Sinoaortic Baroreceptor Denervation Research Articles

Renal Blood Flow Dynamics and Arterial Pressure Lability in the Conscious Rat

It is not known whether renal blood flow (RBF) is still autoregulated when the kidney is exposed to large transient blood pressure (BP) fluctuations such as those occurring spontaneously in conscious sinoaortic baroreceptor-denervated (SAD) rats. In this study, BP and RBF were simultaneously recorded in 8 SAD rats (2 weeks before study) and 8 baroreceptor-intact rats during approximately 3 hours of spontaneous activity. The kidney used for RBF recordings was denervated to prevent the interference of changes in renal sympathetic tone with autoregulatory mechanisms. In intact rats, RBF variability (coefficient of variation 9.1+/-0.8%) was larger (P<0.02) than BP variability (5.9+/-0.2%). This was mainly because of slow changes in RBF that were unrelated to BP and also to a prominent oscillation of RBF of approximately 0.25-Hz frequency. Autoregulatory patterns were identified at frequencies <0.1 Hz and provided a modest attenuation of BP fluctuations. In SAD rats, RBF variability (12.4+/-1.6%) was lower (P<0.02) than BP variability (18.2+/-1.1%). Autoregulation powerfully attenuated BP changes <0.1 Hz (normalized transfer gain 0.21+/-0.02 in the 0.0015- to 0.01-Hz frequency range) but at the expense of an oscillation located at approximately 0.05 Hz that possibly reflected the operation of the tubuloglomerular feedback. Large transient hypertensive episodes were not translated into RBF changes in SAD rats. We conclude that autoregulatory mechanisms have an ample capacity to protect the kidney against spontaneous BP fluctuations in the conscious rat. This capacity is not fully used under normal conditions of low BP variability.

REDUCTION OF BLOOD PRESSURE VARIABILITY BY AMLODIPINE IN BARORECEPTOR DENERVATED RATS

To determine the effect of the calcium blocker amlodipine on the variability of mean arterial pressure (MAP), amlodipine besylate was acutely administered to sino-aortic baroreceptor-denervated (SAD) rats (0, 1, 3, 10 mg/kg s.c.), and chronically administered to SAD and sham-denervated rats (0, 50, 150, 500, and 1500 mgċkg−1 feed, 4 days per dose). Acute amlodipine administration caused significant dose-dependent reductions of the mean MAP level and short-term MAP variability at the 3 and 10 mg/kg dose levels, respectively. Chronic administration produced dose-dependent reductions in short-term MAP variability, becoming significant at the 150 and 500 mgċkg−1 feed dose level in SAD and Sham groups, respectively. Day-night differences in blood pressure were significantly attenuated or reversed at the 500 and 1500 mgċkg−1 feed dose levels. Amlodipine had little or no effect upon the 24 h MAP level, long-term MAP variability, and only modestly reduced the MAP response to hexamethonium. These results demonstrate that amlodipine can reduce MAP variability independent of changes in the mean blood pressure level.

Influence of GABA in the nucleus of the solitary tract on blood pressure in baroreceptor-denervated rats.

We have previously reported that inhibition of the nucleus of the solitary tract (NTS) in chronically sinoaortic baroreceptor-denervated (SAD) rats has no effect on blood pressure in contrast to the marked increase in blood pressure it elicits in baroreceptor-intact rats. This could result either from a lack of tonic excitatory input to this region or from overriding inhibition of NTS neurons involved in the control of blood pressure. The present study aimed to distinguish between these two possibilities by examining the changes in blood pressure elicited by injection of bicuculline (Bic), a gamma-aminobutyric acid (GABA) antagonist, into the NTS of SAD and control rats. In chloralose-anesthetized baroreceptor-intact rats or acutely SAD rats, injection of 10 pmol Bic into the NTS elicited minimal changes in blood pressure. In contrast, in chronic SAD rats injection of Bic into the NTS elicited a large decrease in blood pressure. The maximal decrease in blood pressure elicited by Bic in chronic SAD rats was equivalent to the maximal decrease in blood pressure that could be evoked by direct excitation of the NTS with L-glutamate. These results suggest that the lack of a tonic role of the NTS in the regulation of blood pressure in chronic SAD rats is a result of maximal GABA-mediated inhibition of relevant NTS neurons.

Role of the brain renin-angiotensin system in the maintenance of blood pressure in conscious spontaneously hypertensive and sinoaortic baroreceptor-denervated rats.

1. Evidence suggesting an involvement of the brain renin-angiotensin system (RAS) in the development/maintenance of hypertension in spontaneously hypertensive rats (SHR) relies, in part, on early experimental data reporting centrally mediated antihypertensive effects of saralasin. However, recent data using non-peptide AT1 receptor antagonists does not always support this theory because these compounds usually do not lower blood pressure when given centrally. 2. In the present study we have re-assessed the central effects of saralasin in conscious SHR as well as in sinoaortic baroreceptor-denervated (SAD) rats. Both of these models exhibit heightened sensitivity to the central pressor effects of angiotensin II (AngII) and, thus, any potential antihypertensive activity would provide functional evidence of activated brain RAS mechanisms in these models. 3. In SHR, saralasin failed to lower mean arterial pressure (MAP) when given intracerebroventricularly (i.c.v.) as bolus or infusion doses that blocked the centrally mediated pressor effect of AngII. 4. In SAD rats, there was a marked impairment of the baroreceptor-heart rate reflex function and enhanced centrally mediated pressor responses to AngII. However, i.c.v. saralasin infusions again did not alter MAP. 5. Collectively, these results suggest that the central RAS is not involved in the maintenance of MAP in SHR and SAD rats, both of which are models exhibiting a functional hyperresponsiveness to AngII.

Baroreceptor input regulates osmotic control of central vasopressin secretion.

Sinoaortic baroreceptor denervation (SAD) results in increased osmotically induced secretion of vasopressin (VP) and oxytocin (OT) and increased cardiovascular responses to many centrally acting pressor agents. Studies were conducted to determine whether SAD increases the cardiovascular and endocrine responses to direct and peripheral osmotic stimulation of the supraoptic nucleus (SON). SON microdialysis was performed in urethane-anesthetized male rats with measurement of dialysate peptides, mean arterial pressure (MAP) and heart rate. Experiment 1 tested the effect of direct stimulation of the SON with hypertonic NaCl in SAD, sham-operated (control) and intake-matched (matched) rats. Osmotically induced VP release into the SON was significantly greater in SAD than in control or matched groups. VP release peaked at 36 +/- 13 and 15 +/- 7 pg in SAD and controls, respectively, with no increase observed in the matched group. Plasma VP was significantly elevated after SON osmotic stimulation with no differences observed among the groups. The pressor response to osmotic stimulation was greater in SAD (29 +/- 4 mm Hg) than in control (20 +/- 3 mm Hg) and matched animals (15 +/- 3 mm Hg). Experiment 2 tested the effect of intraperitoneal injection of hypertonic NaCl on SON VP and OT release. SAD rats showed an increased central VP response to peripheral osmotic stimulation, a 64-fold increase in SAD as compared to a 4-fold one in controls. Central OT release was not significantly altered (peak of 22 +/- 6 vs. 11 +/- 4 pg, SAD vs. control). A direct SON osmotic challenge given 3.5 h after the intraperitoneal test confirmed an increased VP responsiveness in the SAD group. Plasma VP and OT were significantly increased after intraperitoneal hypertonic saline with no difference observed between groups. The MAP response to intraperitoneal hypertonic saline was greater in the SAD group with an elevation of 37 +/- 4 versus 18 +/- 3 mm Hg observed in SAD versus control subjects. These results demonstrate that baroreceptor denervation produces a state of heightened osmotic sensitivity for VP neurons, with evidence for increased central VP release to both direct and peripheral hypertonic NaCl stimulation.

Cardiac hypertrophy and telemetered blood pressure 6 wk after baroreceptor denervation in normotensive rats.

We investigated cardiac morphometry 6 wk after sinoaortic baroreceptor denervation (SAD) in Long-Evans rats. SAD (n = 19) was associated with an 11% increase in the weight of the left ventricle (LV) plus septum (P < 0.001) and a 39% increase in that of the right ventricular (RV) free wall (P < 0.001), relative to sham-operated rats (n = 18). RV wall thickness was significantly increased in SAD animals, but there was no difference in the LV wall thickness and volumes of the RV and LV between groups. Constrictor responses to methoxamine and dilation responses to acetylcholine were assessed in an in vitro perfused mesenteric circulation preparation, but neither response was affected by SAD. Baroreceptor denervation was associated with marked and significant increases in the variability (2.8-fold) and daily peak (39 mmHg) levels of telemetered mean arterial pressure (MAP) and small (5%) but significant increases in the daily mean MAP level. Our results are consistent with an effect of increased MAP variability on ventricular weight but cannot rule out possible contributions from other mechanisms.

Hemodynamic and norepinephrine responses to pacing-induced heart failure in conscious sinoaortic-denervated dogs.

The present study was undertaken to determine the effects of chronic sinoaortic (baroreceptor) denervation (SAD) on the hemodynamic and sympathetic alterations that occur in the pacing-induced model of congestive heart failure. Two groups of dogs were examined: intact (n = 9) and SAD (n = 9). Both groups of dogs were studied in the control (prepace) state and each week after the initiation of ventricular pacing at 250 beats/min. After the pacemaker was turned off, hemodynamic and plasma norepinephrine levels returned toward control levels in the prepaced state and after 1 and 2 wk of pacing. However, by 3 wk all hemodynamic and norepinephrine levels remained relatively constant over the 10-min observation period with the pacemaker off. With the pacemaker off, left ventricular end-diastolic pressure went from 2.7 +/- 1.4 (SE) mmHg during the prepace state to 23.2 +/- 2.9 mmHg in the heart failure state in intact dogs (P < 0.01). Left ventricular end-diastolic pressure increased to 27.1 +/- 2.2 mmHg from a control level of 4.2 +/- 1.9 mmHg i SAD dogs (P < 0.0003). Mean arterial pressure significantly decreased in intact and SAD dogs. Resting heart rate was significantly higher in SAD dogs and increased to 135.8 +/- 8.9 beats/min in intact dogs and 136.1 +/- 6.5 beats/min in SAD dogs. There were no significant differences in the hemodynamic parameters between intact and SAD dogs after pacing. Plasma norepinephrine was significantly lower in intact than in SAD dogs before pacing (197.7 +/- 21.6 vs. 320.6 +/- 26.6 pg/ml; P < 0.005). In the heart failure state, plasma norepinephrine increased significantly in both intact (598.3 +/- 44.2 pg/ml) and SAD (644.0 +/- 64.6 pg/ml) groups. There were no differences in the severity or the magnitude of the developed heart failure state in SAD vs. intact dogs. We conclude from these date that the arterial baroreflex is not the sole mechanism for the increase in sympathetic drive in heart failure.

Involvement of vasodilator mechanisms in arterial pressure lability after sino-aortic baroreceptor denervation in rat.

1. To examine the regional haemodynamic basis of arterial pressure lability seen after sino-aortic baroreceptor denervation (SAD), simultaneous beat-to-beat recordings of arterial pressure and indices of regional blood flows (Doppler probes around the subdiaphragmatic and lower abdominal aortae and the superior mesenteric artery) were performed in the same conscious rats (n = 7) before, 1 and 14 days after SAD. 2. Acute SAD increased arterial pressure, decreased regional blood flows and vascular conductances, and potentiated the depressor and vasodilator effects of ganglionic blockade with trimethaphan, suggesting sympathetic overactivity. All parameters chronically returned to or near normal. 3. Both acute and chronic SAD increased the variability of arterial pressure and of regional conductances. Arterial pressure lability was characterized by a mixture of depressor and pressor events which were associated with regional vasodilatations and vasoconstrictions, respectively. This haemodynamic pattern was not affected by acute beta-adrenoceptor blockade with propranolol. 4. In conscious rats, the baroreceptor reflex acts to buffer the spontaneous variability of regional vascular conductances and thereby stabilizes arterial pressure. Sino-aortic baroreceptor denervation-induced arterial pressure lability does not depend on the level of sympathetic activation, and is determined by the relative contribution of depressor and pressor events accompanied by extensive vasodilatations and vasoconstrictions, respectively. Vasodilatations are not caused by the stimulation of vascular beta 2-adrenoceptors.

Effects of sinoaortic baroreceptor denervation on depletion-induced salt appetite.

This study examined the effects of denervation of the carotid sinus and aortic arch baroreceptors on sodium depletion-induced salt appetite in rats. Depletion of extracellular fluid began with two injections of furosemide (10 mg/kg sc), 30 min apart, and removal of all ambient sodium from the cages. Water and sodium-deficient chow were available overnight. The next morning, access to 0.3 M NaCl was provided, and intakes of water and saline were measured every 30 min for 2 h and again at 24 h. Three such tests were administered. Groups of sham and sinoaortic baroreceptor-denervated (SAD) rats had equivalently negative water and sodium balances before access to saline the next morning. Sham-denervated rats drank sufficient saline in 2 h to achieve positive sodium balance and subsequently ingested sodium in excess of need for another 22 h. SAD rats drank half as much saline as sham-denervated rats by 2 and 24 h and remained in negative balance at 2 h. Sham-denervated rats increased their intakes of saline solution with repeated tests, but SAD rats did not. These findings suggest that arterial baroreceptors provide critical neural input for the normal expression of salt appetite.

Baroreflex modulation of blood pressure and heart rate variabilities in rats: assessment by spectral analysis

The role of the baroreflex in the spectral characteristics of mean arterial pressure (MAP) and heart rate (HR) was investigated in 12 control rats and 9 rats with chronic sinoaortic baroreceptor denervation (SAD) during 1) basal conditions and 2) ganglionic blockade with chlorisondamine and restoration of the basal MAP level. In SAD rats, power spectral density of MAP, estimated by a fast Fourier transform, was reduced in the low-frequency (LF, 0.27- to 0.74-Hz) band. Ganglionic blockade highly decreased LF power spectral density of MAP in control rats. No relationship was found between the MAP response to chlorisondamine, taken as an index of the sympathetic vasomotor tone, and the basal LF power spectral density. Transfer function analysis between MAP and HR showed that, in control rats, coherence was high for frequencies surrounding the LF and high-frequency peaks. In SAD rats, coherence was abolished in the LF band but maintained in the high-frequency band. In conclusion, approximately 80% of the LF power spectral density of MAP depends on the sympathetic nervous system activity, and the baroreflex accounts for one-half of this power and for the coherence between MAP and HR oscillations in the LF band.

Role of arteria baroreceptor input on thirst and urinary responses to intracerebroventricular angiotensin II

Intracerebroventricular (icv) infusion of angiotensin II (ANG II) in rats elicits greater water intake under hypotensive, compared with normotensive, conditions. The present experiments used sinoaortic baroreceptor-denervated (SAD) rats and sham-operated rats to examine if the modulatory effects of arterial blood pressure on water intake in response to icv ANG II are mediated by arterial baroreceptors. Mean arterial blood pressure (MAP) was raised or lowered by intravenous (i.v.) infusions of phenylephrine (1 or 10 micrograms.kg-1 x min-1) or minoxidil (25 micrograms.kg-1 x min-1), respectively. The angiotensin-converting enzyme inhibitor captopril (0.33 mg/min) was infused i.v. to prevent the endogenous formation of ANG II during testing. Urinary excretion of water and solutes was measured throughout. Water intake elicited by icv ANG II was inversely related to changes in MAP. Specifically, rats drank more water in response to icv ANG II when MAP was reduced by minoxidil but drank less water when MAP was elevated by phenylephrine. The influence of changing MAP on the icv ANG II-induced drinking responses was not affected by SAD. These results suggest that the modulatory effects of arterial blood pressure on icv ANG II-induced drinking can occur in the absence of sinoaortic baroreceptor input.

Cardiac baroreflex dynamics during the defence reaction in freely moving rats

To determine the extent of baroreceptor reflex involvement in the cardiovascular changes observed during electrically induced defence reaction, the mean arterial blood pressure (MBP) and heart rate (HR) of conscious intact or sinoaortic baroreceptor denervated (SAD) rats were continuously recorded from indwelling cannulae during a 1-min period of electrical stimulation of the mesencephalic tectum. Electrical stimulation produced stimulus intensity-dependent behaviours including freezing at lower intensities and flight at higher intensities. The cardiovascular responses in intact rats were dependent on both the intensity and duration of the stimulus. A linear increase in MBP was observed with increasing stimulus intensities. However, while a slight bradycardia was observed during the freezing behaviour, a marked tachycardia occurred during flight. Simultaneous increases of MBP and HR were seen throughout the first 15 s of the flight response, after which the HR rapidly fell to baseline levels, whereas the MBP remained at a hypertensive plateau until the end of the stimulus. The baroreflex HR curve showed a parallel shift to the left during the first half of the freezing period, being fully reset 40 s after that. So, while the baroreflex gain remained unchanged, the reflex set point was lowered during the freezing stage of the defence reaction. The experiments with SAD rats corroborated the above data. The baroreceptor denervation reversed the freezing bradycardia to tachycardia. Moreover, the denervation potentiated the flight tachycardia and prevented its later reset. MBP responses of baroreceptor denervated rats did not differ from the sham-operated group. The sustained hypertension, thus, appears to be mediated by mechanisms other than the mere baroreceptor reflex deactivation. In summary, our data suggest that the baroreflex inhibition seems to be both partial and transient during the defence reaction induced by the electrical stimulation of the rat mesencephalic tectum.

Effect of selective denervation of baroreceptors on pulmonary ventilation and arterial pressure lability in rat.

Earlier studies report that sinoaortic baroreceptor denervation (SAD) in rats causes moderate elevation of mean arterial pressure along with a marked increase of arterial pressure lability (APL). In this context, we studied the effects of selective aortic denervation (AD) or selective carotid denervation (CD) on the regulation of blood pressure. In addition, we evaluated the effects of selective or total baroreceptor denervation on pulmonary ventilation and ventilation-related changes of arterial pressure. Mean arterial pressure was evaluated by computer-assisted techniques, and ventilation was measured by whole body plethysmography on conscious freely moving rats. With this approach, equal increases of mean arterial pressure were obtained for rats that had undergone AD, CD, and SAD. The APL was higher in SAD rats than in selectively denervated rats. CD and AD rats had an elevated APL relative to sham-operated animals, and its increase was approximately equal for the two selectively denervated groups. Total as well as selective denervation had relatively small effects on ventilation and on the general pattern of breathing. In all groups, this pattern consisted of regular ventilation, periodically interrupted by single deeper breaths. In SAD, AD, and CD animals, these larger tidal volumes were associated with marked transient reductions of mean arterial pressure, whereas small decreases of pressure occurred in sham-operated rats. The results indicate that both groups of baroreceptors must be present to keep mean arterial pressure at its normal level. Moreover, both receptor groups are equally important in reducing APL. Ventilation contributes to generation of APL after total or selective baroreceptor removal. Such ventilation-induced pressure changes are kept at a minimum in baroreceptor-intact rats.

Sinoaortic denervation does not increase cardiovascular/endocrine responses to stress.

Sinoaortic baroreceptor denervation is reported to produce exaggerated centrally derived cardiovascular and endocrine responses. We examined the effect of sinoaortic denervation (SAD) on the cardiovascular and endocrine responses to two acute stressors, footshock and immobilization, in male Sprague-Dawley rats. Parameters measured were mean arterial pressure (MAP), heart rate (HR) and plasma levels of oxytocin (OT) and vasopressin (VP). Baseline MAP was elevated in the SAD group (approximately 25 mm Hg) and footshock stress increased arterial pressure equivalently in both groups. This stress caused tachycardia and increased plasma OT, with a tendency for the SAD group to show blunted responses. Immobilization increased HR but caused no change in MAP and no significant difference between the groups. This form of stress also increased plasma OT, and again the SAD group showed a diminished response. Plasma VP was not significantly altered by either stressor. The results of these studies indicate that SAD does not uniformly increase the cardiovascular and endocrine responses to all stressors or centrally derived stimuli. These results also suggest that the lack of an increase in plasma VP is not related to baroreceptor-mediated inhibition of secretion under stressful conditions.

Pathogenesis of hypertension in the sinoaortic-denervated spontaneously hypertensive rat.

The present study was performed to examine the relation between the gain of the baroreceptor reflex and the pathogenesis of hypertension in the spontaneously hypertensive rat. Spontaneously hypertensive or Wistar-Kyoto rats underwent either sinoaortic baroreceptor denervation or sham denervation at 28-35 days of age. Four months later these rats were chronically instrumented for measurements of arterial pressure and heart rate. Sixty-minute computerized measurements of arterial pressure showed no difference between spontaneously hypertensive sham (163 +/- 5 mm Hg) and spontaneously hypertensive baroreceptor-denervated (166 +/- 5 mm Hg) rats, or Wistar-Kyoto sham (114 +/- 3 mm Hg) and Wistar-Kyoto baroreceptor-denervated (121 +/- 4 mm Hg) rats. The gain of baroreceptor reflex control of heart rate was assessed by measuring maximal heart rate responses to changes in arterial pressure elicited by bolus injection of phenylephrine and nitroprusside (gain = slope of linear regression equation of change in heart rate versus change in arterial pressure). Baroreceptor reflex gain was significantly higher in Wistar-Kyoto sham rats (-2.10 beats/min/mm Hg) than spontaneously hypertensive sham rats (-0.94 beats/min/mm Hg). Baroreceptor denervation significantly decreased baroreceptor reflex gain in both Wistar-Kyoto (-0.26 mm Hg) and spontaneously hypertensive (-0.22 beats/min/mm Hg) groups. Since baroreceptor denervation did not exacerbate the development of hypertension in adult spontaneously hypertensive rats or lead to hypertension in Wistar-Kyoto rats, we conclude that a primary dysfunction in the baroreceptor reflex alone is not responsible for the development of hypertension in this model.

Time-course effects of sinoaortic denervation on contractile state of the rat myocardium.

Sinoaortic baroreceptor denervation (SAD) in the rat immediately produces hypertension and tachycardia, as the result of an increased sympathetic tone to the heart and resistance vessels. Adaptive processes are then installed, changing according to the duration of the SAD. In this work we studied the time course of adaptive changes occurring in the rat heart within a 30-day period. Heart rate and mean blood pressure were measured before mechanical studies in the isometrically contracting left ventricle papillary muscles. Results showed that heart rate and mean blood pressure increased immediately after the SAD. Heart rate normalized 15 days later, although hypertension persisted. Thirty days later both rate and pressure normalized. Mechanical studies showed that isometric force development (F) and its first-time derivative (dF/dt) behaved similar to controls until the 1st wk but displayed a contractile depression in the 2nd wk after SAD. However, after 30 days this depression subsided and both F and dF/dt were back to normal values. The beta-adrenoceptor responsiveness also changed during this 30-day period. Three days after denervation there was an increased sensitivity to isoproterenol action in the muscles. This sensitivity was progressively reduced as the time after denervation increased. The absence of a similar behavior with the rest-potentiated contractions suggests that these time-course adaptive changes are specific for beta-adrenoceptor stimulation.

Neural control of urinary sodium excretion during hypertonic NaCl load in conscious rabbits: role of renal and hepatic nerves and baroreceptors

We examined responses of renal nerve activity, urine flow, and urinary Na+ excretion to a hypertonic NaCl infusion in chronically instrumented conscious rabbits with unilateral renal denervation. The intravenous infusion of 20% NaCl, at 0.2 ml/min for 30 min, increased plasma osmolality by 27 +/- 5 mOsm/kg, and plasma Na+ by 16 +/- 3 mEq/l, and decreased hematocrit by 5 +/- 1%. These changes were accompanied by a marked decrease in renal nerve activity by 82 + 7%. Urine flow and urinary Na+ excretion increased gradually and peaked at the end of infusion. The innervated kidney excreted 23.3 +/- 3.3 ml urine and 5.5 +/- 0.7 mEq Na+ for the subsequent 60 min. However, the contralateral denervated kidney excreted only 9.5 +/- 2.0 ml urine and 2.2 +/- 0.6 mEq Na+; these values were significantly less than those of the innervated kidney. To examine the role of the sinoaortic and cardiopulmonary baroreceptors and the hepatic nerves in the response of renal nerve activity to the hypertonic NaCl infusion, renal nerve activity was examined in conscious rabbits with sinoaortic baroreceptor denervation (SAD) plus vagotomy and/or section of the anterior and posterior hepatic nerves (SAPH). In rabbits with SAD plus vagotomy or SAPH, the NaCl infusion also decreased renal nerve activity. After combining SAPH and SAD plus vagotomy, the decrease in renal nerve activity was completely blocked. These results indicate that hypertonic NaCl infusion elicits a marked decrease in renal nerve activity which is mediated predominantly by sinoaortic and cardiopulmonary baroreflexes and the hepatic nerves, and that the decrease in renal nerve activity plays an important role in the augmentation of renal function.

Sympathoadrenal activation in sinoaortic-denervated rats following endotoxin

We evaluated the role of the baroreceptor reflex in mediating the sympathoadrenal activation during endotoxicosis, using acutely as well as chronically denervated rats. Three groups of experiments were conducted. In the first experiment, hemodynamic and plasma catecholamine responses following endotoxin (5 mg/kg iv) were measured in alpha-chloralose-anesthetized rats with acute sinoaortic baroreceptor denervation (SAD) or sham operation. In the second experiment, chronically sinoaortic-denervated rats and sham controls were used and experiments were conducted as in acute preparations. In the third experiment hydralazine (1 mg/kg iv) was given to chronically denervated rats and sham controls to evaluate the singular contribution of hypotension-evoked baroreflex disinhibition in the absence of endotoxin. In both acute and chronic preparations, endotoxin induced marked elevation of plasma norepinephrine and epinephrine in the presence as well as the absence of arterial baroreceptors (P greater than 0.05). Plasma catecholamines were significantly increased by hydralazine-induced hypotension in the sham group, but this elevation was far less than that induced by endotoxin. Hypotension alone did not significantly increase plasma catecholamines in SAD rats. These results suggest that the baroreflex is not the major factor in mediating sympathoadrenal activation during endotoxicosis and that non-baroreflex mechanisms may be involved in stimulating such activation.

USE OF NICOTINE, BRADYKININ AND VERATRIDINE TO ELICIT CARDIOVASCULAR CHEMOREFLEXES IN UNANAESTHETIZED RABBITS

1. We have characterized in unanaesthetized rabbits the reflex effects of injecting nicotine into the pericardial sac or left atrium on heart rate, arterial pressure, systemic vascular resistance and the amplitude and frequency of respiration. These effects were compared with those of atrial administration of nicotine and veratridine, and intrapericardial administration of veratridine and bradykinin. 2. Injection of nicotine (6.25-400 micrograms) into the pericardial sac caused dose-dependent falls of heart rate and arterial pressure, and a brief period of hypopnoea. The fall in arterial pressure was mainly due to a fall in systemic vascular resistance. The threshold dose was 25 micrograms. Near maximal falls in heart rate (108 beats/min) and arterial pressure (47 mmHg) occurred at a dose of 200-400 micrograms. The latency between injection and the onset of bradycardia was 3.0 s. 3. The effects of intrapericardial nicotine on arterial pressure and respiration were antagonized in a dose-dependent fashion by intrapericardial mecamylamine (1-100 micrograms/kg) but were unaffected by intrapericardial hyoscine methylbromide (10 micrograms/kg) or vecuronium (1-10 micrograms/kg). The haemodynamic and respiratory effects were abolished by intrapericardial procaine. The haemodynamic effects were increased, though not significantly, by sino-aortic baroreceptor denervation. In decerebrate, artificially ventilated rabbits, bilateral cervical vagotomy converted the hypotensive and bradycardic response into a slowly developing tachycardia without change in arterial pressure. 4. Left atrial injection of nicotine (6.25-100 micrograms) caused bradycardia, a rise in arterial pressure, and prolonged hyperpnoea preceded by transient hypopnoea. After sino-aortic barodenervation it caused profound falls in heart rate and arterial pressure and transient hypopnoea, which were abolished by intrapericardial procaine. 5. Intrapericardial injection of veratridine (50-100 micrograms) had no consistent effect under control conditions. After sino-aortic barodenervation it caused falls in heart rate and arterial pressure which were abolished by intrapericardial procaine. Left atrial injection of veratridine caused highly variable haemodynamic effects. 6. Intrapericardial bradykinin (2.5-25 micrograms) caused rises in both arterial pressure and heart rate. These were abolished by intrapericardial procaine. 7. We conclude that when nicotine is injected into the pericardial sac of conscious rabbits the reflex haemodynamic and respiratory effects are due to the selective activation of neuronal-type nicotinic cholinoceptors on vagal afferents that originate in the epicardium. The reflex effects of left atrial nicotine are probably due to the excitation of a combination of carotid chemoreceptors and cardiac receptors. 8. The effects of nicotine, veratridine and bradykinin that we observed in conscious rabbits were profoundly different from those reported in anaesthetized rabbits.

Cardiovascular effects of posterior hypothalamic stimulation in baroreflex-denervated rats

The overall purpose of this study was to examine the effect of sinoaortic baroreceptor denervation (SAD) on the cardiovascular and sympathetic outflow responses to electrical stimulation of the posterior hypothalamus. In anesthetized rats that had undergone SAD 7-10 days before experimentation, electrical stimulation of the posterior hypothalamus elicited greater increases in mean arterial pressure, iliac vascular resistance, mesenteric vascular resistance, and lumbar sympathetic nerve activity than in sham-operated baroreceptor-intact animals. Similarly, the pressor effects of intravenous norepinephrine were also augmented in the baroreceptor-denervated group compared with the baroreceptor-intact group. When posterior hypothalamic and intravenous norepinephrine pressor stimuli, which produced equivalent pressor responses in sham-operated baroreceptor-intact animals, were compared in baroreceptor-denervated animals, the pressor effects of the central hypothalamic stimulus were enhanced to a greater degree than the norepinephrine pressor effects. These data provide evidence that arterial baroreceptor reflexes exert greater buffering of pressor stimuli initiated from the central nervous system compared with pressor responses due to peripheral vascular vasoconstrictor agents.