Sinoaortic Baroreceptor-denervated Rats Research Articles

Steady-state and dynamic responses of renal sympathetic nerve activity to air-jet stress in sinoaortic denervated rats.

This study examined the role of arterial baroreceptors in mediating the relationship between changes in the mean level and the amplitude of slow oscillations of renal sympathetic nerve activity (RSNA) during environmental stress. In 7 sham-operated (control) and 7 chronically (2 weeks before study) sinoaortic baroreceptor denervated (SAD) conscious rats, arterial pressure (AP) and RSNA were simultaneously recorded during two 15-minute periods, before and during the application of a mild environmental stressor (jet of air). Air-jet stress induced a similar degree of sympathoexcitation in both groups of rats. During stress in control rats, AP and RSNA spectral power in the mid-frequency (MF) range (0.27 to 0.74 Hz) increased, mainly as a consequence of an amplification of strongly coherent oscillations of approximately 0.4 Hz frequency. In SAD rats, MF fluctuations of AP and RSNA were reduced but not abolished before stress, tended to increase during stress, and were linearly related under both experimental conditions. However, in the MF range, there was no well-defined oscillation at any specific frequency. At the peak coherence frequency ( approximately 0.4 Hz), the gain of the transfer function from RSNA to AP did not change during stress in control rats and was similar to that measured in SAD rats, indicating that it mainly reflected the properties of the feedforward effect of RSNA on AP (ie, vascular reactivity). In summary, the parallelism between stress-induced changes in the mean level of RSNA and the amplitude of slow RSNA oscillations requires the functional integrity of the baroreceptor reflex, which is consistent with the hypothesis that slow AP and RSNA rhythms are resonant oscillations within the baroreceptor reflex loop.

Spontaneous renal blood flow autoregulation curves in conscious sinoaortic baroreceptor-denervated rats.

These experiments examined whether the conscious sinoaortic baroreceptor-denervated (SAD) rat, owing to its high spontaneous arterial pressure (AP) variability, might represent a model for renal blood flow (RBF) autoregulation studies. In eight SAD and six baroreceptor-intact rats, AP and RBF were recorded (1-h periods) before and after furosemide (10 mg/kg followed by 10 mg. kg(-1). h(-1) iv) administration. In control conditions, AP variability was markedly enhanced in SAD rats (coefficient of variation: 16.0 +/- 1.2 vs. 5.4 +/- 0.5% in intact rats), whereas RBF variability was only slightly increased (8.7 +/- 0.6 vs. 6.1 +/- 0.5% in intact rats), suggesting buffering by autoregulatory mechanisms. In SAD rats, but not in intact rats, the AP-RBF relationships could be modeled with a four-parameter sigmoid Weibull equation (r(2) = 0.24 +/- 0.07, 3,600 data pairs/rat), allowing for estimation of an autoregulatory plateau (10.1 +/- 0.7 ml/min) and a lower limit of RBF autoregulation (P(LL) = 93 +/- 6 mmHg, defined as AP at RBF 5% below the plateau). After furosemide treatment, autoregulation curves (r(2) = 0.49 +/- 0.07) in SAD rats were shifted downward (plateau = 8.6 +/- 0.8 ml/min) and rightward (P(LL) = 102 +/- 5 mmHg). In five of six intact rats, P(LL) became measurable (104 +/- 1 mmHg), albeit with limited accuracy (r(2) = 0.09 +/- 0.03). In conclusion, the conscious SAD rat offers the possibility of describing RBF autoregulation curves under dynamic, unforced conditions. The tubuloglomerular feedback and myogenic mechanisms cooperate in setting P(LL) and thus in stabilizing RBF during spontaneous depressor episodes.

Frequency response of renal sympathetic nervous activity to aortic depressor nerve stimulation in the anaesthetized rat.

1. The contribution of central baroreceptor reflex pathways to the dynamic regulation of sympathetic nervous activity (SNA) has not been properly examined thus far. The aim of this study was to characterize the transfer function of the central arc of the baroreceptor reflex (from baroreceptor afferent activity to SNA) over a wide range of frequencies. 2. In nine baroreceptor-intact and six sino-aortic baroreceptor-denervated rats anaesthetized with urethane, the renal SNA was recorded while applying sinusoidal stimulation to the aortic depressor nerve at 26 discrete frequencies ranging from 0.03 to 20 Hz. At each modulation frequency, cross-power spectrum analysis using a fast Fourier transform algorithm was performed between the stimulation and renal SNA, which provided the transfer function of the central arc. 3. In both baroreceptor intact and denervated rats, the transfer gain increased by a factor of about three between 0.03 and 1 Hz. At higher frequencies, the gain decreased but remained above the static gain of the system up to 12 Hz. There was a slight phase lead up to 0.4 Hz, then a continuously increasing phase lag. A three-element linear model satisfactorily described the experimental transfer function. The model combined a derivative gain (corner frequency approximately 0.15 Hz), an overdamped second-order low-pass filter (natural frequency approximately 1 Hz) and a fixed time delay (approximately 100 ms). 4. These results indicate that the central arc of the baroreceptor reflex shows derivative properties that are essential for compensating the filtering of fast oscillations of baroreceptor afferent activity and thus for the generation of fast oscillations of renal SNA (e.g. those related to the cardiac cycle).

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.

Role of nitrosyl factors in the hemodynamic adjustments to heat stress in the rat.

The present study examined the mechanisms responsible for the hindlimb vasodilation produced by elevating core body (colonic) temperature (Tco) of alpha-chloralose-anesthetized rats from 37 to 39 degrees C. Elevating Tco to 39 degrees C produced equivalent decreases in hindlimb vascular resistance in sham-operated (-48 +/- 2%) and sinoaortic baroreceptor-denervated rats (-44 +/- 3%) rats. There were no changes in mean arterial blood pressure, heart rate, or lumbar sympathetic nerve activity in either group. The prior administration of the alpha 1-adrenoceptor antagonist prazosin (100 micrograms/kg i.v.) did not prevent the heat-induced decrease in hindlimb resistance in sham-operated rats (-52 +/- 7% vs. baseline). In contrast, the fall in hindlimb resistance was markedly attenuated (-20 +/- 5% vs. baseline) in sham-operated rats that had received a prior injection of the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (100 mumol/kg i.v.). Dexamethasone (1 mg/kg i.v.), administered to prevent the possible induction of inducible NOS, did not modify the heat-induced hindlimb vasodilation in sham-operated rats (-41 +/- 5%). These results demonstrate that the elevation of Tco to 39 degrees C in alpha-chloralose-anesthetized rats produces a relative vasodilation in the hindlimb that is not obviously linked to an alteration in lumbar sympathetic nerve activity. Because the vasodilation occurred in the presence of prazosin, it is unlikely that the decline in resistance is due to the loss of the vasoconstrictor potency of neurally derived catecholamines. The findings that NG-nitro-L-arginine methyl ester, but not dexamethasone, diminished the heat-induced hindlimb vasodilation suggests that the fall in resistance is due in part to constitutive NOS and supports a role for NOS as a mediator of thermoregulatory active vasodilation.

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.

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.

Cardiovascular effects of the N-methyl-D-aspartate receptor antagonist MK-801 in conscious rats.

Evidence from microinjection studies in anesthetized rats suggests that central excitatory amino acid pathways using N-methyl-D-aspartate receptors are involved in the regulation of the cardiovascular system. To test the hypothesis that these pathways are tonically involved in the maintenance of or the baroreceptor reflex regulation of cardiovascular function, we have examined the effects of intravenous injection of the centrally acting, noncompetitive N-methyl-D-aspartate receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801), on the mean arterial pressure, heart rate, renal sympathetic nerve activity, and behavior of conscious, freely moving sham-operated and sinoaortic baroreceptor-denervated rats. Administration of MK-801 produced, within 5 minutes, dose-dependent elevations in mean arterial pressure, heart rate, and renal sympathetic nerve activity that were sustained for 0.5 to 2.5 hours. For an equivalent dose, MK-801 produced approximately twice the peak changes in mean arterial pressure and heart rate in the sinoaortic baroreceptor-denervated rats than in the sham-operated rats. Pretreatment results were as follows: 1) The ganglion blocker chlorisondamine markedly attenuated the hypertension and tachycardia in the sham-operated and sinoaortic baroreceptor-denervated rats, 2) pretreatment with the alpha 1-adrenergic receptor antagonist prazosin virtually abolished the hypertension, and 3) the beta 1-adrenergic receptor antagonist atenolol markedly reduced the tachycardia. MK-801 also produced stereotypic behaviors and ataxia in the sham-operated and sinoaortic baroreceptor-denervated rats; however, qualitatively and quantitatively similar changes in behavior were induced in the latter by doses approximately five time lower than required in sham operated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison between the cardiovascular effects of 8‐hydroxy‐2‐(di‐n‐propylamino) tetralin (8‐OH‐DPAT) and clonidine in the conscious sino‐aortic denervated rat

1. The purpose of this study was to investigate the role of an intact baroreceptor reflex mechanism in the expression of the cardiovascular response to 8-OH-DPAT and to determine whether there are any differences between the activation of central alpha 2-adrenoreceptors and 5-HT1A receptors in this respect. To this end, the effects of 8-OH-DPAT and clonidine have been assessed on blood pressure, heart rate, ECG and cardiac contractility indices in conscious sino-aortic baroreceptor denervated (SAD) rats and their sham-operated controls. 2. In both sham-operated and SAD rats, intravenous (i.v.) administration of 8-OH-DPAT (32 micrograms kg-1) and clonidine (8 micrograms kg-1) produced falls in systemic blood pressure, left ventricular systolic pressure and dP/dtmax. 3. 8-OH-DPAT produced similar bradycardia in each group of rats; in contrast, clonidine had a greater effect in the SAD animals. Increases of the PQ interval mirrored the heart-rate changes with both compounds. 4. No significant changes in end diastolic blood pressure or in the myocardial contractility indices dP/dtmax/P and Vmax were evident. 5. This study provides support for the view that i.v. 8-OH-DPAT lowers blood pressure and heart rate through a central mechanism. The effects occur independently of an intact baroreceptor reflex and are not associated with effects on myocardial contractility. 8-OH-DPAT shows close qualitative similarities to clonidine in this model.

Effects of verapamil on blood pressure and heart rate in neurogenic hypertensive rats

The effects of verapamil (220 μg/kg per min i.v.) on blood pressure and heart rate were studied in sinoaortic baroreceptor denervated and sham-operated rats. In the conscious animals the verapamil-induced hypotension was accompanied by a significant heart rate increase in the first group (from 52 ± 7 to 422 ± 10 beats/min) and a decrease in the second group (from 485 ± 13 to 400 ± 9 beats/min). The verapamil-induced tachycardia observed in sham-operated rats was prevented by atropine plus propranolol but not by adrenal demedullation. Tachycardia was present in urethane-anesthetized sham-operated rats, similar to the sinoaortic baroceptor-denervated rats. After verapamil a significant heart rate reduction was observed in sham-operated but not in sinoaortic baroreceptor-denervated rats. The results in conscious rats suggest that the direct inhibitory action of this drug on sinus node automaticity is suppressed by baroreflex tachycardia and that anesthesi masks this response.