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Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin 53706
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ABSTRACT |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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We examined the ventilatory effects of exogenous dopamine (DA)
and norepinephrine (NE) administration in chloralose-anesthetized, paralyzed, artificially ventilated adult goats before and after carotid
body denervation (CBD). Intravenous (iv) DA bolus injections and slow
iv infusions caused dose-dependent inhibition of phrenic nerve activity
(PNA) in carotid body (CB)-intact animals during normoxia and hyperoxia
but not during hypercapnia. NE administration in CB-intact goats caused
dose-dependent inhibition of PNA of similar magnitude to DA trials. The
DA D2-receptor agonists
quinelorane and quinpirole inhibited PNA, whereas the DA
D1-receptor agonist SKF-81297 had
no effect. After CBD, the ventilatory depressant effects of DA
persisted, but responses were significantly attenuated compared with
CB-intact trials. CBD abolished the inhibitory effect of low-dose NE
administration but did not alter ventilatory responses to high-dose NE
injection. The peripheral DA
D2-receptor antagonist domperidone
substantially attenuated the inhibitory effects of DA bolus injections
and infusions and reversed the inhibitory ventilatory effect of
high-dose DA administration to excitation in some animals. The
-adrenoceptor antagonist phentolamine had no effect on DA-induced
ventilatory depression. 
-Adrenoceptor stimulation with isoproterenol
produced similar hemodynamic effects to DA administration but had no
effect on PNA. We conclude that DA and NE exert both CB-mediated and
non-CB-mediated inhibitory effects on respiratory motor output in
anesthetized goats. The ventilatory depressant effects that persist in
peripherally chemodenervated animals are DA
D2-receptor mediated, but their
exact location remains speculative.
dopamine; norepinephrine; domperidone; carotid body; phrenic nerve
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INTRODUCTION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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DOPAMINE (DA) is a prominent amine that is found in relatively large quantities in type I cells of the carotid body (CB) of different mammals (8, 16, 21). The role of DA in CB function has been studied extensively. Studies have indicated that DA in the CB acts as a neuromodulator of CB function (6, 21). Much evidence indicates that DA has a modulatory role that is inhibitory to the chemosensory activity of the CB. Thus exogenous administration of DA inhibits CB discharge in cats (7, 14, 17, 23, 30, 35, 36, 46-48), rabbits (15, 17), dogs (5), and goats (3). Consistent with these observations, exogenous DA depresses ventilation in animals (2, 7, 10, 23, 24, 27, 35, 48) and human subjects (44), whereas peripheral DA-receptor blockade stimulates ventilation and CB neural activity (3, 4, 24, 27, 47).
An underlying assumption is that the activity of peripheral dopaminergic mechanisms is principally mediated by the CB and that the inhibition of the chemosensory discharge from the carotid sinus nerve (CSN) accounts for the DA-induced hypoventilation. However, there have been a number of observations that suggest that CB inhibition may not be the only mechanism by which DA can inhibit ventilation. Ventilatory depressant effects of DA persist in hyperoxia (2, 35, 48), which is suggestive of a non-CB effect. Furthermore, ventilatory inhibition has been observed after DA administration in anesthetized CB-denervated (CBD) rats (10), cats (48), and dogs (5) and in awake goats after a CB excision (2). In contrast, however, other studies have demonstrated that CBD abolishes the ventilatory depressant effects of DA (7, 10, 23, 27, 33, 34, 48). Also, it is not clear whether the inhibitory ventilatory effects of DA that persist in CBD animals are mediated through dopaminergic mechanisms.
We have recently obtained direct evidence that DA is inhibitory to the CB of the goat (3), and this finding is consistent with previous reports in our laboratory of a CB-mediated inhibitory effect of DA on ventilation (2, 27). In the present study, we wished to 1) examine whether inhibitory dopaminergic mechanisms are functional in peripherally chemodenervated goats and 2) determine what proportion of the inhibitory ventilatory response to DA is mediated through CB mechanisms. Our data provide evidence for both CB-mediated and non-CB-mediated inhibitory effects of DA on respiratory motor output in anesthetized goats.
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METHODS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Animal Preparation
A total of 16 adult female and castrated male goats [40.7 ± 2.8 (SE) kg body wt] of mixed breed were used in this study. After induction of anesthesia with intravenous (iv) thiopental sodium (15-20 mg/kg) for intubation, animals were placed in dorsal recumbency under a thermostatically controlled heating blanket to maintain normal body temperature (38-40°C). Anesthesia was maintained with-chloralose given iv, with the infusion rate
adjusted (10-15 mg · kg
1 · h1)
to maintain adequate anesthesia and steady-state blood pressure. Femoral arterial and venous catheters were implanted for monitoring systemic arterial blood pressure (ABP) and for drug
administration, respectively. Arterial blood samples were drawn
anaerobically into heparinized syringes and immediately analyzed for
arterial pH, PCO2, and
PO2
(pHa,
PaCO2, and
PaO2, respectively) (Radiometer ABL 3M, Copenhagen, Denmark). Arterial bicarbonate concentration and the base excess were calculated. Corrections were
made for temperature differences between the goat and the blood-gas
analyzer. Sodium bicarbonate (Fujisawa USA, Deerfield, IL) was
administered iv, as necessary to maintain arterial bicarbonate concentration 
23 mM. Intravenous fluid (lactated
Ringer, 100 ml/h, Baxter, Deerfield, IL) was given in an effort to
maintain normal extracellular fluid volume. A bilateral midcervical
vagotomy and superior laryngeal nerve denervation were performed to
eliminate putative inputs from aortic chemoreceptors and superior
laryngeal nerve paraganglia. In preliminary experiments, we observed
that the inhibitory effect of DA on ventilation was unaffected by
vagotomy (CB intact), suggesting that the DA-induced ventilatory
depression was not dependent on the integrity of the aortic
chemoreceptors and/or vagal afferents. The laryngeal nerves
have been shown to contain paraganglia morphologically and
biochemically similar to the CB (12). Although the function of the
paraganglia is unknown, it is speculated that they possess
chemoreceptor properties (13).
A C6 phrenic nerve root was dissected free from surrounding tissue low in the neck, cut distally, and desheathed for neural recording. The nerve was placed on bipolar platinum-hook electrodes and immersed in mineral oil to prevent desiccation. Nerve activity was preamplified 10,000 times (CWE BMA 831, Arlington, PA), filtered (band pass 0.01-5.0 kHz), and further amplified (Tektronix 5A22N, Beaverton, OR). The output was visualized on an oscilloscope (Tektronix 5111) and polygraph chart recorder (Gould TA 2000, Valley View, OH), fed to an audiomonitor (Grass AM 7, Quincy, MA), and recorded on tape by using a modified videocasette recorder (Vetter Digital 3000A and 500I, Rebersburg, PA) for off-line analysis. The amplified signal was rectified and integrated (Gould Integrator 13-4615-70) to obtain a moving average of peak phrenic nerve activity (PNA).
Measurements
Once surgical preparations were completed, the animals were paralyzed with pancuronium bromide (2.0 mg initial dose, then 1.0 mg/h iv) to prevent disruption of the preparation and artificially ventilated (Harvard ventilator). Respiratory frequency was set between 15 and 20 breaths/min and tidal volume between 300 and 500 ml, depending on the size of the animal. Inspired O2 fraction was adjusted to maintain PaO2 above 90 Torr. It was necessary to add CO2 to the inspired gases so that breathing was above the apneic threshold for stable phrenic recording. Arterial blood gases were sampled frequently to ensure maintenance of blood-gas and acid-base homeostasis during artificial ventilation.Protocol
Once the surgery was completed and the preparation stabilized, the apneic threshold for ventilation was determined by lowering the inspired CO2 level until phasic phrenic activity disappeared. PaCO2 was determined at this point, and inspired CO2 fraction was then raised, until PaCO2 was 5 ± 1 Torr above the threshold level and phrenic activity was stable. Drugs were given iv after stable neural activity was recorded for at least 5 min. CB function was confirmed with bolus injections of sodium cyanide (NaCN; 50.0 µg/kg), which elicited a brisk augmentation of PNA. Intravenous DA bolus injections (0.1-50.0 µg/kg) and slow infusions (5.0 and 50.0 µg · kg1 · min1;
1 ml/min for 5 min) were tested in randomized order. The dead space of
the manifold system was 2 ml. Drugs were delivered via 1-ml boluses
into the dead space of the catheter and flushed with 5 ml of 0.9%
NaCl. Infusions were administered via an infusion pump (Harvard
Apparatus model 22). Arterial blood samples were drawn during control
periods before bolus injections and immediately before and in the final
minute of DA infusions. DA bolus injections and infusions were repeated
in hyperoxia (n = 7) and hypercapnia (n = 6).
DA is a precursor of norepinephrine (NE), and because of our previous
observations that NE is inhibitory to ventilation in the goat (37, 38),
in five animals, iv bolus injections of NE (1.0-10.0 µg/kg) were
examined for comparative purposes. In view of the substantial
hemodynamic effects of DA in this preparation (see
RESULTS), in five goats, we
attempted to mimic the hypotensive effect of DA administration with the
-adrenoceptor agonist isoproterenol (Iso; 0.5-5.0 µg/kg). In
two goats, the effects of the selective DA
D2-receptor agonists quinelorane
(0.1-50.0 µg/kg) and quinpirole (0.1-50.0 µg/kg) and of
the selective DA D1-receptor
agonist SKF-81297 (10.0-50.0 µg/kg) were examined.
Animals were then exposed to bilateral CBD. The occipital artery,
including the CSN, was exposed by a ventral midline incision, ligated,
and cut on both sides. It was necessary to further increase inspiratory
CO2 fraction after CBD to maintain
stable phrenic activity. CBD was confirmed by an absence of phrenic
response to iv NaCN bolus injections. DA and NE trials were repeated in CBD goats. In two goats, a lingual artery was cannulated, and the tip
of the catheter was advanced into the common carotid artery upstream
from the CB for close intra-arterial delivery of DA. This allowed for
the comparison of iv vs. intracarotid effects of DA on respiratory
motor output after CBD. Finally, in 10 peripherally chemodenervated
animals, the DA D2-receptor
antagonist domperidone (Dom) was administered (1.0 mg/kg iv), and DA
and NE trials were repeated. In two goats, the -adrenoceptor
antagonist phentolamine was given (1.0 mg/kg iv), and DA and NE trials
were repeated.
Drugs
All drugs were prepared on the day of each experiment. Doses of all drugs were calculated on the basis of salt weight. DA HCl, NE bitartrate, quinelorane 2HCl, quinpirole HCl, SKF-81297, and Iso HCl were dissolved in sterile saline (0.9% NaCl) to obtain stock solutions (1.0 or 10.0 mg/ml), which were further diluted in saline for iv administration in equal-volume (1-ml) injections (20 ml for infusions). Dom was dissolved in 5 ml of 0.1% lactic acid. Phentolamine mesylate was dissolved in 5 ml of warm sterile water. NaCN was dissolved in 0.9% NaCl to achieve a concentration of 5 mg/ml. DA HCl and NaCN were obtained from Sigma Chemical, St. Louis, MO, and Iso HCl from Abbott Laboratories, Chicago, IL. All other drugs were obtained from Research Biochemicals International, Natick, MA. Diluent injections had no effect on PNA, heart rate (HR), or systemic blood pressure.Data and Statistical Analysis
Phrenic burst frequency and peak integrated phrenic amplitude (quantified as the maximal breath-by-breath deflection from baseline, in arbitrary units), systolic and diastolic blood pressures, and HR were averaged over the last 10 s of the control period (30 s for 50.0 µg/kg DA and 10.0 µg/kg NE trials) and for 10 s (or 30 s) immediately after drug administration of bolus iv injections (allowing time for circulatory delay). For DA infusions, respiratory and cardiovascular variables were averaged over 1 min immediately before the beginning of the infusions and for the last minute of the infusions. PNA (frequency × peak amplitude) was taken as an index of ventilation. All results are expressed as means ± SE. To facilitate comparisons between animals and between treatments, respiratory data are expressed in relative terms, i.e., as percent change. Statistical significance was evaluated by using Student's paired t-tests and one-way analysis of variance where appropriate, with P values <0.05 taken as significant.| |
RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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CB-intact Group
DA bolus injections. DA bolus injections (0.1-50.0 µg/kg iv) were examined in 16 goats with intact CSN under normoxic conditions (pHa = 7.27 ± 0.01; PaCO2 = 52.9 ± 0.6 Torr; PaO2 = 96.3 ± 1.8 Torr). DA administration caused dose-dependent inhibition of PNA in all animals. Typically, DA injections caused a slowing of respiratory frequency and a decrease in peak phrenic amplitude. The magnitude and duration of the DA-induced ventilatory inhibition varied from goat to goat, but ventilatory responses were dose related in all animals, often leading to phrenic apnea, particularly at the higher dose of 50.0 µg/kg (7 out of 16 goats, lasting 85.1 ± 20.8 s). Durations of the DA-induced ventilatory inhibition were 15.5 ± 3.3 s for 0.1 µg/kg, 26.0 ± 5.2 s for 1.0 µg/kg, 68.8 ± 13.0 s for 5 µg/kg, 108.6 ± 18.7 s for 10 µg/kg, and 205.5 ± 27.0 s for 50 µg/kg DA. Results were highly reproducible in each experiment. Examples of the inhibitory effect of DA bolus injections on PNA are illustrated in Fig. 1 and are summarized for 10 goats (in which the entire protocol was completed) in Fig. 2A.
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In addition to ventilatory inhibition, there were significant changes in ABP after DA administration. Typically, at low doses (0.1-5.0 µg/kg) and up to 10 µg/kg, DA had a significant hypotensive effect, predominantly due to significant decreases in diastolic blood pressure (Fig. 1A), and caused a small, but significant, increase in HR. At the higher dose of 50.0 µg/kg, DA administration either reduced ABP similar to low-dose DA administration but greater in magnitude (5 out of 16 goats) or it caused a biphasic pressor response, consisting either of an initial increase and subsequent slow gradual decrease in systolic and diastolic blood pressures below control values (6 out of 16 goats) or of an initial increase in systolic blood pressure but decrease in diastolic blood pressure (widening of pulse pressures), which was also followed by a progressive fall in ABP below control values (5 out of 16 goats). These changes were accompanied by a moderate tachycardia. An example of one type of pressor response to high-dose DA administration is shown in Fig. 1A.
The ventilatory and pressor responses to DA were unrelated both in time course and magnitude. Ventilatory depression always preceded noticeable changes in ABP. Furthermore, peak ventilatory and cardiovascular responses were poorly correlated with the peak pressor response usually occurring when the ventilatory effects were subsiding. On occasion, with the higher DA doses, inhibitory phrenic responses persisted while ABP had returned toward control values.
DA bolus injections were repeated in seven goats with intact CSN during hyperoxia (pHa = 7.26 ± 0.02; PaCO2 = 52.4 ± 1.8 Torr; PaO2 = 323.3 ± 31.1 Torr). Ventilatory responses to iv bolus injections of NaCN (50.0 µg/kg iv) were approximately halved under hyperoxic conditions in these experiments. In hyperoxia, DA bolus injections caused typical dose-dependent inhibition of PNA, which was not significantly different from DA responses in normoxia in the same goats (Fig. 3A). Pressor and HR responses to DA were similar during hyperoxia and normoxia.
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In six CB-intact goats, DA trials were repeated during hypercapnic conditions (pHa = 7.15 ± 0.02; PaCO2 = 66.9 ± 2.7 Torr; PaO2 = 101.4 ± 4.4 Torr). In these animals, the inhibitory effects of DA on ventilation were substantially reduced compared with trials performed in the same animals during normocapnic conditions (Fig. 4A). However, DA bolus injections caused dose-related changes in ABP that were similar for both groups.
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DA infusions. In nine goats, slow iv
infusions of 5.0 and 50.0 µg · kg1 · min1
DA were examined during normoxic conditions
(pHa = 7.28 ± 0.01; PaCO2 = 51.6 ± 1.1 Torr;
PaO2 = 100.8 ± 1.6 Torr). DA
infusions caused dose-dependent progressive inhibition of PNA in all
animals (Fig. 2B), leading to
phrenic apnea, particularly at the higher dose of 50 µg · kg1 · min1
DA (7 out of 9 goats). The inhibitory effects of DA on PNA were accompanied by substantial blood pressure changes. Typically, 5.0 µg · kg1 · min1
DA infusion caused a slow fall in ABP, which reached its nadir during
the final minute of the 5-min infusion period. A significant increase
in HR accompanied the DA-induced hypotension. In contrast, the 50.0 µg · kg1 · min1
DA dose caused a biphasic pressor response consisting of an initial decrease in ABP (predominantly due to a significant decrease in diastolic blood pressure), which peaked midway through the infusion period (146.7 ± 6.4 s) and was subsequently followed by a
progressive increase in ABP (predominantly due to a significant
increase in systolic blood pressure) and a widening of pulse pressures.
ABP responses to 50.0 µg · kg1 · min1
DA infusion were also accompanied by a significant
tachycardia.
In seven goats, DA infusions were repeated during hyperoxic conditions (pHa = 7.25 ± 0.02; PaCO2 = 51.9 ± 1.8 Torr; PaO2 = 321.7 ± 40.9 Torr). Ventilatory and cardiovascular responses to DA infusions were not significantly different in hyperoxia compared with DA trials in the same animals during normoxia (Fig. 3B). DA infusions were repeated in six goats during hypercapnia (pHa = 7.16 ± 0.02; PaCO2 = 64.4 ± 2.3 Torr; PaO2 = 101.6 ± 5.9 Torr). Ventilatory responses to DA infusions in hypercapnia were substantially attenuated compared with normocapnic DA trials in the same six goats (Fig. 4B). ABP responses to DA infusions, however, were similar in time course and magnitude for both groups.
NE. NE bolus injections (1.0-10.0 µg/kg iv) were performed in five goats with intact CSN under normoxic conditions. NE injections caused dose-dependent inhibition of PNA (Fig. 5). Typically, NE injections caused a slowing of respiratory frequency and a decrease in peak phrenic amplitude. The magnitude of the inhibitory responses varied from goat to goat but was similar to the inhibitory effects of DA bolus injections examined in the same animals (Fig. 5B). However, for a given dose, the duration of the inhibitory response to NE administration was usually greater than that produced by DA administration. NE injection was associated with pronounced dose-related increases in ABP and HR.
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Iso. The effects of iv Iso bolus injections (0.5-5.0 µg/kg) were examined in five goats, which showed typical ventilatory and cardiovascular responses to DA administration. Under control conditions, with CSN intact, low-dose Iso injections (0.5-2.0 µg/kg) typically caused a decrease in ABP similar to low-dose DA administration. Higher Iso doses (up to 5.0 µg/kg) caused increases in systolic pressure and decreases in diastolic pressure similar to high-dose DA trials. Iso trials usually resulted in a moderate, but significant, tachycardia. In all five goats, however, Iso had no effect on PNA.
DA agonists. Bolus injections of the
DA D2-receptor agonists
quinelorane (0.1-50.0 µg/kg iv) and quinpirole (0.1-50.0
µg/kg iv) and of the DA
D1-receptor agonist SKF-81297
(10.0-50.0 µg/kg iv) were examined in two goats with intact CB
in normoxia. Dose-dependent ventilatory depression was observed after
administration of either DA
D2-receptor agonist. The magnitude
of the phrenic inhibition was significantly less than that produced by
comparable doses of DA in the same preparation. Ventilatory inhibition
with quinelorane or quinpirole was primarily due to changes in peak
phrenic amplitude. Phrenic apnea was observed after high-dose (10.0
µg/kg) injection of quinpirole in one goat. In contrast, DA
D1-receptor stimulation with
SKF-81297 had no effect on PNA. All three DA-receptor agonists caused
significant decreases in ABP greater in magnitude than DA trials. These
goats were not treated with Dom or phentolamine.
Phentolamine. In two CB-intact goats,
DA bolus injections (0.1-50.0 µg/kg) and infusions (5.0 and 50.0 µg · kg1 · min1)
were repeated after -adrenoceptor blockade with phentolamine (1.0 mg/kg). -Adrenoceptor blockade was confirmed by a blunting of
ventilatory and pressor responses to 1.0 µg/kg NE administration after phentolamine treatment. Phentolamine administration did not
affect inhibitory ventilatory responses to DA trials, but it caused a
significant decrease in ABP. Cardiovascular responses to DA bolus
injections and infusions were similar before and after phentolamine
administration, except that the increase in systolic blood pressure in
response to high-dose DA administration before phentolamine treatment
was attenuated after -adrenoceptor blockade.
CB-Denervated Group
DA bolus injections. DA bolus injections (0.1-50.0 µg/kg iv) were repeated in 10 goats after bilateral CBD (pHa = 7.18 ± 0.02; PaCO2 = 62.4 ± 1.6 Torr; PaO2 = 94.2 ± 2.8 Torr). Compared with DA trials in the same 10 goats before CBD, inhibitory ventilatory responses to DA were significantly attenuated in peripherally chemodenervated goats for all doses of DA, with the exception of the high-dose 50.0 µg/kg DA (Fig. 2A). The durations of the inhibitory responses were also significantly attenuated after CBD. In all CBD animals, however, dose-dependent inhibition of PNA persisted in response to DA administration (Figs. 1B and 2A). Similarly to CB-intact trials, the magnitude of the ventilatory depression varied from goat to goat. Inhibitory responses were manifest by changes in respiratory frequency and peak phrenic amplitude leading to apnea in two goats with high-dose DA administration. The direction and magnitude of ABP and HR responses to DA trials were not significantly different after CBD, compared with DA trials in the same animals before CBD. However, on average, increases in systolic blood pressure after high-dose DA administration were not observed. Control ABP and HR were significantly increased in all animals after bilateral CBD.DA infusions. Slow iv DA infusions
(5.0 and 50.0 µg · kg1 · min1)
were repeated in nine goats after CBD
(pHa = 7.18 ± 0.02;
PaCO2 = 62.4 ± 2.1 Torr;
PaO2 = 96.0 ± 3.5 Torr).
Again, DA infusions caused dose-dependent inhibition of PNA. However,
ventilatory responses to DA infusions were significantly attenuated
after CBD (Fig. 2B). Cardiovascular
responses to DA infusions were similar in time course and magnitude to
DA trials before CBD.
NE. In five goats, NE trials were reexamined after CBD. Ventilatory responses to 1.0 µg/kg NE were significantly attenuated after CBD (Fig. 5A). In contrast, the ventilatory depressant effects of 5.0 and 10.0 µg/kg NE persisted in peripherally chemodenervated goats, and these responses were not significantly different from CB-intact trials (Fig. 5A). However, the durations of the inhibitory responses were significantly reduced after CBD. Cardiovascular responses to NE bolus injections were similar before and after CSN section.
Dom Group
DA bolus injections. In 10 CBD goats, iv DA bolus injections (0.1-50.0 µg/kg) were repeated in normoxia (pHa = 7.18 ± 0.01; PaCO2 = 62.8 ± 1.7 Torr; PaO2 = 93.5 ± 2.7 Torr), after pretreatment with Dom (1.0 mg/kg iv). Dom administration significantly increased PNA (+56.6 ± 14.6%, n = 10) because of an increase in peak phrenic amplitude. In two goats, Dom had no effect on PNA. After peripheral DA D2-receptor blockade with Dom, the inhibitory effects of DA bolus injections on PNA, which persisted after CBD, were substantially attenuated. This effect is shown in Fig. 1C for one goat, and group data are shown for all 10 goats in Fig. 2A.Dom administration significantly reduced ABP and HR compared with pre-Dom values in CBD animals. After Dom treatment, pressor and HR responses to DA administration were significantly attenuated. Low-dose DA injections (0.1-5.0 µg/kg) had no significant effect on systolic and diastolic blood pressures or HR. With 10.0 µg/kg DA injections, a mild hypotensive effect was observed similar to pre-Dom DA trials, whereas 50.0 µg/kg DA on average caused a significant increase in systolic blood pressure and HR.
DA infusions. Slow iv infusions of DA
(5.0 and 50.0 µg · kg1 · min1)
were repeated in nine CBD goats under control conditions
(pHa = 7.18 ± 0.02;
PaCO2 = 62.3 ± 2.1 Torr;
PaO2 = 95.4 ± 3.6 Torr), after
pretreatment with Dom (1.0 mg/kg iv). Dom substantially attenuated the
ventilatory depressant effects of DA infusions (Fig.
2B). Cardiovascular responses to 5.0 µg · kg1 · min1
DA infusions were attenuated but qualitatively similar to DA trials
performed in the same animals before Dom treatment. The 50.0 µg · kg1 · min1
DA infusion typically caused increases in systolic and diastolic pressures after DA D2-receptor
blockade. These changes were accompanied by a significant increase
in HR.
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The main findings of the present study are as follows. 1) Exogenously administered DA elicits both CB-mediated and non-CB-mediated inhibitory effects on respiratory motor output in anesthetized goats. 2) The ventilatory depressant effects of DA that persist in peripherally chemodenervated goats are mediated by peripheral DA D2-receptors, since pretreatment with the selective peripheral DA D2-receptor antagonist Dom substantially attenuates the inhibitory effects of DA on PNA.
The observation of ventilatory depressant effects of DA in the present study is consistent with previous reports from our laboratory (2, 24, 27, 37, 38) and with observations in other animal species (7, 10, 23, 35, 48) and human subjects (44), although an excitation of breathing has been observed after DA administration in dogs (7) and with high-dose DA infusion in humans (22, 44). Our data further support other studies in anesthetized (3, 5, 10, 14, 15, 17, 23, 30, 35, 36, 47, 48) and awake (2, 27) animals and in vitro studies (46), demonstrating that DA inhibits the CB. In the present study, inhibitory ventilatory responses to iv DA bolus injections and infusions were significantly attenuated after bilateral section of the CSN, supporting the conclusion that the DA-induced ventilatory inhibition was in part mediated by CB chemoreceptors.
In addition, our data clearly demonstrate a non-CB-mediated inhibitory effect of DA on ventilation. In peripherally chemodenervated animals, exogenous DA administration caused dose-dependent inhibition of PNA when delivered either as iv bolus injections or slow iv infusions. Other studies have demonstrated ventilatory inhibition in CBD animals in response to DA administration, but the results of these studies are mixed and the mechanism(s) of the DA-induced hypoventilation has (have) not been elucidated. In anesthetized CBD rats, Cardenas and Zapata (10) observed ventilatory depression with iv DA bolus injections (1.0-10.0 µg/kg) in one-half of animals tested, but inhibitory responses to DA were abolished after CBD in the other half. In anesthetized cats, ventilatory depression in response to iv DA administration persists in CBD animals, whereas in the same preparation ventilatory responses to intracarotid DA administration (up to 20 µg/kg) depend entirely on the integrity of the CSN (48). Furthermore, CBD has been reported to abolish the ventilatory depressant effects of iv DA infusion (23, 27, 48), whereas others have reported inhibitory ventilatory responses to comparable DA doses after CBD in the same species (2, 35).
In the present study, with CSN intact, ventilatory responses to DA bolus injections and infusions were similar during normoxia and hyperoxia. Similarly, Nishino and Lahiri (35) reported that the ventilatory depressant effect of DA infusion was similar across a range of PaO2 values. Bisgard et al. (2) demonstrated that the inhibitory effects of DA on ventilation in awake goats are attenuated, but not eliminated, in hyperoxia, and similar results have been observed in anesthetized cats (48). However, in humans the inhibitory effect of DA on ventilation is absent during hyperoxia (44), and in dogs hyperoxia prevents further depression of CB activity by DA (5). In anesthetized cats, Nishino and Lahiri (35) observed a decrease in ventilation after DA infusion during hyperoxia in the absence of a corresponding decrease in carotid chemoreceptor activity, suggestive of a depressant effect of DA that is independent of the CB. In the present study, the persistent inhibitory effect of DA on ventilation in hyperoxia (presumably when CB activity is suppressed) is further suggestive of a non-CB site of action of DA.
In contrast, the inhibitory effects of DA bolus injections and infusions on PNA were substantially attenuated during hypercapnia in a dose-dependent manner. This most likely demonstrates that the increased chemical drive during hypercapnia reduces or overcomes the inhibitory effects of DA on ventilation. It is probable that this represents an effect on the CB as well as on the central chemoreceptors.
In addition, our data after Dom administration demonstrate that the ventilatory depressant effects of DA that persist in peripherally chemodenervated goats are mediated by peripheral DA D2-receptors. It is well established that Dom effectively blocks peripheral DA D2-receptors (25, 32), which have been shown to mediate CB inhibition (27, 32, 47). We have previously demonstrated that Dom blocks DA-induced chemosensory inhibition (3) and DA-induced ventilatory depression (4, 24, 27, 37) in the goat. Thus the present observation of DA D2-receptor-mediated ventilatory inhibition is consistent with these findings, except that in this study DA-induced respiratory depression was mediated by inhibitory DA D2-receptors located outside of the CB. This was further demonstrated by the inhibitory effects of the selective DA D2-receptor agonists quinelorane and quinpirole on PNA in two goats, whereas the selective DA D1-receptor agonist SKF-81297 had no respiratory effect.
Consistent with our finding of DA D2-receptor-mediated ventilatory depression in response to DA administration in CBD animals, Bisgard et al. (2) reported that the DA antagonist haloperidol abolishes the ventilatory inhibitory effect of DA that persists after CB excision in awake goats. Haloperidol, a butyrophenone, is effective in diminishing the effects of exogenous DA on the CB (5, 17, 30, 36). However, antagonists such as haloperidol cross the blood-brain barrier and thus have access to CNS dopaminergic receptors involved in respiratory control that may exert complex effects on respiration (8, 33, 34). The use of Dom in the present study allowed the investigation of the effects of peripheral DA blockade without effects on CNS DA receptors, since Dom does not readily cross the blood-brain barrier (1, 25, 28).
Dom administration significantly increased PNA in 8 out of 10 peripherally chemodenervated goats. In awake goats, Dom produces hyperventilation during normoxia (4, 24, 27), consistent with reports of a sustained increase in carotid chemoreceptor afferent activity after Dom administration in anesthetized cats (47) and goats (3) and in agreement with studies demonstrating increased carotid chemoreceptor activity after DA receptor blockade with haloperidol (5, 17, 30, 36) or other DA antagonists in vivo (30) and in vitro (46). These studies support the hypothesis that there is tonic dopaminergic inhibition of the CB during normoxia and that endogenous DA may play an important role in modulating CB function. The present finding of enhanced PNA in CBD animals after Dom administration suggests the removal of tonic inhibition from endogenous DA at some other peripheral site.
2-Adrenergic receptors are
present in the cat CB, where they exert an inhibitory influence on CB
activity and on the chemoreceptor response to hypoxia (26). In limited
trials, in the present study, phentolamine was ineffective in blocking
the inhibitory ventilatory effects of DA administration. This suggests
that the DA-induced ventilatory depression was not -adrenoceptor
mediated, and this is consistent with previous reports in animals (31, 37) and human subjects (44).
NE was administered in these experiments based on the striking similarity in the inhibitory actions of both catecholamines on ventilation in the goat (37, 38), which suggests that a common inhibitory mechanism could underlie their ventilatory effects. The present data confirm that NE is inhibitory to ventilation in the goat (37, 38) and further demonstrate the involvement of CB chemoreceptors in this response, since the inhibitory effects of low-dose NE on PNA were attenuated after CBD. Consistent with this finding, we have recently obtained direct evidence that NE is inhibitory to CB chemosensory activity in the goat (unpublished observations). In addition, ventilatory depression was observed after high-dose NE administration in CBD animals. Interestingly, the ventilatory depressant effects of NE observed in peripherally chemodenervated animals were attenuated after Dom administration, and this is consistent with previous observations in our laboratory (37) and with those of Folgering et al. (17), who found that haloperidol blocked the inhibitory effect of NE on CSN activity in cats and rabbits. It has been suggested that DA participates in the CB mechanism underlying NE-induced ventilatory inhibition (37). The present data suggest that NE may also be acting through a dopaminergic pathway outside of the CB to inhibit ventilation.
The ventilatory depressant effects of DA in this study were accompanied
by substantial changes in ABP. However, -adrenoceptor stimulation
with Iso produced similar pressor responses to DA administration but
had no effect on PNA, suggesting that the inhibitory effects of DA on
ventilation were independent of its hemodynamic effects. Moreover, for
most doses, DA administration had a significant hypotensive effect that
would not be expected to produce ventilatory depression.
An interesting observation in the present study was that in peripherally chemodenervated animals intracarotid administration of DA produced greater inhibitory effects on breathing than comparable doses given iv. This is suggestive of an intracranial site of action of DA that is readily accessible to the arterial blood supply in this region. The presence of DA receptors in the CNS is well documented, and studies have indicated that DA influences central respiratory regulation (8, 33, 34). However, a central mechanism is unlikely to explain the inhibitory effects of DA on ventilation in the present study, since DA (18) and Dom (1, 25, 28) do not readily cross the blood-brain barrier. This suggests a site of action that is accessible to the peripheral circulation. A candidate site may be the area postrema, a midline circumventricular organ that lies outside of the blood-brain barrier. For many years, the area postrema has been recognized as a chemosensitive trigger zone in the emetic reflex (9). However, respiratory responses to electrical and chemical stimulation of the area postrema have been reported in cats and rabbits (19, 39). Gatti et al. (19) observed dose-dependent ventilatory depression in response to local application of excitatory amino acids to the area postrema. Furthermore, the area postrema has reciprocal connections with the nucleus tractus solitarii (42) and other brain regions involved in respiratory control (cf. Ref. 40). Interestingly, DA D2-receptors have been identified in the area postrema, and DA agonists have been shown to act at this site to produce physiological responses (20).
Alternatively, the inhibitory ventilatory effects of DA that persist in peripherally chemodenervated animals may be due to actions on the petrosal and/or nodose ganglia. The cell bodies of centrally projecting CB chemoafferent fibers are located in the petrosal ganglion, which is known to express the genetic information encoding the DA D2-receptor subtype (11). The nodose ganglion contains the cell bodies of centrally projecting vagal afferents, including aortic chemoreceptors and cardiopulmonary afferents. It has recently been demonstrated that DA elicits a concentration-dependent depolarization of the rat nodose ganglion in vitro, specifically, via the activation of DA D2-receptors (29). Interestingly, serotonin (5-HT) causes dose-dependent depolarization of nodose ganglion cells in vitro (43), and supranodose vagotomy abolishes the inhibitory ventilatory effects of 5-HT that persist after midcervical vagotomy in the cat (41) and rat (45).
In 6 out of 10 CBD goats, high-dose DA bolus injections (50.0 µg/kg) caused an increase in PNA after Dom administration. Excitatory effects of DA on ventilation have been described in dogs (7) and humans (22, 44). In the dog, intracarotid-injected DA produces a transient excitation of carotid chemosensory activity (5), and we have recently obtained similar results in the goat (3). Excitatory effects of DA have also been observed in the cat CB in vitro (46). Furthermore, it has been shown that DA-receptor blockade with Dom (47) or other DA antagonists (17, 30, 36, 46) reverses DA-induced CB inhibition to excitation. These studies support the hypothesis that there are low-affinity excitatory receptors for DA in the CB (21, 30). However, in the present study, excitatory effects were observed in CBD animals, suggesting that there may be peripheral excitatory DA receptors outside of the CB in the goat.
In summary, the present data clearly demonstrate that exogenous DA administration inhibits ventilation in anesthetized goats through CB and non-CB mechanisms. The ventilatory depressant effects of DA that persist in peripherally chemodenervated animals are DA D2-receptor mediated, since the inhibitory effects of DA administration were substantially attenuated after Dom treatment. The present study also confirms that NE is inhibitory to breathing in the goat and demonstrates that NE also exerts non-CB-mediated inhibitory effects on ventilation, in part through dopaminergic pathways. The inhibitory effects of DA on respiratory motor output appear to be independent of the hemodynamic effects associated with DA administration.
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ACKNOWLEDGEMENTS |
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We thank Gordon Johnson and Josue Pizarro for excellent technical assistance.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grants HL-53969 and HL-07654.
Address for reprint requests: K. D. O'Halloran, Dept. of Comparative Biosciences, School of Veterinary Medicine, Univ. of Wisconsin, 2015 Linden Drive West, Madison, WI 53706-1102 (E-mail: kenoh{at}svm.vetmed.wisc.edu).
Received 15 December 1997; accepted in final form 6 May 1998.
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REFERENCES |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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PNA, integrated
phrenic nerve activity; ETCO2,
end-tidal CO2.
A: dopamine (injected intravenously at
arrows) causes dose-dependent inhibition of PNA with carotid sinus
nerves intact. B: ventilatory
depressant effects of dopamine persist, but are significantly
attenuated, after bilateral carotid body denervation.
C: dopamine
D2-receptor blockade with
domperidone abolishes inhibitory ventilatory effect of dopamine that
persists after carotid body denervation.
Significantly different
(P < 0.05) from Intact.
Significantly different
(P < 0.05) from CBD.
