Acute Resetting Research Articles

Protein Kinase C Differentially Regulates Entrainment of the Mammalian Circadian Clock

The environmental day-night cycle provides the principal synchronizing signal for behavioral activity in most mammals. Light information is relayed to the master circadian pacemaker, the suprachiasmatic nucleus (SCN), via synaptic transmission from the retina directly to the SCN, where a predominately glutamate-driven cellular signaling pathway is able to reset biochemical, physiological, and behavioral activities. In the present study, we aimed to decipher the key roles played by protein kinase C (PKC) in regulating light-induced behavioral resetting under both a temporal and intensity-dependent manner; in addition, we also investigate PKC contributions to advancing and delaying re-entrainment paradigms. Our findings show that during the early night PKC acts in a temporal manner, where PKC inhibition selectively attenuates light-induced behavioral resetting in response to subsaturating and saturating light intensities. Declines in light response were also evident upon PKC inhibition during the late night, but restricted to bright light stimuli. The positive regulatory actions of PKC were further demonstrated in response to an 8-h delayed re-entrainment paradigm where inhibition of PKC resulted in slower re-entrainment. Further, analysis of both classic and novel PKC isozymes present within the SCN showed significant circadian variation in the mRNA expression of PKCα, indicating possible isozyme-specific mediators in photic signaling. Our data provide evidence of a PKC contribution to both acute light-induced clock resetting, which is intensity and time of day dependent, and a functional role in circadian photoentrainment. (Author correspondence: g.lall@kent.ac.uk)

Pregnancy and acute baroreflex resetting in conscious rabbits.

To test the hypothesis that acute resetting of baroreflex control of heart rate (HR) is enhanced during pregnancy, we determined whether the rightward shift in the baroreflex relationship between arterial pressure and HR after arterial pressure is raised [~25 mmHg for 30 min, due to infusion of phenylephrine (PE) or methoxamine (Meth)] is greater in late pregnant compared with nonpregnant conscious rabbits. Baroreflex function was assessed by monitoring HR responses to both stepwise steady-state changes (n = 14) and rapid ramp changes (n = 10) in arterial pressure. Pregnancy decreased reflex gain, increased reflex minimum HR, and shifted the curves to a lower pressure level, when either the steady-state or ramp method was used (all changes, P < 0.05). When PE was used to increase pressure, resetting of steady-state curves was observed both before and during pregnancy, but the magnitude of the resetting was less in the pregnant rabbits. Further inspection of the data revealed that the size of the shift in pregnant rabbits was inversely related to the dose of PE. Because the pressure rise was the same in all experiments, PE appears to nonspecifically counteract acute resetting. When Meth was used instead to increase pressure, resetting of steady-state curves was similar in pregnant and nonpregnant rabbits and was unrelated to dose. Similarly, when reflex curves were generated using the ramp method, and either Meth or low doses of PE were used to increase pressure, no differences in the degree of resetting were observed between pregnant and nonpregnant rabbits. In summary, high doses of PE counteract acute resetting of baroreflex control of HR. More importantly, while baroreflex function is depressed, the ability of the baroreflex to reset appears to be preserved during pregnancy.

Chronic blockade of brain "ouabain" prevents sympathetic hyper-reactivity and impairment of acute baroreflex resetting in rats with congestive heart failure.

In rats with congestive heart failure (CHF) post myocardial infarction (MI) acute blockade of brain "ouabain" reverses sympathetic hyperactivity and chronic blockade prevents the desensitization of baroreflex function. This study was conducted to determine: i) if chronic blockade of brain "ouabain" maintains normal sympathetic reactivity; and ii) if acute baroreflex resetting (another parameter of baroreflex function) also becomes impaired, and if so, does brain "ouabain" contribute to impairment in acute baroreflex resetting. CHF post MI was induced by acute coronary artery ligation in Wistar rats. Animals were treated with 200 microg x day(-1) i.c.v. or i.v. Fab fragments (which bind brain "ouabain" with high affinity), or treated with 200 microg x day(-1) i.c.v. gamma-globulins (control group). The length of treatment was 0.5-8 weeks or 4-8 weeks post MI. At 8 weeks mean arterial pressure (MAP), central venous pressure (CVP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were recorded in concious rats at rest and in response to: i) air-jet stress, ii) i.c.v. guanabenz (an alpha2-adrenoceptor agonist), and iii) a 30 min i.v. infusion of nitroprusside (NP). Excitatory responses to air stress and inhibitory responses to guanabenz of MAP, HR, and RSNA were significantly enhanced in rats with CHF versus the sham-operated treated group. This enhancement was prevented in the CHF group treated with i.c.v., but not i.v., Fab. Nitroprusside induced a sustained decrease in MAP (approximately 25 mmHg) and a transient decrease in CVP. Heart rate and RSNA increased significantly within 1 min of beginning the infusion. The peak increases as well as the product of changes in MAP-HR and RSNA-HR were significantly smaller in rats with CHF treated with gamma-globulins versus sham rats and versus CHF rats treated with i.c.v. Fab. In sham-operated rats and CHF rats treated with i.c.v. Fab, RSNA and HR began to decrease within 3-4 min of beginning the NP infusion and had returned to baseline by 20 min. In contrast, RSNA and HR remained increased throughout the infusion in the CHF rats treated with gamma-globulins. These data indicate that in rats with CHF acute resetting of the arterial baroreflex in response to a lower BP becomes impaired, and chronic blockade of brain "ouabain" prevents both this change in baroreflex resetting as well as sympathetic hyperactivity.

Chronic blockade of brain "ouabain" prevents sympathetic hyper-reactivity and impairment of acute baroreflex resetting in rats with congestive heart failure

In rats with congestive heart failure (CHF) post myocardial infarction (MI) acute blockade of brain "ouabain" reverses sympathetic hyperactivity and chronic blockade prevents the desensitization of baroreflex function. This study was conducted to determine: i) if chronic blockade of brain "ouabain" maintains normal sympathetic reactivity; andii) if acute baroreflex resetting (another parameter of baroreflex function) also becomes impaired, and if so, does brain "ouabain" contribute to impairment in acute baroreflex resetting. CHF post MI was induced by acute coronary artery ligation in Wistar rats. Animals were treated with 200 µg·day-1 i.c.v. or i.v. Fab fragments (which bind brain "ouabain" with high affinity), or treated with 200 µg·day-1 i.c.v. gamma-globulins (control group). The length of treatment was 0.5-8 weeks or 4-8 weeks post MI. At 8 weeks mean arterial pressure (MAP), central venous pressure (CVP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were recorded in concious rats at rest and in response to: i) air-jet stress, ii) i.c.v. guanabenz (an α2-adrenoceptor agonist), and iii) a 30 min i.v. infusion of nitroprusside (NP). Excitatory responses to air stress and inhibitory responses to guanabenz of MAP, HR, and RSNA were significantly enhanced in rats with CHF versus the sham-operated treated group. This enhancement was prevented in the CHF group treated with i.c.v., but not i.v., Fab. Nitroprusside induced a sustained decrease in MAP (~ 25 mmHg) and a transient decrease in CVP. Heart rate and RSNA increased significantly within 1 min of beginning the infusion. The peak increases as well as the product of changes in MAP-HR and RSNA-HR were significantly smaller in rats with CHF treated with gamma-globulins versus sham rats and versus CHF rats treated with i.c.v. Fab. In sham-operated rats and CHF rats treated with i.c.v. Fab, RSNA and HR began to decrease within 3-4 min of beginning the NP infusion and had returned to baseline by 20 min. In contrast, RSNA and HR remained increased throughout the infusion in the CHF rats treated with gamma-globulins. These data indicate that in rats with CHF acute resetting of the arterial baroreflex in response to a lower BP becomes impaired, and chronic blockade of brain "ouabain" prevents both this change in baroreflex resetting as well as sympathetic hyperactivity.Key words: heart failure, acute baroreflex resetting, sympathetic hyperactivity, nitroprusside.

Viscoelastic mechanisms of aortic baroreceptor resetting to hypotension and to hypertension.

Viscoelastic and electrophysiological mechanisms have been implicated in the resetting of baroreceptors in hypertension, but resetting in response to hypotension has been less studied. To evaluate the temporal relationship between viscoelastic mechanisms and acute resetting, we examined the "in vivo" behavior of aortic caliber and aortic baroreceptor activity during step changes in pressure. Fifteen-minute hemorrhage in Wistar rats produced stable hypotension (30 mmHg) and viscoelastic contraction (111 +/- 14.2 microns systolic caliber; P < 0.01). Integrated aortic activity fell to 19.8 +/- 3.9% of control (P < 0.001) after 3 s of hypotension but recovered to 64 +/- 4.1% 15 min later (P < 0.01 from 3 s). Recovery of baroreceptor activity was linearly correlated to viscoelastic contraction (r = 0.963; P < 0.0001). Thirty-minute phenylephrine infusion (1.0-4.0 micrograms/min) produced stable hypertension (30 mmHg) and viscoelastic dilation (211 +/- 37.0 microns systolic caliber). Integrated aortic activity increased to 218.0 +/- 18% of control values (P < 0.001) 30 s after hypertension and was reduced to 164.0 +/- 12.0% (P < 0.001 from 3 s) within 30 min. Reduction of baroreceptor activity correlated linearly with viscoelastic relaxation (r = 0.963; P < 0.0001). The results indicate that in the in vivo rat aorta, viscoelastic mechanisms parallel and may contribute to the baroreceptor resetting during hypotension and hypertension.

Acute baroreflex resetting: differential control of pressure and nerve activity.

This study evaluated acute resetting of carotid baroreflex control of arterial blood pressure and renal or thoracic sympathetic nerve activity in thiopental-anesthetized mongrel dogs with the use of a vascularly isolated carotid sinus preparation, the experimental model used previously to characterize acute resetting in carotid baroreceptor afferent fibers. Carotid baroreceptors were conditioned with a pulsatile pressure for 20 minutes at three pressure ranges: low (50 to 75 mm Hg), mid (100 to 125), or high (150 to 175). Blood pressure and nerve activity were recorded in response to slow ramp increases in sinus pressure; nonlinear regression and best-fit analyses were used for determination of curve fit parameters of the blood pressure and nerve activity versus sinus pressure response curves. Carotid sinus pressure thresholds for blood pressure and renal nerve activity responses at all conditioning pressures were significantly different; however, only the pressure threshold for thoracic nerve activity at the low conditioning pressure was significantly different from the responses at other conditioning pressures. Average renal activity resetting (0.506 +/- 0.072) was significantly greater than blood pressure resetting (0.335 +/- 0.046) in the same dogs, and thoracic activity (0.200 +/- 0.057) was not different from blood pressure resetting (0.194 +/- 0.031) in the same dogs. In a previous investigation, our laboratory had demonstrated that type 1 carotid baroreceptors acutely reset at a value of about 0.15. These results indicate that (1) renal and thoracic nerve activities and blood pressure acutely reset to a greater degree than type 1 carotid baroreceptors and that (2) renal activity acutely resets to a greater degree than blood pressure and thoracic nerve activity.

Lack of effect of 4-aminopyridine on acute resetting of the type I carotid baroreceptor

Acute resetting of the type I carotid baroreceptor was examined before and after exposure to 10 −4 M 4-aminopyridine (4-AP), a blocker of the transient K + A current ( I A), using a vascularly isolated carotid sinus preparation in thiopental anesthetized dogs. Type I baroreceptor firing patterns were analysed to determine threshold pressure ( P th) at different conditioning pressures. Additionally, the ability of 10 −4 M 4-AP to induce vasoconstriction in canine carotid sinus, internal carotid and common carotid artery vascular ring segments was tested as a possible contributing mechanism to resetting. Our findings demonstrated that 10 −4 M 4-AP did not alter acute baroreceptor resetting or induce carotid artery vasoconstriction.

Indomethacin reduces acute baroreceptor resetting in the dog.

1. The influence of local perfusion of the carotid sinus with the cyclo-oxygenase blocker indomethacin on acute baroreceptor resetting was investigated in anaesthetized dogs. 2. The carotid sinus was isolated and perfused with oxygenated Krebs-Henseleit solution. Single units from the carotid sinus nerve were recorded. The carotid sinus was conditioned with static pressures of 50, 100 and 150 mmHg for 15 min. Following the conditioning period a carotid sinus pressure (CSP)-discharge curve was constructed using static stepwise increases in CSP. 3. Perfusion of the carotid sinus with indomethacin (20 microM) caused an elevation in the threshold at every conditioning pressure (96.8 +/- 4.8 vs. 83.8 +/- 4.1 mmHg for 100 mmHg, P < 0.01; 91.9 +/- 4.7 vs. 70.3 +/- 4.4 mmHg for 50 mmHg, P < 0.01; and 103.5 +/- 4.4 vs. 96.4 +/- 4.1 mmHg for 150 mmHg, P = 0.06, respectively) and a significant reduction in the peak discharge rate at each conditioning pressure (32.0 +/- 4.4 vs. 48.2 +/- 5.5 spikes/s for 100 mmHg, P < 0.01; 32.2 +/- 5.8 vs. 45.8 +/- 5.1 spikes/s for 50 mmHg, P < 0.01; 32.0 +/- 3.7 vs. 51.1 +/- 8.1 spikes/s for 150 mmHg, P < 0.01). The resetting ratio (change in threshold/change in conditioning CSP) for both downward resetting (conditioning CSP from 100 to 50 mmHg) and upward resetting (conditioning CSP from 100 to 150 mmHg) was significantly decreased after indomethacin (0.10 +/- 0.02 vs. 0.27 +/- 0.02 for downward resetting, P < 0.01 and 0.14 +/- 0.03 vs. 0.25 +/- 0.01 for upward resetting, P < 0.01, respectively). 4. Conversely, perfusion of the carotid sinus with arachidonic acid (20 microM) significantly decreased the threshold at each conditioning CSP and increased the peak discharge rate at each conditioning CSP. The resetting ratio was significantly increased after arachidonic acid. 5. There was no change in resting carotid diameter or in the carotid sinus pressure-carotid diameter relationship after indomethacin or arachidonic acid. 6. Removal of the endothelial cells in the carotid area with saponin did not prevent the effects of indomethacin on baroreceptor resetting. 7. These results suggest that prostaglandins have a tonic effect on the activity of the carotid sinus baroreceptor and may play a role in acute baroreceptor resetting.

Acute resetting of the carotid sinus baroreflex by aortic depressor nerve stimulation.

The effect of prolonged aortic depressor nerve (ADN) stimulation on carotid sinus baroreflex regulation of arterial pressure (AP) and renal sympathetic nerve activity (RSNA) was examined in anesthetized rabbits. Ramp increases in carotid sinus pressure (CSP) were repeated before and after 5 min of bilateral ADN stimulation. One minute after ADN stimulation the curve relating AP to CSP had shifted up and to the right, characterized by significant increases (P < 0.05) in the maximum (91 +/- 2 to 101 +/- 3 mmHg; mean +/- SE), midpoint (118 +/- 7 to 125 +/- 8 mmHg CSP), and minimum (45 +/- 3 to 53 +/- 4 mmHg) of the AP reflex curve. There was a parallel shift downward of the curve relating RSNA to CSP, characterized by significant decreases in the maximum [100 +/- 0 to 66 +/- 8% of maximum control RSNA value (%max)], the range (90 +/- 2 to 59 +/- 8%max), and the gain (-1.0 +/- 0.2 to -0.5 +/- 0.1%max/mmHg) of the RSNA reflex curve. Values returned to control within 10 min of cessation of ADN stimulation. These results suggest that central neurons processing baroreflex information from one set of mechanoreceptors can be reset by convergent signals arising from another baroreceptor site.

Characterization of the neonatal heart rate baroreflex during and after ECMO

Prolonged continuous blood pressure (BP) and heart rate (HR) recordings from neonates of 35 to 42 weeks gestation were studied during and after ECMO. Data segments with significant deviation of BP were extracted for further analysis. The simultaneous changes in BP and HR were compared and the slope of the regression determined baroreflex sensitivity (BRS). Of 464 BP deviations, 98% produced curves with a negative slope consistent with the presence of a baroreflex. The average BRS was -1.0 ± 0.8 bpm/mmHg (mean ± S.D.) and curves were steeper during rising BP than falling BP (-1.1 ± 0.9 beats/min per mmHg versus -0.9 ± 0.6, P = 0.001). The baroreflex was more sensitive during ECMO than after ECMO to both rising BP (-1.0 ± 0.5 beats/min per mmHg versus -0.7 ± 0.5, P = 0.004) and falling BP (-1.0 ± 0.6 beats/min/mmHg versus -0.7 ± 0.5, P = 0.04). HR response curves obtained during different BP fluctuations on the same recording had varying threshold, consistent with acute resetting. One infant demonstrated chronic baroreceptor resetting over 3 days to a rise in resting BP. The near-term, critically ill neonate has an active baroreflex which is capable of resetting. ECMO was associated with accentuation of the baroreflex response.

Is there a central nervous system component to acute baroreflex resetting in rats?

This study was designed to evaluate a possible central nervous system (CNS) component to acute baroreflex resetting. In nine arterial baroreceptor-denervated, chloralose-urethan-anesthetized rats, a control (C) aortic nerve stimulation curve (3-5 V, 1 ms, 0-64 Hz) was obtained. Next, a constant "baroreceptor" input was delivered to the CNS (left aortic nerve stimulation, 10 min, 10.2 +/- 1.5 Hz). Within the first 13 s of aortic nerve stimulation, maximum inhibition of lumbar sympathetic nerve activity (LSNA) was 60 +/- 7.8% of baseline and at 1 min it increased to 68 +/- 5.6% of baseline. At the end of the 10-min aortic nerve stimulation, LSNA was not different from the response at 1 min (68 +/- 5.6% = 74 +/- 4.1%). Immediately after the constant stimulation (within 30 s), a test or reset (RS) curve was obtained (0-64 Hz). A recovery (RC) curve was obtained 10-20 min later. The slope of the linear portion of the curve and the stimulation frequency that produced 50% maximum inhibition (ES50) were compared among the three baroreflex curves (C, RS, RC,) and no significant differences were found. Thus, although a CNS component to baroreflex adaptation was evident during the first minute of aortic nerve stimulation, a longer term acute resetting of the baroreflex curve did not occur.

Rapid resetting of human baroreflex working range: insights from sympathetic recordings during acute hypoglycaemia.

1. Human muscle nerve sympathetic activity (MSA), which is governed by baroreflexes and involved in blood pressure homeostasis, is increased during acute insulin-induced hypoglycaemia. 2. To elucidate the detailed relationship between MSA and blood pressure during hypoglycaemia, 0.15 i.u. (kg body weight)-1 regular human insulin was given intravenously to eight fasting, healthy volunteers. Microneurographic recording of MSA in the peroneal nerve was made with simultaneous monitoring of arterial blood pressure by a finger cuff (Finapres). The course of MSA and blood pressure was monitored for 30 min before and 60 min after insulin injection. In three subjects control recording without insulin injection was made for the same duration. 3. Stimulus-response regression lines were constructed by plotting diastolic blood pressure against the occurrence frequency of MSA for the period of initial rest, the period of maximal MSA outflow during hypoglycaemia and the period of glucose counter-regulation. The control experiments were analysed for the corresponding periods. 4. The stimulus-response line was stable throughout the control experiments, whereas it was shifted either to the left or to the right during hypoglycaemia, and regularly shifted to the left (i.e. towards a lower blood pressure) during glucose counter-regulation, without change of slope. 5. It is concluded that the changes in MSA during acute hypoglycaemia are not secondary to baroreflex regulation but instead are characterized by acute resetting of the baroreflex working range without change of sensitivity.

Assessment of Threshold and Saturation Pressure in the Baroreflex Function Curve:A New Mathematical Analysis.

The baroreflex function has been assessed with logistic function analysis, a mathematical model suitable for function curves of sigmoid shape. The nonlinear (sigmoid) relationship between carotid sinus pressure (CSP) and systemic arterial pressure (SAP) reflects threshold and saturation of the SAP responses to CSP changes. The threshold and saturation pressures (TP and SP) are often determined by gross inspection from the experimental recordings. Objective and accurate determination of TP and SP may be achieved by mathematical analysis. Kent et al. (Cardiology, Vol. 57, pp. 295-310, 1972) provided equations that estimated SP and TP to be +/- 1.317/k from the midrange CSP (k, the slope coefficient of a curve). Tan et al. (Circ. Res., Vol. 65, pp. 63-70, 1989) recently used an equation to calculate TP based on the consideration that it is about 95% of the maximal SAP. In this report, we elaborated new equations for the estimation of SP and TP, which approximate midrange pressure +/- 2/k. The accuracy of these new equations compared to other equations was tested using various sets of simulation data. In addition, experiments were conducted in anesthetized dogs with isolated carotid sinus. The open-loop CSP-SAP curves were obtained following various holding pressure (HPs) to demonstrate the phenomenon of baroreflex acute resetting. The effects of using different equations on the values of TP, SP, and delta TP/delta HP (extent of resetting) were analyzed. Both simulation and experimental data revealed that the equations of Kent et al. gave rise to values of TP and SP far different from the realistic values. The values of TP calculated by equation of Tan et al. were dependent on the maximal SAP and the slope of the function curve. The TP and SP (+/- 2/k from the midrange pressure of the sigmoid curve) obtained by our new equations were not significantly affected by the maximal SAP and the curve slope. The mathematical analysis may be particularly useful for comparison among various baroreflex curves with different maximal SAP and/or curve slope.

Rapid resetting of the baroreceptors in renal hypertensive rats.

The characteristics and extent of rapid or acute resetting of the aortic baroreceptors were studied in long-term renal hypertensive rats during 30 minutes of sustained hypertension produced by phenylephrine infusion. The aortic baroreceptors of hypertensive rats exhibited complete resetting to hypertension because during the control period the systolic threshold pressure for activation of the baroreceptors was similar (137 +/- 5 vs. 142 +/- 4 mm Hg) to the control diastolic pressure. Five minutes after onset of hypertension, a resetting of 32% (percent change of mean pressure threshold divided by total change of mean pressure) was demonstrable. The extent of resetting was 39%, 38%, and 41% after 10, 20, and 30 minutes of hypertension, respectively. When the percent change of systolic threshold pressure divided by total change of control diastolic pressure was used to calculate the extent of resetting, similar results were obtained. The extent of displacement of the entire baroreceptor pressure-response curves was similar to that of pressure thresholds. Reversibility of the resetting process was not complete within 30 minutes of pressure normalization after the administration of phenylephrine was interrupted. These data indicate that the characteristics and extent of rapid resetting of the baroreceptors of renal hypertensive rats, which were reset to operate at hypertensive levels, are similar to those previously described in normotensive rats.

Extent of rapid baroreceptor resetting during first hours of hypertension.

Rapid or acute resetting of the aortic baroreceptors was studied in anesthetized rats during the onset and maintenance of hypertension produced by subdiaphragmatic aortic constriction for up to 6 h. After 2 min of hypertension, the systolic threshold pressure for activation of the baroreceptors increased by 33% of the total 27-mmHg increase of the control diastolic pressure. Maximal resetting of 46 and 52% was demonstrable after 20 and 30 min of hypertension. The shifts in pressure threshold were accompanied by parallel shifts in the entire baroreceptor function curves. After 30 min of hypertension, resetting was only partially (60%) reversed within the 30 min of pressure normalization. Resetting did not progress with time. Six hours after aortic constriction, resetting was only 38% (vs. 32% after 30 min). The data indicate that acute or rapid resetting of the aortic baroreceptors reaches a maximum within 20-30 min (40-50%) and remains stable for up to 6 h, with no apparent change in the baroreceptor gain.

Determinants of sensitization of carotid baroreceptors by pulsatile pressure in dogs.

The threshold pressure of single baroreceptor units is decreased after compared with before exposure to pulsatile pressure according to previous studies in our laboratory. The purpose of the present study is to characterize the determinants of sensitization of arterial baroreceptors by pulsatile pressure. Carotid sinus nerve activity was recorded in dogs anesthetized with chloralose. Two indexes of baroreceptor "sensitivity" were obtained by comparing nerve activity before and immediately after exposure of the isolated carotid sinus to pulsatile pressure for periods up to 10 minutes. Sensitization occurred 1) when the threshold pressure of single baroreceptor units determined with a slow nonpulsatile ramp decreased after as compared with before pulsing and 2) when multiple unit activity increased after as compared with before pulsing at various mean levels of static pressure. Sensitization was evident after pulsing at mean pressure of 50 and 100 mm Hg, but not at 150 and 200 mm Hg, and was caused by the pulsatile change in diameter or deformation and not by the pulsatile change in wall tension. The magnitude of the effect was directly related to the duration of the pulsing period and to the frequency and amplitude of the pressure pulses. The sensitization could not be explained by increased diameter (sonomicrometers) or strain of the carotid sinus at the same pressure after pulsing; thus, there was an increase in "strain sensitivity" that outlasted the period of pulsing by up to several minutes. In most experiments the shift from static to pulsatile pressure at 50 and 100 mm Hg caused an increase in nerve activity, yet sensitization occurred after pulsing when one would have expected postexcitatory hyperpolarization or depression of activity upon return to static pressure. The sensitization was not caused by the release of prostacyclin from the endothelium since it was not reduced after endothelial denudation or inhibition of cyclooxygenase with indomethacin (30-80 microM) or ibuprofen (250 microM). We speculate that sensitization of baroreceptors by pulsatile pressure may contribute to the decreased sympathetic activity after periods of elevated pulse pressure (e.g., after exercise). We also propose that the decreased sensitivity of baroreceptors after acute elevation of arterial pressure (acute resetting) may be offset in part by the sensitizing effect of increased pulsatile stretch.

Peripheral and central mechanisms of baroreflex resetting.

1. A change in the arterial pressure-sympathetic activity or heart rate relation (baroreflex resetting) can result from resetting of baroreceptors ('peripheral' resetting) or from an altered coupling within the central nervous system of afferent baroreceptor to efferent nerve activities ('central' resetting). 2. 'Peripheral' resetting involves a shift in the pressure-baroreceptor activity curve in the direction of the prevailing level of arterial pressure, e.g. after elevations in pressure, the baroreceptor pressure threshold (Pth) is increased and activity reduced at equivalent pressures and vascular strains. 3. 'Peripheral' resetting occurs during the diastolic phase of a cardiac cycle (instantaneous resetting), after brief exposure to elevated pressure (acute resetting), and during chronic hypertension or when chronic structural changes in the vasculature have occurred (chronic resetting). 4. Mechanisms include: (i) changes in the mechanical properties of the vessel wall that may alter the tension on the receptors; (ii) ionic mechanisms operating at the neuronal membrane such as activation of Na+,K+-ATPase; and (iii) release of endothelial factors that may modulate baroreceptor sensitivity. 5. Acute resetting of baroreceptors can be prevented or attenuated when the sustained elevations in pressure are pulsatile rather than static. Increases in flow increase carotid sinus nerve activity at constant pressure and strain and decrease the Pth of baroreceptors. 6. 'Central' resetting can involve neural-humoral interactions or an altered responsiveness of central neurons mediating the baroreflex to changes in afferent baroreceptor activity. 7. During static pressure, the continuous baroreceptor discharge causes significant 'central' resetting, i.e. sympathetic activity escapes from baroreflex inhibition. In contrast, during pulsatile pressure, the pulse phasic baroreceptor discharge minimizes 'central' resetting causing sustained sympathetic inhibition.

Mechanisms of Resetting of Arterial Baroreceptors: An Overview

Arterial baroreceptors are reset when their afferent nerve activity is reduced at an equivalent arterial pressure and vascular strain. Resetting occurs as a result of stretch of the baroreceptors, usually during an acute or chronic rise in arterial pressure. It may be seen during the diastolic phase of a cardiac cycle (instantaneous resetting), after brief exposure to a sustained elevation of pressure (acute resetting), and after chronic elevation of pressure or in physiologic or pathologic states associated with structural changes in the vascular regions of baroreceptors (chronic resetting). The mechanisms reviewed here include mechanical, ionic and chemical factors. Viscoelastic properties of the carotid sinus and aortic arch may explain the instantaneous resetting that occurs with each cardiac cycle when activity begins in early systole and stops in early diastole. Viscoelastic properties and ionic mechanisms may play a role in acute resetting. Inhibition of Na+K+ ATPase reduces the magnitude of acute resetting. The release of chemicals from the endothelium may modulate baroreceptor activity. Exogenous prostacyclin suppresses and indomethacin augments acute resetting in the rabbit, suggesting that the release of endogenous prostacyclin during a rise in arterial pressure attenuates resetting. Changes in pulsatility and blood flow also may modulate baroreceptor activity. The addition of pulsatile pressure at an increased mean pressure attenuates resetting.(ABSTRACT TRUNCATED AT 250 WORDS)

Characteristics and Extent of Rapid Aortic Baroreceptor Resetting in Rat

The characteristics of rapid or acute resetting of the aortic baroreceptors were studied in anesthetized rats during 30 minutes of sustained hypertension produced by phenylephrine infusion. Two minutes after the onset of hypertension, a resetting of 26% (ratio of change in systolic threshold pressure to total change in diastolic pressure) was demonstrable. This represents 60% of the maximal resetting (43%) observed after 20 minutes. Thereafter, the magnitude of resetting remained stable. Pressure-nerve activity showed a parallel shift after 2 and 20 minutes of hypertension, with a slight tendency to increased slope at elevated pressures, especially in the baroreceptor function curve analyzed after 2 minutes. These results suggest that in rats, no significant difference exists in the time course for resetting of baroreceptor fibers with low vs. high thresholds. In contrast to other studies, reversibility of the resetting process was not complete within 30 minutes of pressure normalization, and the extent of reversal was no greater than 60%. The data of the present study, taken together with those obtained previously after 6 hours of hypertension, suggest that during the onset and maintenance of hypertension in rat, acute or rapid resetting of the baroreceptors reaches its maximum in 20 minutes (40%) and remains stable for up to 6 hours, with no apparent change in the baroreceptor gain.

Mechanisms of complete baroreceptor resetting in hypertension.

It is a universally accepted phenomenon that vascular baroreceptors reset to operate at higher pressure levels in hypertension. A rapid or acute resetting can be demonstrated within the first 5 to 15 minutes after arterial pressure has been elevated. However, this resetting is only partial because the increase in pressure threshold for baroreceptor activation represents a fraction (20 to 40%) of the total pressure increase. This acute resetting changes little within the first hours of hypertension. To achieve complete resetting however, that is when the pressure threshold increase equals the total pressure increase, blood pressure needs to be maintained at an elevated level for 48 hours in the rat. Studies of aortic calibre behaviour performed in freely moving rats demonstrated a striking direct relationship between the time taken for the diastolic calibre to reach maximal dilation and the time taken for complete resetting of the aortic baroreceptors. It was also observed that during transient pressure increases the displacement of the diastolic calibre is much greater than the increase in pulsation, indicating that under physiological conditions sustained distension of the diastolic calibre is an important factor in aortic baroreceptor distortion. The data suggest that complete resetting of the baroreceptors in hypertension occurs when the increased stress on the arterial wall is matched by a proportional permanent increase in diastolic calibre.