Site(s) mediating sympathetic activation with desflurane.

BACKGROUND: Three strategies were employed to better define the afferent site(s) at which desflurane initiates its neurocirculatory activation. METHODS: Young (aged 19-28 yr) healthy volunteers were employed in three separate studies. Monitoring included electrocardiography, radial artery blood pressure, and direct recordings of sympathetic outflow to skeletal muscle blood vessels by microneurography. In each study, anesthesia was established with 2.5 mg/kg propofol, and in studies 1 and 2 was maintained with 5.4% desflurane via a double-lumen tube. In study 1 (n = 7) a double-lumen tube was placed with the bronchial cuff just below the vocal cords to selectively give 14.5% desflurane or 2.4% isoflurane to the upper airway (via the tracheal lumen) or lower airway (via the bronchial lumen). Study 2 (n = 14) consisted of standard placement of a left side double-lumen tube to selectively increase the inspired desflurane concentration of either right or left lung to 11% while decreasing the inspired concentration in the opposite lung to 0%, thereby maintaining constant systemic concentrations of desflurane (gas chromatography). Study 3 consisted of lidocaine or placebo airway treatment before anesthetic induction and administration of 11% inspired desflurane by mask: group A-n = 9, topical and nebulized lidocaine, glossopharyngeal and superior laryngeal nerve blocks, and transtracheal administration of lidocaine; group B-n = 7, similar treatment as group A with placebo (saline); and group C-n = 8, systemic infusions of 2% lidocaine to match plasma concentrations of lidocaine in group A. RESULTS: In study 1, significant increases in heart rate, mean arterial pressure, and sympathetic neural activity (26%, 23%, and 62%, respectively) occurred when desflurane was directed to the upper airway. These responses were approximately twofold to sixfold larger when desflurane was given to the lower airway (lungs). There were no significant increases in these variables when isoflurane was administered to the upper airways, and a significant increase in heart rate occurred only when isoflurane was delivered to the lower airways. In study 2, separate right or left lung increases in desflurane did not change the blood concentration of desflurane or sympathetic neural activity but led to significant increases in heart rate (44%) and mean arterial pressure (32%). The simultaneous administration of desflurane to both lungs increased the millimolar (mM) concentration of desflurane in the blood from 1.17 to 2.39 mM and led to increases in sympathetic neural activity (750%), heart rate (90%), and mean arterial pressure (63%). In study 3, neither regional nor systemic administration of lidocaine reduced the significant neurocirculatory activation caused by the rapid increase in the inspired concentration of desflurane by mask. CONCLUSIONS: There are sites in the upper airway (larynx and above) that respond with sympathetic activation during rapid increases in desflurane concentration independent of systemic anesthetic changes. These responses, while lesser than those seen with rapid increases to the lung, may represent direct irritation of airway mucosa. Heart rate and mean arterial pressure responses to desflurane can be initiated by selectively increasing concentrations to either right or left lung without altering systemic levels of desflurane. From this it is inferred that there are sites within the lungs, separate from systemic sites, that mediate this response. Neither systemic lidocaine nor attempted blockade of upper airway sites with cranial nerve blocks combined with topical lidocaine was effective in attenuating the neurocirculatory activation associated with desflurane.

Muscle chemoreflex causes renal vascular constriction.

The purpose of this study was to investigate the effects of the muscle chemoreflex on vascular conductance in innervated and denervated kidneys. During each experiment, six dogs ran at 10 km/h for 8-16 min, and the muscle chemoreflex was stimulated by reducing hindlimb blood flow (HLBF) (0%-74%) at 4-min intervals. Small reductions in HLBF did not cause changes in arterial blood pressure or renal vascular conductance. However, further reductions of HLBF caused increases in arterial blood pressure and decreases in renal vascular conductance. Decreases in renal vascular conductance occurred in the denervated kidneys when the HLBF was reduced below 1,500 +/- 215 ml/min and occurred in the innervated kidneys when HLBF was reduced below 1,402 +/- 161 ml/min. There was not a significant difference between the reductions in HLBF required to cause a decrease in vascular conductance in the innervated and denervated kidneys. These results demonstrate that reductions in HLBF cause decreases in renal vascular conductance, which are not dependent on renal sympathetic nerve activity.

Phenyl biguanide does not inhibit locomotion in conscious rabbits.

Stimulation of cardiopulmonary vagal C fibers with phenyl biguanide (PBG) reflexly inhibits locomotion in addition to causing depression of blood pressure (BP), heart rate (HR), and respiration in cats and rats. We investigated whether PBG caused somatomotor inhibition during exercise in the rabbit, a species in which it is known that the hemodynamic and respiratory responses to PBG are mediated by cardiac rather than by pulmonary receptors. In eight New Zealand White rabbits, BP, HR, and hindlimb electromyographic (EMG) responses to 60 and 120 micrograms/kg PBG and saline vehicle were evaluated during two separate 3-min exercise bouts at 10 m/min at 0% grade. During exercise, 60 micrograms/kg PBG decreased BP (-27 +/- 4 mmHg) and HR (-95 +/- 16 beats/min) but did not inhibit locomotion as suggested by the EMG response (+112 +/- 8% of preinfusion EMG). Hemodynamic and EMG responses to 120 micrograms/kg PBG were similar to 60 micrograms/kg PBG. Saline infusion during exercise had no effect on HR, BP, or locomotion (+114 +/- 8% of preinfusion EMG). Locomotion is not inhibited by PBG in rabbits, which suggests that PBG-induced reflex somatomotor inhibition observed in other species is primarily mediated by pulmonary rather than by cardiac receptors.

Renal sympathetic and heart rate baroreflex function in conscious and isoflurane anaesthetized normotensive and chronically hypertensive rabbits.

1. Baroreflex control of heart rate (HR) has been studied in normotensive (NT) and hypertensive (HT) awake and anaesthetized animals and man, but baroreflex control of sympathetic nerve activity has not been well studied. We investigated baroreflex control of HR and renal sympathetic nerve activity (RSNA) over a wide range of arterial pressure (AP) in conscious and isoflurane (ISO) anaesthetized NT and HT rabbits. 2. Animals were instrumented to record AP, HR and RSNA. Hypertension was accomplished by renal encapsulation. AP-HR and AP-RSNA baroreflex function curves were obtained while awake and after 1.0, 1.5, 2.0 and 2.5% ISO. All baroreflex curves were fit to sigmoid or exponential functions. 3. In conscious rabbits, HT for 3-5 weeks, AP was significantly higher (75.6 +/- 0.8 vs 102.3 +/- 8.9 mmHg); HR significantly lower (218.0 +/- 5.5 vs 189.5 +/- 5.5 beats/min); and RSNA not different than NT rabbits (14.9 +/- 2.2 vs 9.9 +/- 3.2% max RSNA). 4. ISO shifted AP-HR and AP-RSNA baroreflex curves to the left in NT and HT animals, and significantly attenuated baroreflex range and slope. At low ISO concentrations, baroreflex compensation for decreases in AP is limited to small increases in HR and sympathetic nerve activity. At higher ISO concentrations, baroreflex responses to decreases in AP are lost. RSNA responses to increases in AP are preserved with increasing ISO concentrations while HR responses are progressively attenuated. The sole effect of chronic hypertension was to shift the AP-HR and AP-RSNA barocurves to the right along the pressure axis in both conscious and ISO anaesthetized animals with no additional change in range or slope. 5. At this stage of hypertension development, ISO anaesthesia affects baroreflex function equally in normotensive and hypertensive rabbits.

Effects of pulmonary denervation on renal sympathetic and heart rate responses to hypoxia.

We hypothesized that the renal sympathetic nerve activity (RSNA) response to hypoxia is attenuated because of stimulation of pulmonary receptors by the increase in ventilation. RSNA was measured during 20 min of severe hypoxia (8% O2) in conscious New Zealand White rabbits with intact lung innervation and in rabbits with surgical denervation of the lungs (LDX). LDX decreased resting breathing frequency but had no effect on resting mean arterial pressure (MAP), heart rate (HR), or RSNA. In intact rabbits, 4 min of hypoxia resulted in elevated RSNA (from 14 +/- 2 to 29 +/- 3% of smoke-elicited maximum), bradycardia (delta-65 +/- 12 beats/min), and no change in MAP (delta 2 +/- 2 mmHg). Bradycardia diminished with time, but elevated RSNA was maintained throughout the 20-min exposure. LDX enhanced the initial bradycardia (delta-113 +/- 11 beats/min, P < 0.01) but had no effect on the RSNA response (35 +/- 2% of maximum) to hypoxia. LDX did not alter steady-state responses of HR or RSNA, but MAP declined over time (-11 +/- 2 mmHg). These results suggest that in conscious rabbits pulmonary receptors have a minor influence on control of sympathetic activity to viscera during severe hypoxemia.

Muscle chemoreflex alters vascular conductance in nonischemic exercising skeletal muscle.

Previous studies have shown that the muscle chemoreflex causes an augmented blood pressure response to exercise and partially restores blood flow to ischemic muscle. The purpose of this study was to investigate the effects of the muscle chemoreflex on blood flow to nonischemic exercising skeletal muscle. During each experiment, dogs ran at 10 kph for 8-16 min and the muscle chemoreflex was evoked by reducing hindlimb blood flow at 4-min intervals (0-80%). Arterial blood pressure, hindlimb blood flow, forelimb blood flow, and forelimb vascular conductance were averaged over the last minute at each level of occlusion. Stimulation of the muscle chemoreflex caused increases in arterial blood pressure and forelimb blood flow and decreases in forelimb vascular conductance. The decrease in forelimb vascular conductance demonstrates that the muscle chemoreflex causes vasoconstriction in the nonischemic exercising forelimb. Despite the decrease in vascular conductance, the increased driving pressure caused by the pressor response was large enough to produce an increased forelimb blood flow.

Intrapericardial blocking agents have extracardiac effects in dogs.

The purpose of this study was to determine if intrapericardial infusion of hexamethonium, propranolol, or atropine affected extracardiac receptors in anesthetized dogs. Intrapericardial hexamethonium (> or = 25 mg) decreased renal sympathetic nerve activity (RSNA) in a dose-dependent fashion. After 250 mg, RSNA began to decrease in 65 +/- 7 s. Whereas vagal stimulation caused a muscarinic receptor-mediated increase in tracheal smooth muscle tone (as indicated by a 9.6 +/- 1.1 mmHg increase in endotracheal cuff pressure), the increase in cuff pressure (1.8 +/- 0.4 mmHg) was attenuated after intrapericardial tropine (4 mg). When the ansa and vagus were stimulated simultaneously, beta-adrenergic receptor-mediated smooth muscle relaxation opposed the muscarinic receptor-mediated constriction resulting in an increase in cuff pressure of only 3.6 +/- 0.9 mmHg. After intrapericardial propranolol (8 mg), simultaneous ansa and vagal stimulation caused a 7.0 +/- 1.6 mmHg increase in cuff pressure, demonstrating that intrapericardial propranolol blocked beta-adrenergic receptor-mediated relaxation of tracheal smooth muscle. These results show that hexamethonium, atropine, and propranolol infused intrapericardially have extracardiac effects.

Cardiac receptors modulate the renal sympathetic response to dynamic exercise in rabbits.

Activation of cardiac sensory receptors with vagal afferents can result in inhibition of sympathetic outflow to the peripheral circulation. This study investigated whether the regulation of renal sympathetic nerve activity (RSNA) during dynamic exercise was modulated by cardiac sensory receptors. RSNA, blood pressure, and heart rate were measured in seven New Zealand White rabbits during treadmill exercise while cardiac receptors were intact (saline), during cardiac neural block with 2% procaine (2% PCN), and during cardiac efferent receptor block with methscopolamine and atenolol (M + A). Drugs were infused into the pericardial space via a chronic catheter. Two exercise protocols were used: 7 m/min (5 min) and 12 m/min (2 min) at 0% grade. The increases in HR during exercise at 7 and 12 m/min were attenuated with 2% PCN or M + A. At 12 m/min, blood pressure was significantly lower with 2% PCN (76 +/- 4 mmHg) or M + A (76 +/- 3 mmHg) than with saline (86 +/- 2 mmHg). Abolition of cardiac afferent input with 2% PCN resulted in a potentiated RSNA response to exercise at 7 m/min (+134 +/- 37%) and 12 m/min (+234 +/- 45%) relative to saline (+62 +/- 24 and +101 +/- 28%) or M + A (+19 +/- 9 and +52 +/- 19%, P < 0.05). These results suggest that cardiac sensory receptors attenuate sympathetic drive to the kidney during dynamic exercise in conscious rabbits.

Respiratory alterations with intrapericardial procaine in the conscious rabbit.

1. Intrapericardial procaine, used to produce cardiac nerve blockade in both conscious and anaesthetized animals, has been reported to also produce changes in respiration. This study systematically investigated the effects of two doses of intrapericardial procaine on respiration in the conscious rabbit. 2. Rabbits were pre-instrumented with a chronic diaphragm electromyogram (dEMG) recording electrode and intrapericardial catheter. Arterial pressure, heart rate, dEMG and respiratory excursions (recorded with a pneumograph) were monitored in the conscious rabbit before and after intrapericardial and intravenous infusion of 2 and 5% procaine. Efficacy of cardiac nerve blockade was tested by intravenous infusion of phenyl biguanide. Arterial blood gases were determined at rest and during changes in respiration. 3. Following a low dose of intrapericardial procaine (12 mg), dEMG and respiratory excursions increased (65 +/- 13 and 76 +/- 32%, respectively) with no change in breathing frequency or arterial blood gases. Following a high dose of intrapericardial procaine (30 mg), four of six animals exhibited a similar response. However, four of the six rabbits also exhibited a second type of response pattern characterized by a further increase in respiratory efforts (430 +/- 336%), abolition of dEMG, and a mild hypoxaemia. 4. Intravenous infusion of a low dose of procaine was without effect, whereas intravenous infusion of a high dose of procaine produced minor behavioural responses. 5. In four additional anaesthetized rabbits, it was demonstrated that high doses of intrapericardial procaine anaesthetized the phrenic nerve to produce the observed alterations in respiration. 6. We conclude that if intrapericardial procaine is used to block cardiac nerves in conscious rabbits, it should be used in a low concentration and at the lowest possible total dose to avoid complications due to changes in respiration.

Cardiac but not pulmonary receptors mediate depressor response to IV phenyl biguanide in conscious rabbits.

Phenyl biguanide (PBG) stimulates pulmonary and cardiac receptors in the cat and rabbit. Previous reports have suggested that pulmonary receptors mediate the reflex respiratory responses and cardiac receptors mediate the reflex hypotension and bradycardia. Using selective denervation of the lung (LDX) and intrapericardial procaine to block cardiac nerves (CDX), we investigated the specific role of pulmonary and cardiac receptors in the reflex response to PBG infusion (60 micrograms/kg iv) in the conscious rabbit. Breathing frequency, arterial pressure, heart rate, and renal sympathetic nerve activity (RSNA) were recorded before and after LDX and CDX. Before LDX and CDX, PBG infusion produced tachypnea, hypotension, and bradycardia. This was accompanied by a withdrawal of RSNA to a level not different from that evoked by ganglionic blockade. These responses were preserved after LDX but were abolished after CDX with intrapericardial procaine. Intrapericardial infusion of PBG produced no response. These results indicate that in conscious rabbits both the respiratory and cardiovascular responses to PBG infusion are mediated by cardiac receptors not accessible from the epicardial surface. Furthermore, the reflex hypotension is mediated largely by withdrawal of sympathetic nerve activity resulting in a decreased peripheral resistance.

Effect of dynamic exercise on renal sympathetic nerve activity in conscious rabbits.

Renal sympathetic nerve activity (RSNA) increases abruptly at the onset of treadmill exercise in conscious rabbits. This study investigated whether the rise in RSNA is related to the intensity of the exercise and whether an elevated level of RSNA is maintained during submaximal exercise. RSNA, arterial blood pressure (BP), and heart rate (HR) were recorded in 10 New Zealand White rabbits during two treadmill exercise protocols at 0% grade: 7 m/min for 5 min and 12 m/min for 2 min. Peak levels of RSNA were observed in the first 10 s of exercise at 7 and 12 m/min. Through 2 min of exercise, the rise in RSNA was greater (P < 0.05) at 12 m/min (delta 83 +/- 22%) compared with 7 m/min (delta 49 +/- 8%). At 7 m/min, HR and BP reached steady-state levels during the 2nd min of exercise. RSNA remained elevated at delta 43 +/- 10 to delta 54 +/- 13% over resting levels as exercise continued from the 2nd through the 5th min of exercise (P < 0.05). These data demonstrate that the RSNA response to exercise is intensity related and suggest that RSNA remains elevated and thus may contribute to the control of renal blood flow during submaximal dynamic exercise.

Influence of cardiac afferents on time-dependent changes in the renal sympathetic baroreflex of conscious rabbits.

1. The stability of the renal sympathetic baroreflex and nasopharyngeal reflex, and the role of cardiac sensory receptors, was studied in conscious rabbits over a 5 h experimental period. 2. Renal sympathetic nerve activity (SNA) was recorded during (i) slow ramp changes in mean arterial pressure (MAP) of 1-2 mmHg/s induced by inflating perivascular balloon cuffs, and (ii) the inhalation of cigarette smoke. Experiments were repeated in other rabbits after blocking cardiac afferents with 5% intrapericardial procaine. 3. Baroreflex responses to the first two caval cuff inflations of the day were significantly greater than subsequent responses. After this, triplicate sets of reflex curves were relatively stable during a 2 h period in the morning. When the experiment was repeated in the afternoon, there was a significant attenuation of baroreflex range and a small fall in resting renal SNA which were abolished by pericardial procaine. 4. Changes in baroreflex properties were minimal when the reflex was assessed only twice, at the beginning and end of a 5 h period. No change was seen in the nasopharyngeal reflex whether the rabbits had been subjected to few or to many cuff inflations. 5. We conclude that time dependent changes can occur in the renal sympathetic baroreflex of conscious rabbits which must be allowed for by appropriate protocol design. These include increasing inhibitory influences from cardiac sensory receptors in experimental situations requiring multiple reflex estimations.

Cardiac afferents attenuate renal sympathetic baroreceptor reflexes during acute hypertension.

We have studied the effect of acute hypertensive episodes on the renal sympathetic baroreceptor reflex in conscious rabbits and the role played by cardiac afferents and endogenous opiate mechanisms. Renal sympathetic nerve activity was recorded during brief perivascular balloon-induced ramp changes in mean arterial pressure before and during 40-minute elevations in resting pressure. Methoxamine infusion was adjusted to increase pressure by +30 and +45 mm Hg in the presence of autonomic blockade of the heart with atenolol and methscopolamine. Experiments were repeated in other rabbits after blocking cardiac afferents with 5% intrapericardial procaine or during intravenous naloxone (4-6 mg/kg, then 0.12 mg/kg/min). We found a progressively severe attenuation of the renal sympathetic baroreceptor reflex during increasing elevations in resting pressure. The upper plateau and range of the reflex curve were both reduced by one third and two thirds during moderate and severe hypertension, respectively. The average gain fell by 64% and 87%, and the range-independent gain and hypotensive reversal response were also reduced. There was no resetting of the reflex to higher pressures as would be expected. One third of the reflex inhibition was prevented by blocking cardiac afferents; none of it was affected by intravenous naloxone, which had previously been shown to reverse the renal baroreceptor reflex depression elicited by hemorrhagic hypotension. Factors possibly responsible for the remaining two thirds of the hypertension-induced sympathoinhibition are suggested to be either central depression of sympathetic tone after elevation of arterial baroreceptor discharge during the hypertensive episode or additional inhibitory afferent input arising from the pulmonary circulation.

A continuous noncontact method for measuring in situ vascular diameter with a video camera.

A new, continuous, on-line, video diameter-measuring technique, utilizing a video camera mounted on the sidearm of a stereo microscope, is described. Vessel diameter is derived from changes in the video output signal of the camera or a video recorder when the vessel of interest is displayed horizontally on a monitor and well contrasted with its background. A comparator threshold is set on the filtered video output signal and generates an output pulse that is used to gate horizontal video sync pulses to a digital counter-timer. The number of pulses counted for each video field (no. of horizontal video lines) is proportional to the vessel diameter. The video-derived diameter is calibrated using known standards and correlates well with sonomicrometer-derived diameters of the carotid artery and jugular vein during increasing pressure ramps (r greater than 0.999). The diameter update rate is 60 Hz, and the resolution of the system is one horizontal video line, independent of the vessel size. With suitable magnification and contrast both arteries and veins as small as 200 micron have been measured using this system.

Reinnervation of pulmonary stretch receptors.

The Breuer-Hering reflex (BHR) reappears 12-14 wk after surgical lung denervation in beagle dogs (J. Appl. Physiol. 54: 1451-1456, 1983). To demonstrate that this is due to reinnervation of pulmonary stretch receptors, we recorded nerve activity from regenerated branches of the left vagus nerve in five beagle dogs. Ten days postdenervation the BHR was absent, whereas by 19 mo it was clearly present. Multifiber pulmonary afferent activity was observed in all five dogs with single-fiber activity observed in three. Sectioning the right vagus nerve did not alter the BHR, but sectioning all the regenerated branches of the left vagus abolished the reflex. In two additional dogs studied 17 mo postsurgery, recordings were made from few fiber nerve bundles of the left cervical vagus. Nerve activity was increased during gentle stroking of the surface of the left upper and lower lobes, indicating receptive fields in both lobes. These data demonstrate that reinnervation of pulmonary stretch receptors does occur and provides evidence that reinnervation of these receptors is responsible for return of the BHR after pulmonary denervation.

Inotropic responses of the left ventricle to changes in heart rate in anesthetized rabbits.

Factors known to influence left ventricular contractility include preload, afterload, circulating catecholamine concentration, efferent sympathetic discharge, and heart rate. Heart rate influences have been primarily determined in the dog, whereas the influence of heart rate in smaller mammals has not been determined. Eight pentobarbital-anesthetized rabbits were instrumented to measure electrocardiogram, heart rate, left ventricular pressure, end-diastolic pressure, dP/dt, and mean and pulsatile aortic pressures. Systematic bradycardia was induced by stimulating the peripheral end of the sectioned right vagus nerve. Between 293 and 235 beats/min, there was no change in (dP/dt)max as heart rate was decreased. Below this range there was a direct relationship between (dP/dt)max and heart rate. Preload remained unchanged down to 132 beats/min. There was a small but significant decrease in afterload (0.09 mmHg X beat-1 X min-1; 1 mmHg = 133.32 Pa) throughout the decrease in heart rate. Infusion of propranolol (2.0 mg/kg) produced no marked change in the heart rate - (dP/dt)max relationship, although both resting heart rate and (dP/dt)max were reduced. This study demonstrates that (dP/dt)max is not influenced by changes in heart rate above 235 beats/min in the pentobarbital-anesthetized rabbit. These results differ from findings in other animals, and demonstrate that species and heart rate ranges must be considered when drawing conclusions regarding (dP/dt)max as a reliable index of contractility.

Mechanical effects of vasoactive drugs on carotid sinus.

Carotid sinus diameter (CSD) is influenced by changes in sympathetic tone and vasoactive agents. This study was designed to determine which mechanical properties of the carotid sinus region were influenced by infusing vasoconstrictors (epinephrine, 4.56 X 10(-6) M, and phenylephrine, 9.85 X 10(-5) M) and a vasodilator (nitroprusside, 1.68 X 10(-4) M). CSD, carotid sinus length (CSL), pressure (CSP), and compliance (CSC), and arterial pressure were all recorded simultaneously from the isolated constant-flow-perfused carotid sinus region of 11 anesthetized dogs (35 mg/kg pentobarbital sodium) before and after drug perfusion. CSC was measured by a method previously described in which 13 microliters of perfusate is injected into the segment in a step-like manner and the resultant step change in pressure recorded. The compliance of the vessel segment is read on-line after a calibration procedure. CSD and CSL were measured using sonomicrometer length gauges positioned across and along the length of the carotid sinus segment. At a CSP of 99.9 +/- 0.6 (SE) mmHg, CSD, CSL, and CSC were 8.50 +/- 0.44 mm, 9.44 +/- 0.84 mm, and 0.46 +/- 0.05 microliter/mmHg, respectively. Decreasing CSP to 50 mmHg significantly reduced CSD and CSL and increased CSC. Increasing CSP to 150 mmHg produced opposite results. Vasoconstrictor drug infusion significantly decreased and vasodilator drug infusion significantly increased both CSD and CSL, producing parallel shifts in the CSP-CSD and -CSL curves toward and away from the pressure axis. The shift to new pressure-volume curves resulted in no change in CSC in response to the vasoactive agents.