm vascular resistance (FVR) and CVP] and the resultant vasoconstriction are closely and inversely associated with the amount of circulating blood volume. Thus, a high-gain FVR response will be elicited by a hypovolemic state. Exposure to microgravity during spaceflight results in reduced plasma volume. It is therefore reasonable to expect that the FVR response to cardiopulmonary baroreceptor unloading would be accentuated following adaptation to microgravity. Such data could provide better insight about the physiological mechanisms underlying alterations in blood pressure control following spaceflight. We therefore exposed eleven men to 6 degrees head-down bedrest for 7 days and measured specific hemodynamic responses to low levels of the lower body negative pressure to determine if there are alterations in cardiopulmonary baroreceptor stimulus-FVR reflex response relationship during prolonged exposure to an analog of microgravity.     

Role of baroreceptor resetting in cardiovascular regulation: acute resetting

Recent studies show that the arterial baroreceptor reflex cannot be defined by a single buffer curve. The reflex blood pressure and heart rate curves depend on the pressure to which the baroreceptors are exposed. If arterial pressure is elevated for longer than 3-5 min the threshold and the entire buffer curve are shifted to higher pressures. On the other hand, a reduced arterial pressure shifts the buffer curve to lower pressures. Part of this phenomenon, which has been called rapid or acute resetting, may be explained by changes in the baroreceptor discharge in response to exposure to sustained alterations in pressure. The reflex response, however, resets more than can be explained by changes in the baroreceptor discharge. A central component to the resetting process is suggested. Resetting allows the baroreceptor reflex to operate over a wide range of arterial pressures rather than being confined to a single range defined by one buffer curve. Resetting is not complete. That is, if the receptors are exposed to a change in pressure of 30 mm Hg the buffer curves shift by less than 30 mm Hg. Thus a signal concerning mean pressure is not eliminated by the resetting process.     

Glutamatergic inputs to the CVLM independent of the NTS promote tonic inhibition of sympathetic vasomotor tone in rats

GABAergic neurons in the caudal ventrolateral medulla (CVLM) are driven by baroreceptor inputs relayed via the nucleus tractus solitarius (NTS), and they inhibit neurons in rostral ventrolateral medulla to reduce sympathetic nerve activity (SNA) and arterial pressure (AP). After arterial baroreceptor denervation or lesions of the NTS, inhibition of the CVLM continues to increase AP, suggesting additional inputs also tonically activate the CVLM. This study examined whether the NTS contributes to baroreceptor-independent drive to the CVLM and whether glutamate promotes baroreceptor- and NTS-independent activation of the CVLM to tonically reduce SNA. In addition, we evaluated whether altering central respiratory drive, a baroreceptor-independent regulator of CVLM neurons, influences glutamatergic inputs to the CVLM. Splanchnic SNA and AP were measured in chloralose-anesthetized, ventilated, paralyzed rats. The infusion of nitroprusside decreased AP below threshold for baroreceptor afferent firing (<50 mmHg) and increased SNA to 209+/-22% (P<0.05), but the subsequent inhibition of the NTS by microinjection of the GABA(A) agonist muscimol did not further increase SNA. In contrast, after inhibition of the NTS, blockade of glutamatergic inputs to CVLM by microinjection of kynurenate increased SNA (274+/-54%; P<0.05; n=7). In vagotomized rats with baroreceptors unloaded, inhibition of glutamatergic inputs to CVLM evoked a larger rise in SNA when central respiratory drive was increased (219+/-16% vs. 271+/-17%; n=5; P<0.05). These data suggest that baroreceptor inputs provide the major drive for the NTS-mediated excitation of the CVLM. Furthermore, glutamate tonically activates the CVLM to reduce SNA independent of the NTS, and this excitatory input appears to be affected by the strength of central respiratory drive.     

Contribution of central ANG II to acute stress-induced changes in baroreflex function in young rats

The aim of the present investigation was to characterize the baroreflex in weaned 23- to 25-day-old rats when maternal influences were no longer present. The relationship between mean arterial pressure (MAP) and heart rate (HR) was determined during baroreceptor loading with phenylephrine and baroreceptor unloading with sodium nitroprusside in conscious rats, first in the freely moving state and subsequently during acute stress. In unstressed rats, the slope of the relationship between MAP and HR was greater during baroreceptor loading than baroreceptor unloading. Acute stress significantly attenuated the slope of the response to baroreceptor loading but increased the slope of the response to baroreceptor unloading. Pretreatment with intracerebroventricular or intravenous losartan, an AT(1) receptor antagonist, or intracerebroventricular alpha-helical corticotropin-releasing hormone (alpha-hCRH), a receptor antagonist, before the stress significantly reduced the stress-induced attenuation of slope during baroreceptor loading. Hence, young postweaning rats can alter baroreflex function during acute stress in a manner that would favor increases in MAP. Even at this young age, a central action of ANG II and CRH contributes to these stress-induced adaptations.     

Baroreflex modulation of ultradian oscillations of blood pressure and heart rate in unanesthetized dogs

Telemetered, free-running dogs were studied to determine the role of cardiovascular control systems in modulation of ultradian oscillations of arterial pressure (MAP) and heart rate (HR). Data, aquired (2 Hz) by a stable telemetry system, was stored on a digital computer and analyzed for its harmonic content by a Fast Fourier Transform (FFT) algorithm. Both AP and HR consistently demonstrated rhythms having a period of from 0.6 to 1.0 h. Modulation of these rhythms by arterial pressure control systems was assessed in dogs studied before and carotid sinus baroreceptor denervation, before and after denervation of the aortic arch baroreceptors and before and after a combination of both these procedures. The data indicate the power spectral density (PSD) of MAP, but not HR, is increased (p less than 0.05) after denervation of the carotid sinuses alone, while the primary frequency of the oscillations was unchanged. On the other hand, denervation of the aortic arch baroreceptors alone was without effect on either the frequency or PSD of these oscillations. A combination of both carotid sinus and aortic arch denervation resulted in an increased (p less than 0.05) PSD of MAP oscillations but not in their frequency. These data indicate that the carotid sinuses modulate rhythmic behavior of MAP by buffering the magnitude, but not frequency, of the oscillations. Moreover, since oscillations were present in dogs after denervation of both the carotid sinus and aortic arch baroreceptors, these ultradian oscillations are not a result of a non-linear negative feedback mechanisms arising from these pressure sensitive regions.     

A neural set point for the long-term control of arterial pressure: beyond the arterial baroreceptor reflex

Arterial baroreceptor reflex control of renal sympathetic nerve activity (RSNA) has been proposed to play a role in long-term control of arterial pressure. The hypothesis that the "set point" of the acute RSNA baroreflex curve determines the long-term level of arterial pressure is presented and challenged. Contrary to the hypothesis, studies on the long-term effects of sinoaortic denervation (SAD) on arterial pressure and RSNA, as well as more recent studies of chronic baroreceptor "unloading" on arterial pressure, suggest that the basal levels of sympathetic nerve activity and arterial pressure are regulated independent of arterial baroreceptor input to the brainstem. Studies of the effect of SAD on the long-term salt sensitivity of arterial pressure are consistent with a short-term role, rather than a long-term role for the arterial baroreceptor reflex in regulation of arterial pressure during changes in dietary salt intake. Renal denervation studies suggest that renal nerves contribute to maintenance of the basal levels of arterial pressure. However, evidence that baroreflex control of the kidney plays a role in the maintenance of arterial pressure during changes in dietary salt intake is lacking. It is proposed that a "baroreflex-independent" sympathetic control system must exist for the long-term regulation of sympathetic nerve activity and arterial pressure. The concept of a central nervous system "set point" for long-term control of mean arterial pressure (CNS-MAP set point), and its involvement in the pathogenesis of hypertension, is discussed.     

Arterial baroreceptors control plasma vasopressin responses to graded hypotension in conscious dogs

We studied the role of cardiac and arterial baroreceptors in the reflex control of arginine vasopressin (AVP) and renin secretion during graded hypotension in conscious dogs. The dogs were prepared with Silastic cuffs on the thoracic inferior vena cava and catheters in the pericardial space. Each experiment consisted of a control period followed by four periods of inferior vena caval constriction, during which mean arterial pressure (MAP) was reduced in increments of approximately 10 mmHg. The hormonal responses were measured in five dogs under four treatment conditions: 1) intact, 2) acute cardiac denervation (CD) by intrapericardial infusion of procaine, 3) after sinoaortic denervation (SAD), and 4) during combined SAD+CD. The individual slopes relating MAP to plasma AVP and plasma renin activity (PRA) were used to compare the treatment effects using a 2 x 2 factorial analysis. There was a significant (P < 0.01) effect of SAD on the slope relating plasma AVP to MAP but no effect of CD and no SAD x CD interaction. In contrast, the slope relating PRA and MAP was increased (P < 0.05) by SAD but was not affected by CD. These results support the hypothesis that stimulation of AVP secretion in response to graded hypotension is primarily driven by unloading arterial baroreceptors in the dog.     

Effect of Barodenervation on Cardiovascular Responses Elicited from the Hypothalamic Arcuate Nucleus of the Rat

We have previously reported that chemical stimulation of the hypothalamic arcuate nucleus (ARCN) in the rat elicited increases as well as decreases in blood pressure (BP) and sympathetic nerve activity (SNA). The type of response elicited from the ARCN (i.e., increase or decrease in BP and SNA) depended on the level of baroreceptor activity which, in turn, was determined by baseline BP in rats with intact baroreceptors. Based on this information, it was hypothesized that baroreceptor unloading may play a role in the type of response elicited from the ARCN. Therefore, the effect of barodenervation on the ARCN-induced cardiovascular and sympathetic responses and the neurotransmitters in the hypothalamic paraventricular nucleus (PVN) mediating the excitatory responses elicited from the ARCN were investigated in urethane-anesthetized adult male Wistar rats. Bilateral barodenervation converted decreases in mean arterial pressure (MAP) and greater splanchnic nerve activity (GSNA) elicited by chemical stimulation of the ARCN with microinjections of N-methyl-D-aspartic acid to increases in MAP and GSNA and exaggerated the increases in heart rate (HR). Combined microinjections of NBQX and D-AP7 (ionotropic glutamate receptor antagonists) into the PVN in barodenervated rats converted increases in MAP and GSNA elicited by the ARCN stimulation to decreases in MAP and GSNA and attenuated increases in HR. Microinjections of SHU9119 (a melanocortin 3/4 receptor antagonist) into the PVN in barodenervated rats attenuated increases in MAP, GSNA and HR elicited by the ARCN stimulation. ARCN neurons projecting to the PVN were immunoreactive for proopiomelanocortin, alpha-melanocyte stimulating hormone (alpha-MSH) and adrenocorticotropic hormone (ACTH). It was concluded that increases in MAP and GSNA and exaggeration of tachycardia elicited by the ARCN stimulation in barodenervated rats may be mediated via release of alpha-MSH and/or ACTH and glutamate from the ARCN neurons projecting to the PVN.     

Systolic pressure predicts plasma vasopressin responses to hemorrhage and vena caval constriction in dogs

We have proposed that the reflex increase in arginine vasopressin (AVP) secretion in response to hypovolemia is due to arterial baroreceptor unloading. If arterial pressure is the key to the mechanism, the slope relating plasma AVP to arterial pressure should be the same in response to hemorrhage, a model of true hypovolemia, and in response to thoracic inferior vena caval constriction (IVCC), a model of central hypovolemia. We tested this hypothesis in conscious, chronically instrumented dogs (n = 8). The mean coefficient of determination (r(2)) values obtained from the individual regressions of log AVP onto systolic pressure (SP) and mean arterial pressure (MAP) in response to hemorrhage were 0.953 +/- 0.009 and 0.845 +/- 0.047, respectively. Paired comparisons indicated a significant difference between the means (P < 0.05), hence, SP was used in subsequent analyses. The mean slopes relating the log of plasma AVP to SP in response to hemorrhage and IVCC were -0.034 +/- 0.003 and -0.032 +/- 0.002, respectively, and the means were not significantly different (P = 0.7). The slopes were not altered when the experiments were repeated during acute blockade of cardiac receptors by intrapericardial procaine. Finally, sinoaortic denervation (n = 4) markedly reduced the slope in both the hemorrhage and IVCC treatments. We conclude that baroreceptors monitoring arterial pressure provide the principal reflex control of AVP secretion in response to hypovolemia.     

Aortic diastolic caliber changes as a determinant for complete aortic baroreceptor resetting

It is well known that baroreceptors reset to operate at higher pressure in hypertension. The time course and mechanisms responsible for resetting are still unclear. There is a rapid or acute partial resetting that reaches its maximum within the first 5-15 min but changes little within the first hours. This resetting is, however, partial and becomes complete only if the pressure change is held permanently. Resetting is complete when the change in pressure threshold for baroreceptor activation matches the total pressure change. In the rat, complete resetting to hypo- or hypertension occurs in 48 h. The aortic caliber was studied in freely moving rats during the development of sustained hypertension produced by subdiaphragmatic aortic constriction. A striking coincidence was observed between the time taken for the diastolic caliber to reach maximal dilation and the time taken for complete resetting of the aortic baroreceptors. Moreover, during sudden pressure increases, the displacement of the diastolic caliber is much greater than the increase in pulsation, which indicates that in conscious rats the operational level of the resting diastolic caliber is an important factor for aortic baroreceptor distortion.     

Altered cardiovascular reflex responses during positive pressure breathing

Cardiovascular responses during hyperinflation produced by positive end-expiratory pressure (PEEP) are considered to be reflexly influenced by pulmonary mechanoreceptors. Numerous studies have indicated heart and vascular effects attributed to mechanical events and cardiopulmonary mechanoreflexes. Yet interactions of these modalities with the systemic baroreflexes are not clear. We examined aspects of these modulatory interactions by distinguishing changes in pulmonary, heart, and vascular responses during PEEP-hyperinflation before and after progressive elimination of chemo-, mechano-, and baroreflex influences in the closed-chest anesthetized rabbit. During respiratory alkalosis PEEP was imposed in increments of 2.5 cm H2O (range 0.0 to 7.5 cm H2O) before and during control of carotid intrasinus pressure and following aortic denervation and vagotomy. Heart rate responses during PEEP increased prior to aortic denervation, decreased following elimination of baroreflexes, and were abolished after vagotomy. The fall in mean arterial pressure (MAP) during PEEP was accentuated during elimination of the baroreflexes and ameliorated following vagotomy. Mean right atrial (MRAP), intrapleural (MIP), and right atrial transmural pressure increased during PEEP prior to vagotomy. Regression analyses of MAP versus MRAP and MAP versus MIP suggest that vagally receptors reflexly influence venous as well as systemic arterial vascular pressure. Conclusion indicate that when superimposed on mechanical events, cardiopulmonary mechanoreceptors and arterial baroreceptors effect conflicting facilitory reflex influences on heart and vascular responses during PEEP-hyperinflation.     

兔肾性高血压时的动脉压力感受器反射

14只雄性家兔在双肾缩扎术后12周,经氨基甲酸乙酯静脉麻醉,分别在缓冲神经完整、切断两侧减压神经或切断两侧窦神经后静注新福林或硝普钠升降血压以改变动脉压力感受器活动,观察其心率、后肢血管阻力和肾交感神经活动的反射性变化,并与正常血压兔的反射效应相比较。主要结果如下:(1) 动物双肾动脉缩扎后12周,平均动脉血压(131±9mmHg)较正常动物血压(95±10mmHg)有显著升高(P<0.001);(2) 缓冲神经完整时,新福林和硝普钠升降血压诱发的心率反射性变化与正常血压动物相比显著减弱(P<0.001),而后肢血管阻力和肾交感神经活动的反射性调节无明显改变,表明肾性高血压动物的心率反射性调节与外周循环的反射性调节机能不相平行;而由股动脉内直接注射新福林或硝普钠时,股动脉灌流压的增减幅度与正常血压动物相比并无明显差异;(3) 切断两侧减压神经或切断两侧窦神经后,在正常动物仅使反射性心率调节作用减弱,而后肢血管阻力和肾交感神经活动的反射性调节无明显改变;但在高血压动物,除心率的反射性调节进一步减弱外,新福林和硝普钠升降血压时后肢血管阻力和肾交感神经活动的反射性调节效应也显著地减弱(P<0.001),提示肾性高血压时动脉压力感受器反射的潜在调节能力降低。由此似表明,肾性高血压时动脉压力感受器反射     

Afferent pathways in cardiovascular adjustments induced by volume expansion in anesthetized rats

The role of baroreceptors, cardiopulmonary receptors, and renal nerves in the cardiovascular adjustments to volume expansion (VE) with 4% Ficoll (Pharmacia; 1% body wt, 0.4 ml/min) were studied in urethan-anesthetized rats. In control animals, VE produced a transitory increase in mean arterial pressure (MAP), which peaked at 10 min (17 +/- 4 mmHg) and increases in renal (128 +/- 6 and 169 +/- 19% of baseline at 10 and 40 min, respectively) and hindlimb vascular conductance (143 +/- 6 and 150 +/- 10%). These cardiovascular adjustments to VE were unaffected by bilateral vagotomy. After sinoaortic denervation, the increase in MAP induced by VE was greater than in control rats (30 +/- 4 mmHg). However, renal vasodilation in response to VE was blocked, whereas hindlimb vasodilation was similar to that observed in control rats. After unilateral renal denervation (ipsilateral to flow recording), the initial renal vasodilation was blocked. However, 40 min after VE, a significant renal vasodilation (125 +/- 4%) appeared. The hindlimb vasodilation and MAP responses were unaffected by renal denervation. These results demonstrate that the baroreceptor afferents are an essential component of cardiovascular adjustments to VE, especially in the control of renal vascular conductance. They also suggest that renal vasodilation induced by VE is mediated by neural and hormonal mechanisms.     

Dynamic interactions between arterial pressure and sympathetic nerve activity: role of arterial baroreceptors

The role of arterial baroreceptors in controlling arterial pressure (AP) variability through changes in sympathetic nerve activity was examined in conscious rats. AP and renal sympathetic nerve activity (RSNA) were measured continuously during 1-h periods in freely behaving rats that had been subjected to sinoaortic baroreceptor denervation (SAD) or a sham operation 2 wk before study (n = 10 in each group). Fast Fourier transform analysis revealed that chronic SAD did not alter high-frequency (0.75-5 Hz) respiratory-related oscillations of mean AP (MAP) and RSNA, decreased by approximately 50% spectral power of both variables in the midfrequency band (MF, 0.27-0.74 Hz) containing the so-called Mayer waves, and induced an eightfold increase in MAP power without altering RSNA power in the low-frequency band (0.005-0.27 Hz). In both groups of rats, coherence between RSNA and MAP was maximal in the MF band and was usually weak at lower frequencies. In SAD rats, the transfer function from RSNA to MAP showed the characteristics of a second-order low-pass filter containing a fixed time delay ( approximately 0.5 s). These results indicate that arterial baroreceptors are not involved in production of respiratory-related oscillations of RSNA but play a major role in the genesis of synchronous oscillations of MAP and RSNA at the frequency of Mayer waves. The weak coupling between slow fluctuations of RSNA and MAP in sham-operated and SAD rats points to the interference of noise sources unrelated to RSNA affecting MAP and of noise sources unrelated to MAP affecting RSNA.     

What sets the long-term level of sympathetic nerve activity: is there a role for arterial baroreceptors?

Much of our knowledge of the influence of the sympathetic nervous system on the control of blood pressure is built on experimental approaches that focus very much on time scales <24 h. Although direct recordings of sympathetic nerve activity (SNA) over short time scales provide important information, it is difficult to place their relevance over the longer term where the development of chronic changes in blood pressure are likely to be a mixture of hormonal, renal, and neural influences. Recently new experimental approaches are now revealing a possible role for arterial baroreceptors in the chronic regulation of SNA. These studies reveal that chronic increases in blood pressure are associated with chronic changes in SNA that may be due to nonresetting of the blood pressure-SNA baroreflex relationship. This review discusses the implications of such information, highlighting new technologies for long-term recording of SNA that appear to hold much promise for revealing the role of SNA to the kidney for the long-term control of blood pressure.     

Resetting baroreceptors to a lower arterial pressure level by enalapril avoids baroreflex mediated activation of sympathetic nervous system by nifedipine.

Baroreceptor-unloading-mediated activation of sympathetic nervous system (SNS) by antihypertensive agents, such as dihydropyridine calcium channel blockers (CCB), has been considered to compromise the beneficial effects of the therapy and lead to unsatisfying clinical outcome. The present study was aimed at finding a novel way of using CCB without activating SNS. In anaesthetized Wistar rats, baroreceptor-unloading-mediated reflex activation of SNS, as indicated by tachycardia and increase of plasma catecholamines, was observed after mean arterial pressure (MAP) was decreased by 15 mmHg during 4-h administration of nifedipine, a CCB. However an angiotensin-converting enzyme inhibitor (ACEI), enalapril did not cause tachycardia or increase plasma catecholamine levels when it decreased MAP by 15 mmHg. After 100 min (supposedly baroreceptor resetting or adaptation to hypotension had occurred), enalapril infusion was gradually replaced by nifedipine infusion in 40 min. Nifedipine was infused for another 100 min, which kept the lowered MAP unchanged and did not activate SNS. In anaesthetized spontaneously hypertensive rats (SHR), baroreceptor-mediated reflex activation of SNS was observed after MAP was decreased by 25 mmHg during 4-h nifedipine administration. However enalapril did not cause tachycardia or increase plasma catecholamine levels when it decreased MAP by 25 mmHg. After 100 min, enalapril infusion was gradually replaced by nifedipine infusion in 40 min. Nifedipine was then infused for another 100 min, which kept the lowered MAP unchanged and did not activate SNS. The present study indicated that reflex activation of SNS caused by antihypertensive effect of CCB could be avoided if, prior to CCB administration, baroreceptors have been reset to a lower MAP by a drug that does not activate baroreceptor reflex.     

Aspects of cardiovascular reflexes in pathologic states

Cardiovascular reflexes that are mediated by receptors in the heart and blood vessels control a variety of important hemodynamic and humoral functions. The action of these receptors can be shown to be abnormal in several pathologic states. Left atrial receptors exhibit a depressed discharge sensitivity in dogs with chronic congestive heart failure caused by an aortocaval fistula. The reflex effects of atrial receptor stimulation are also depressed in heart failure. Left ventricular receptor stimulation has been implicated in the abnormal vascular responses to exercise in patients with aortic stenosis. The arterial baroreflex control of heart rate is abnormal in animals and humans with various forms of hypertension. Arterial baroreceptors from hypertensive animals show a resetting of their pressure-discharge curve to higher pressures. The arterial baroreflex is also depressed in chronic heart failure. This effect may result from an abnormality of the efferent limb of the reflex arc or from changes in the interaction between baroreceptors and cardiac receptors centrally. A final possibility may be abnormal arterial baroreceptor discharge characteristics in heart failure.