Sympathetic Nerve Activity In Rabbits Research Articles

Reduced preprandial dipping accounts for rapid elevation of blood pressure and renal sympathetic nerve activity in rabbits fed a high-fat diet

Consumption of a high-fat diet (HFD) by rabbits results in increased blood pressure (BP), heart rate (HR), and renal sympathetic nerve activity (RSNA) within 1 wk. Here, we determined how early this activation occurred and whether it was related to changes in cardiovascular and neural 24-h rhythms. Rabbits were meal-fed a HFD for 3 wks, then a normal-fat diet (NFD) for 1 wk. BP, HR, and RSNA were measured daily in the home cage via implanted telemeters. Baseline BP, HR, and RSNA over 24 h were 71 ± 1 mm Hg, 205 ± 4 beats/min and 7 ± 1 normalized units (nu). The 24-h pattern was entrained to the feeding cycle and values increased from preprandial minimum to postprandial maximum by 4 ± 1 mm Hg, 51 ± 6 beats/min, and 1.6 ± .6 nu each day. Feeding of a HFD markedly diminished the preprandial dip after 2 d (79–125% of control; p < 0.05) and this reduction lasted for 3 wks of HFD. Twenty-four-hour BP, HR, and RSNA concurrently increased by 2%, 18%, and 22%, respectively. Loss of preprandial dipping accounted for all of the BP increase and 50% of the RSNA increase over 3 wks and the 24-h rhythm became entrained to the light-dark cycle. Resumption of a NFD did not alter the BP preprandial dip. Thus, elevated BP induced by a HFD and mediated by increased sympathetic nerve activity results from a reduction in preprandial dipping, from the first day. Increased calories, glucose, insulin, and leptin may account for early changes, whereas long-term loss of dipping may be related to increased sensitivity of sympathetic pathways. (Author correspondence: geoff.head@baker.edu.au)

Hemodynamic Profile in Rabbits of Fospropofol Disodium Injection Relative to Propofol Emulsion Following Rapid Bolus Injection

The effects of aqueous fospropofol disodium (FP) and propofol emulsion (PE) on hemodynamics and sympathetic nerve activity in rabbits following bolus injection were evaluated. Barodenervated and neuraxis-intact rabbits received PE at 4 mg/kg (PE(4)) or FP equal to 4 or 8 mg/kg propofol equivalents (FP(4) and FP(8), respectively) intravenously as a rapid bolus injection, and mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were recorded for 20 min. The plasma propofol pharmacokinetic behavior from FP and PE was evaluated to support the pharmacodynamic observations. In barodenervated animals, MAP and RSNA decreased significantly in all groups (PE(4) > FP(8) > FP(4)). HR decreased only in the PE(4) group. The time for the maximum reduction of MAP was significantly longer with FP(8) compared with PE(4). MAP decreased, and RSNA and HR increased significantly in the neuraxis-intact animals (PE(4) > FP(8) > FP(4)). The time for maximum reduction of MAP was essentially the same in all neuraxis-intact groups. Plasma propofol levels from FP were lower than those from PE in the first 4 min following administration. The results suggest that the tachycardia observed in humans following injection of FP is not a direct physiological effect of the agent.

Exercise training in heart failure: reduction in angiotensin II, sympathetic nerve activity, and baroreflex control

neurohumoral excitation has been considered the hallmark of heart failure. At the humoral level, cardiac dysfunction has been shown to be associated with increased angiotensin II, aldosterone, and vasopressin levels. The clinical implication for such humoral dysregulation is the increase in salt and

Evaluation of mean arterial blood pressure, heart rate, and sympathetic nerve activity in rabbits after administration of two formulations of etomidate

ObjectiveTo evaluate and compare the effects of the aqueous sulfobutyl ether β-cyclodextrin (SBE-CD) etomidate formulation and the commercial etomidate formulation on mean arterial pressure (MAP), heart rate, and sympathetic outflow using neuraxis-intact and baro-denervated rabbits. Study designProspective experimental study. AnimalsTwenty-seven male New Zealand white rabbits. MethodsUnder basal anesthesia (urethane) and ventilation with intermittent positive pressure (IPPV), the New Zealand white rabbits underwent surgical preparation including isolation of the left renal sympathetic nerve and, in the baro-denervated models, additional combined denervation of bilateral carotid sinus, aortic, and vagal nerves. After hemodynamic stabilization, both neuraxis-intact and baro-denervated animals received bolus intravenous (IV) injection (0.6 mg kg−1) of either the SBE-CD or commercial etomidate formulation over 5 seconds (n = 6 animals per group). ResultsMean arterial pressure decreased significantly in all four groups to the same extent. However, the rate of MAP decrease was lower in the SBE-CD-treated groups relative to the commercial formulation. Renal sympathetic nerve activity was decreased significantly less in the SBE-CD group in the baro-denervated studies. Independent pharmacokinetic evaluation demonstrated that the two formulations had comparable plasma concentration–time profiles. Conclusions and Clinical relevanceEtomidate in the commercial drug product is solubilized with propylene glycol, a cosolvent associated with adverse side effects on injection. An aqueous formulation of etomidate has been developed, which utilizes SBE-CD as a solubilizing agent. The data suggest that the SBE-CD etomidate formulation may be a safer IV induction formulation than the commercial etomidate drug product.

Cilnidipine, a N+L-type dihydropyridine ca channel blocker, suppresses the occurrence of ventricular premature arrythmia during ischemia and reperfusion in rabbits

Background: Ca channel blockers are widely prescribed for the treatment of hypertension and coronary artery diseases. However, it is still unknown whether dihydropyridine Ca channel blockers are protective against arrythmias. We investigated whether cilnidipine, a N+L-type Ca channel blocker reduces the incidence of ventricular premature arrythmia during ischemia and reperfusion. Methods and Results: Forty Japanese white rabbits underwent 30 min ischemia and 30 min reperfusion. Cilnidipine (0.5 or 1.0 microgram/kg/min, i.v.), nifedipine (3.0 microgram/kg/min, i.v.) or saline was continuously during ischemia and reperfusion. Electrocardiogram and blood pressure were monitored and the incidences of ventricular premature beats (VPBs) during ischemia and reperfusion were measured. In other 21 rabbits, myocardial interstitial noradrenaline levels were determined before, during and after 30 min of ischemia with cilnidipine (1.0 microgram/kg/min, n = 7), nifedipine (3.0 microgram/kg/min, n = 7) or saline (n = 7) using a microdialysis technique. The incidences of VPBs during ischemia and during reperfusion were significantly attenuated in the cilnidipine 0.5 and 1.0 groups but not in the nifedipine group compared to the control group. Myocardial interstitial noradrenaline levels were significantly reduced in the cilnidipine 1.0 group but not in the nifedipine group compared to the control. Conclusion: Cilnidipine but not nifedipine attenuates the incidence of ventricular premature beats during ischemia and reperfusion and this effect may be related to decreased cardiac sympathetic nerve activity in rabbits.

Method for in vivo calibration of renal sympathetic nerve activity in rabbits

A major difficulty of recording from peripheral sympathetic nerves is that microvolt values reflect characteristics of the recording conditions and limit comparisons between different experimental groups. In this study we assessed methods of calibrating renal sympathetic nerve activity (RSNA) in conscious rabbits. Calibration values were obtained from maximum RSNA responses to nasopharyngeal stimulation, airjet stress or unloading baroreceptors. Curves relating RSNA to blood pressure were produced by raising and lowering blood pressure with vasoactive drugs. To assess whether normalization would eliminate differences between RSNA curves which were most likely due to recording conditions, rabbits were first divided into two groups with high or low basal microvolt levels of RSNA, then again into two groups with high or low heart rate. In both cases, curves were similar if values were normalized by nasopharyngeal stimulation or by the upper plateau value. In hypertensive rabbits, where the baroreflex is suppressed, only the nasopharyngeal method showed this attenuated pattern. This method also eliminated the 50% decay in basal RSNA measured over 5 weeks. We conclude that expressing RSNA in terms of the maximum response to nasopharyngeal stimulation provides a calibration method suitable for comparing nerve activity over the long term as well as showing valid differences in baroreflex curves between different experimental groups.

Chronic endothelin-1 blockade reduces sympathetic nerve activity in rabbits with heart failure.

Endothelin-1 (ET-1) is elevated in chronic heart failure (CHF). In this study, we determined the effects of chronic ET-1 blockade on renal sympathetic nerve activity (RSNA) in conscious rabbits with pacing-induced CHF. Rabbits were chronically paced at 320--340 beats/min for 3--4 wk until clinical and hemodynamic signs of CHF were present. Resting RSNA and arterial baroreflex control of RSNA were determined. Responses were determined before and after the ET-1 antagonist L-754,142 (a combined ET(A) and ET(B) receptor antagonist, n = 5) was administered by osmotic minipump infusion (0.5 mg. kg(-1) x h(-1) for 48 h). In addition, five rabbits with CHF were treated with the specific ET(A) receptor antagonist BQ-123. Baseline RSNA (expressed as a percentage of the maximum nerve activity during sodium nitroprusside infusion) was significantly higher (58.3 +/- 4.9 vs. 27.0 +/- 1.0, P < 0.001), whereas baroreflex sensitivity was significantly lower in rabbits with CHF compared with control (3.09 +/- 0.19 vs. 6.04 +/- 0.73, P < 0.001). L-754,142 caused a time-dependent reduction in arterial pressure and RSNA in rabbits with CHF. In addition, BQ-123 caused a reduction in resting RSNA. For both compounds, RSNA returned to near control levels 24 h after removal of the minipump. These data suggest that ET-1 contributes to sympathoexcitation in the CHF state. Enhancement of arterial baroreflex sensitivity may further contribute to sympathoinhibition after ET-1 blockade in heart failure.

The Regulation of Sympathetic Outflow in Heart Failure

Sympatho-excitation is a hallmark of the chronic heart failure (CHF) state. It has long been assumed that this sympatho-excitation is mediated by a reduction in sensory input from cardiopulmonary and arterial baroreceptors. However, recent data suggest that these reflexes may only be important in the initiation of the sympatho-excitatory state and may not be necessary for the sustained increase in sympathetic nerve activity (SNA) in CHF. Two humoral factors that can influence SNA are nitric oxide (NO) and angiotensin II (AngII). Animals with CHF exhibit a downregulation in central gene expression for the neuronal isoform of nitric oxide synthase (nNOS). In addition, blockade of AngII receptors in combination with NO donation reduces SNA in animals with CHF, while NO donation alone has no effect on SNA. Chronic exercise training (EX) reduces both plasma AngII and SNA in rabbits with CHF while improving baroreflex function. Blockade of AT1 receptors enhances baroreflex function in non-EX CHF rabbits, but has little effect in EX CHF rabbits. These data suggest that the sympatho-excitatory state that is typical of CHF is, in part, due to changes in AngII and NO. Depressed baroreflex function and the elevated SNA can be improved by EX in animals with CHF.

Effects of nonpulsatile left heart bypass on renal sympathetic nerve activity in rabbits.

To determine the effects of nonpulsatile left heart bypass (LHB) on sympathetic nerve activity the renal sympathetic nerve activity (RSNA) was directly measured in rabbits. In anaesthetized rabbits (n=6), LHB was instituted with a centrifugal pump. Before and during LHB, heart rate (HR), arterial pressure (AP), central venous pressure (CVP), left atrial pressure (LAP) and spike counts of RSNA were measured. After bilateral vagotomy (section of the afferent inputs of the cardiac reflex arc) the same parameters were measured before and during LHB. Data were obtained at the same level of mean AP before and during LHB. Mean AP and CVP were not changed by LHB before and after vagotomy. LAP was significantly decreased by LHB before and after vagotomy. RSNA and HR were not significantly changed by LHB before and after vagotomy. Our results clarify the complex baroreflex control during nonpulsatile LHB and indicate that RSNA is not altered by LHB.

Chronic exercise reduces sympathetic nerve activity in rabbits with pacing-induced heart failure: A role for angiotensin II.

Chronic exercise (EX) improves the quality of life and increases the survival of patients with chronic heart failure (CHF). Because sympathetic nerve activity is elevated in the CHF state, it is possible that EX is beneficial in this disease due to a decrease in sympathetic outflow. We evaluated arterial baroreflex function and resting renal sympathetic nerve activity (RSNA) in EX normal and CHF rabbits before and after angiotensin II type 1 (AT(1)) receptor blockade. Four groups of rabbits were studied: a normal non-EX group, a normal EX group, a CHF non-EX group, and a CHF EX group. EX lowered resting RSNA in rabbits with CHF but not in normal rabbits. In addition, EX increased arterial baroreflex sensitivity in the CHF group (heart rate slope: CHF 1. 7+/-0.3 bpm/mm Hg, EX CHF 4.9+/-0.3 bpm/mm Hg; P:<0.01; RSNA slope: CHF 2.2+/-0.2%max/mm Hg, EX CHF 5.7+/-0.4%max/mm Hg; P:<0.01. AT(1) receptor blockade enhanced baroreflex sensitivity in the non-EX CHF rabbits but had no effect in EX CHF rabbits. Concomitant with this effect, EX lowered the elevated plasma angiotensin II concentration in the CHF group. A significant positive correlation was observed between sympathetic nerve activity and plasma angiotensin II. These data strongly suggest that EX reduces the sympathoexcitatory state in the setting of CHF. Enhanced arterial baroreflex sensitivity may contribute to this reduction. In addition, EX lowers plasma angiotensin II concentration in CHF. These data further suggest that the lowering of angiotensin II may contribute to the decrease in sympathetic nerve activity after EX in the CHF state.

Effects of Epidural Ketamine on Blood Pressure and Renal Sympathetic Nerve Activity in Rabbits

The aim of this study was to evaluate the effects of epidural ketamine, an N-methyl-D-aspartic acid (NMDA) antagonist, on haemodynamic responses and renal sympathetic nerve activity (RSNA). Mean arterial blood pressure (MAP), heart rate (HR), RSNA, and integrated RSNA (IRSNA) were recorded in anaesthetized and artificially-ventilated Japanese white rabbits. Epidural ketamine (2 mg kg−1), decreased MAP and IRSNA (P < 0.05), and increased HR (P < 0.05) in intact rabbits (n = 6). Epidural MK-801 (0.024 mg kg−1), another NMDA-receptor antagonist, increased IRSNA, but did not significantly change HR or MAP (n = 6). Pretreatment with epidural naloxone (0.2 mg) did not affect the changes of MAP, HR, and IRSNA induced by ketamine (n = 4), suggesting that opiate receptors were not involved. In sino-aortic denervated rabbits (n = 6), epidural ketamine decreased MAP and IRSNA, but did not significantly change HR, indicating that the ketamine-induced increase in HR occurred via a baroreflex in the neuraxis-intact rabbits. These results indicate that the effects of epidural ketamine on MAP, HR, and RSNA are different from those of MK-801, and suggest that the decrease in sympathetic nerve outflow induced by epidural ketamine is not mediated by NMDA receptors.

Role of endogenous nitric oxide in the brain stem on the rapid adaptation of baroreflex.

It has been shown that nitric oxide in the brain stem plays an important role in the control of sympathetic nerve activity. We examined the role of endogenous nitric oxide in the brain stem in the rapid central adaptation of baroreflex control of sympathetic nerve activity in anesthetized rabbits. Bilateral carotid sinuses were isolated, and a stepwise increase in pressure of 25 or 50 mm Hg for 50 to 60 seconds was applied to the carotid sinuses while the arterial pressure and renal sympathetic nerve activity were recorded. The renal sympathetic nerve activity was inhibited by the stepwise increase in carotid sinus pressure, but thereafter it gradually returned toward the baseline level despite the fact that carotid sinus pressure was kept constant. This procedure was performed after intracisternal injection of N(omega)-nitro-L-arginine methyl ester (L-NAME, 8 micromol), N(omega)-nitro-D-arginine methyl ester (D-NAME, 8 micromol), L-arginine (40 micromol), or the vehicle solution. The magnitude of the immediate and maximal inhibition of renal sympathetic nerve activity caused by a stepwise increase in carotid sinus pressure was similar between the vehicle and L-NAME treatment, but the rate of recovery of the renal sympathetic nerve activity after immediate inhibition was faster after L-NAME than after vehicle. L-Arginine reversed the effects of L-NAME. However, D-NAME or L-arginine alone had no such effects on the rate of recovery of the nerve activity. These results thus suggest that endogenous nitric oxide in the brain stem attenuates rapid adaptation of the arterial baroreflex control of the sympathetic nerve activity in rabbits.

Effects of hypothermia during cardiopulmonary bypass and circulatory arrest on sympathetic nerve activity in rabbits.

Little is known about the effect of hypothermia on neural regulation. We investigated the effects of hypothermia during cardiopulmonary bypass (CPB) on control of renal (RSNA) and lumbar sympathetic nerve activity (LSNA), and plasma catecholamine levels. We directly measured RSNA (n = 14) and LSNA (n = 6) during CPB in anesthetized rabbits. CPB was performed via cannulae in the aortic root for arterial perfusion and the right atrium for venous drainage. Systemic hypothermia was induced by core cooling. RSNA and LSNA were recorded at the nasopharyngeal temperature of 37, 30, 24, and 18 degrees C and after rewarming up to 37 degrees C while keeping mean arterial pressure at 70 mmHg by altering perfusion flow. Other variables such as blood gases or electrolytes were kept constant. RSNA at the temperature of 30, 24, and 18 degrees C significantly decreased by 91, 97, and 95% from control (37 degrees C), respectively. LSNA decreased by 18, 57, and 89% from control as well. The decreases in RSNA at 30 and 24 degrees C were greater than those in LSNA (P < 0.05). At 18 degrees C both RSNA and LSNA nearly disappeared. Circulatory arrest for 20 min during hypothermia at 18 degrees C caused no increase in RSNA while it increased LSNA. Plasma catecholamine levels at 18 degrees C were not different from those at 37 degrees C. Rewarming to 37 degrees C increased RSNA and LSNA by 321 and 92% from control (37 degrees C before cooling), respectively (P < 0.01). Hypothermia progressively decreased and rewarming markedly increased sympathetic nerve activity, but the effects of hypothermia on RSNA and LSNA were not uniform.

Effects of hypothermia during cardiopulmonary bypass and circulatory arrest on sympathetic nerve activity in rabbits

Little is known about the effect of hypothermia on neural regulation. We investigated the effects of hypothermia during cardiopulmonary bypass (CPB) on control of renal (RSNA) and lumbar sympathetic nerve activity (LSNA), and plasma catecholamine levels. We directly measured RSNA (n = 14) and LSNA (n = 6) during CPB in anesthetized rabbits. CPB was performed via cannulae in the aortic root for arterial perfusion and the right atrium for venous drainage. Systemic hypothermia was induced by core cooling. RSNA and LSNA were recorded at the nasopharyngeal temperature of 37, 30, 24, and 18 °C and after rewarming up to 37 °C while keeping mean arterial pressure at 70 mmHg by altering perfusion flow. Other variables such as blood gases or electrolytes were kept constant. RSNA at the temperature of 30, 24, and 18 °C significantly decreased by 91, 97, and 95% from control (37 °C), respectively. LSNA decreased by 18, 57, and 89% from control as well. The decreases in RSNA at 30 and 24 °C were greater than those in LSNA (P < 0.05). At 18 °C both RSNA and LSNA nearly disappeared. Circulatory arrest for 20 min during hypothermia at 18 °C caused no increase in RSNA while it increased LSNA. Plasma catecholamine levels at 18 °C were not different from those at 37 °C. Rewarming to 37 °C increased RSNA and LSNA by 321 and 92% from control (37 °C before cooling), respectively (P < 0.01). Hypothermia progressively decreased and rewarming markedly increased sympathetic nerve activity, but the effects of hypothermia on RSNA and LSNA were not uniform.

A Study of the Effects of the Acute Pulmonary Artery Banding on Baroreflex Regulation of Sympathetic Nerve Activity in Rabbits

A Study of the Effects of the Acute Pulmonary Artery Banding on Baroreflex Regulation of Sympathetic Nerve Activity in Rabbits

Effects of CGRP on baroreflex control of heart rate and renal sympathetic nerve activity in rabbits.

We examined the effects of intravenous infusion of calcitonin gene-related peptide (CGRP) and sodium nitroprusside (SNP) on baroreceptor afferent nerve activity, renal sympathetic efferent nerve activity (RSNA), and heart rate in alpha-chloralose-anesthetized rabbits. Baroreceptor afferent nerve activity was measured from aortic nerves during CGRP- and SNP-induced hypotension. Decreases in aortic nerve activity in response to decreases in mean arterial pressure were not different during CGRP and SNP infusion. Progressive infusion of CGRP (12-120 pmol.kg-1.min-1) increased RNSA by 83 +/- 14 (mean +/- SE), 175 +/- 26, 246 +/- 36, and 343 +/- 41%, and heart rate by 8 +/- 2, 24 +/- 3, 37 +/- 4, and 47 +/- 6 beats/min during falls of blood pressure of 5, 10, 15, and 20 mmHg, respectively. These increases in RSNA and heart rate produced by CGRP were significantly greater than those produced by SNP. The alterations in heart rate and RSNA with CGRP were reversed by restoring blood pressure with phenylephrine HCl. In rabbits with sinoaortic and vagal deafferentation, the responses of heart rate and RSNA to a fall of blood pressure were abolished during both CGRP and SNP infusion. Therefore, it is suggested that the facilitated responses of heart rate and RSNA during CGRP infusion occurred by way of the arterial baroreflex arc.

Central nervous system mechanisms involved in inhibition of renal sympathetic nerve activity induced by arginine vasopressin.

Previous studies have suggested that intravenous infusion of arginine vasopressin (AVP) inhibits sympathetic nerve activity (SNA) in rabbits by its action at the brainstem. This study aimed to determine, first, whether this action of AVP depended on functioning baroreflex mechanisms. The second aim was to determine the role of the nucleus tractus solitarii (NTS) in mediating this action of AVP. Experiments were performed in rabbits anesthetized with alpha-chloralose. Intravenous infusions of AVP (1, 3, and 10 mU/kg/min) resulted in progressive inhibition of renal SNA in rabbits with intact arterial baroreceptors and vagal afferents as well as in rabbits with sinoaortic denervation and bilateral vagotomy. The magnitudes of renal SNA inhibition evoked with AVP were comparable in the two groups. Renal SNA inhibition evoked with AVP at doses of 1 and 3 mU/kg/min in rabbits after sinoaortic denervation and vagotomy was totally blocked by chemical lesions with kainic acid of the bilateral NTS or the area postrema. Lesions of the NTS or the area postrema markedly attenuated (by about 60%) but did not totally block the response evoked with AVP at a dose of 10 mU/kg/min. AVP microinjected directly into the NTS did not evoke changes in renal SNA or arterial pressure, whereas AVP microinjected into the area postrema suppressed renal SNA. These results suggest that intravenous AVP at lower doses inhibited renal SNA by causing excitation of the NTS neurons, and this action of AVP did not depend on functioning baroreflex mechanisms. The second suggestion is that the NTS was unlikely to be the site where AVP directly interacted but instead received a neural connection, presumably from the area postrema, where AVP might directly interact.

Inhibitory effects of cerebellar cortical stimulation on sympathetic nerve activity in rabbits.

In anaesthetized and paralyzed rabbits, renal sympathetic nerve activity was observed by integrating and averaging impulse discharges. The activity was readily depressed by stimulation with a train of a few pulses of lobules I, II, III, VIIa, and VIIIa. The effective sites which caused the marked depression on the sympathetic nerve activity were distributed in the ipsilateral vermal cortex, predominantly in the medial part. The latency of depression was around 200 msec. Stimulation of these lobules caused a reduction of the systemic blood pressure, but this effect required stimulation by repetitive pulses, for a period of up to 10 sec.