Re.q~iration Physiology. 81 (1990) 359-370 Elsevier
359
RESP 01690
Effects of domperidone and medroxyprogesterone acetate on ventilation in man Shahrokh Javaheri and Luis F. Guerra Pulmonao" Secthm and Medical Services, Veterans Affairs Medical Center. and Department of Medicine, University of Cincinnati College of Medicine. Cincinnati, Ohio, U.S.A.
(Accepted for publication 8 May 1990) Abstract. If endogenous dopamine acts as an inhibitory neurotransmitter in the carotid bodies in man, domperidone (DP), a selective dopamine D-2 receptor antagonist should stimulate carotid bodies and augment ventilation. Furthermore, the combination of a central ventilatory stimulant, medroxyprogesterone acetate (M PA), with a peripheral ventilatory stimulant, DP, may produce an additive/synergistic ventilatory effect. We conducted a double-blind, placebo-controlled (P), cross-over trial comparing MPA 20 mg three times daily (TID) and DP (20 mg TID) alone and together in 8 healthy male human subjects. Drug effects were measured after 7 days, and a two-week drug washout period was allowed. MPA significantly increased alveolar ventilation (~'.,x), and slopes of hypercapnic and hypoxic ventilatory responses. Domperidone alone significantly increased the slope of the hypoxic response; however, VA and Pa(.o, did not change significantly. The combination of MPA and DP resulted in ventilatory changes similar to MPA alone. We conclude that in man endogenous dopamine acts as a modulator of chemoreception during hypoxemia, but plays no major role tonically in control of ventilation during normoxemia and normocapnia. Lack of additive effect with combined DP and MPA suggests that these drugs may share the same final common pathway in the process of chemoreception.
Animal, man; Carotid bodies, and dopamine; Chemoreceptor, modulation by dopamine; Drug, domperidone, medroxyprogesterone acetate; Neurotransmitter, dopamine
T h e c a r o t i d b o d i e s m e d i a t e the v e n t i l a t o r y r e s p o n s e to h y p o x e m i a in h u m a n beings. W i t h i n the c a r o t i d b o d i e s (peripheral c h e m o r e c e p t o r s , P C R ) d o p a m i n e has b e e n f o u n d in large c o n c e n t r a t i o n s and m a y serve as a n e u r o t r a n s m i t t e r in the c h e m o r e c e p t i o n o f h y p o x e m i a ( F i d o n e et al., 1980). S u p p o r t i n g e v i d e n c e for this action c o m e s f r o m studies identifying the p r e s e n c e o f d o p a m i n e r e c e p t o r s within the c a r o t i d b o d i e s ( M i r et al., 1984), d e p r e s s i o n o f ventilation in a n i m a l s and h u m a n s with i n t r a v e n o u s a d m i n i s t r a t i o n o f d o p a m i n e ( W e l s h et al., 1978; W a r d a n d Bellville, 1982; O l s o n et al., 1982a), a n d a u g m e n t a t i o n o f v e n t i l a t i o n after a d m i n i s t r a t i o n o f d o p a m i n e r e c e p t o r a n t a g o n i s t s
Correspondence to: S. Javaheri, Director Sleep Laboratory, Pulmonary Section (111F), Veterans Affairs Medical Center Cincinnati, OH 45220, U.S.A.
0034-5687/90/$03.50 (c2 1990 Elsevier Science Publishers B.V. (Biomedical Division)
360
s JAVAIIERI AND L.F. GUERRA
(Olson et al., 1982b; Delpierre et al., 1987 ; Kressin et al., 1986; Bainbridge and Heistad, 1980). However, the role of endogenous dopamine in chemoreception in man still remains controversial. This is because the effects of dopamine receptor antagonists are difficult to interpret, considering the agents used in most studies cross the blood-brain barrier (BBB) which may exert an independent effect on ventilation (Bainbridge and Heistad, 1980; Olson et al., 1982a; Ward, 1987; Bonora et al., 1988; Ilender et al., 1982). Domperidone (DP) is a new, selective dopamine D-2 receptor antagonist which does not cross the BBB (Hender et al., 1982; Brogden et al., 1982; Champion et al., 1986). In animal studies, DP has been shown to augment resting ventilation and increase chemosensitivity to hypoxia and hypercapnia (Kressin et al., 1986). Medroxyprogesterone acetate (MPA) augments resting ventilation in man (Zwillich et al., 1978; Skatrud et al., 1978; Schoene et al., 1980) and it has been shown in some studies (Zwillich et al., 1978; Schoene et al., 1980) to increase chemosensitivity to hypercapnia. Although the exact site of action remains unclear, it is believed that MPA exerts its effect through central nervous system (CNS) stimulation (Dempsey et al., 1986; Kato, 1985). The purpose of this study was to investigate the ventilatory effects of DP in normal man after chronic oral administration and to compare its effect to MPA. Furthermore, the potential additive/synergistic effects of combining a peripheral ventilatory stimulant, DP, with a presumably central ventilatory stimulant, MPA, was evaluated.
Methods
Eight healthy male subjects, ages 28-42 years served as study subjects. All were nonsmokers and were free from any medical illnesses. Informed consent was given by all subjects, and the protocol was approved by the Institutional Review Board at the University of Cincinnati College of Medicine. Baseline spirometric and ventilatory parameters were obtained prior to drug trials and served as a training run. The ventilatory effects of DP and MPA were evaluated when used alone and in combination using a placebo (P) controlled, double-blind, crossover design. Identical capsules containing either P, 20 mg DP, or 20 mg MPA were made by the Pharmacy Department and were blinded to the investigators. Two capsules were taken three times daily (TID) for seven days such that each subject completed the following drug sequences in a random fashion: P + P, DP + P, MPA + P, and MPA + DP. The reason for the choice of MPA at 60 mg per day was that previous studies using MPA as a respiratory stimulant used this dose (Dempsey et al., 1986). In regard to DP, 60 mg per day also appears to be the maximal acceptable amount by most investigators who have used the drug and have dcmonstrated its efficacy in gastrointestinal disorders (Champion et al., 1986; Brogden el al., 1982). Spirometric and ventilatory measurements were obtained on day seven, followed by
D O M P E R I D O N E AND PROGESTERONE
361
a two-week washout period between drug runs. For each subject measurements were performed two hours postprandially and at the same time of day to eliminate the effects of diurnal variation. Measurements were obtained within 1 to 2 h after ingestion of the last doses of various drug regimens. All subjects refrained from beverages containing caffeine derivatives on the day of study. The sequence of measurements made at baseline and after drug runs were identical for all subjects. Weight, height, oral temperature (using a mercury thermometer) and blood pressure were measured after assuming the supine position for at least 5 minutes. Later, arterial blood samples were obtained anaerobically in the sitting position by radial artery puncture. The samples were obtained in 5 ml syringes whose dead space was filled with heparin solution. Care was exercised not to disturb steady state; skin was anesthetized with 2 °Jo lidocaine to eliminate pain and anxiety. The blood was collected over several breath cycles. Arterial blood gases and pH were measured in duplicate in appropriate electrodes (ABL 2, Acid-Base Laboratory, Radiometer, Copenhagen) at 37 °C. Functional residual capacity (FRC) was determined in a plethysmograph (Collins Body Plethysmograph System, W.E. Collins, Inc., Braintree, MA). Spirometric tests were performed in triplicate (Collins/DS, W.E. Collins, Inc., Braintree, MA) and the highest value for each measurement was used for calculations. The ventilatory tests were measured in the sitting position with a nose clip in place and breathing through a mouthpiece connected to a low resistance 2-way valve (Hans-Rudolph, Kansas City, MO). Subjects listened to their music of choice by radio-headphones. Inspiratory flow and volume were measured by a pneumoscan (S-301, K L Engineering Co., Sylmar, CA). Calibration were done by known flow rates from a pneumatic calibrator (Model 65-250, Penwalt Cor., Bellville, N J) and for volume by a 3 L syringe. End-tidal CO2 was sampled at the mouthpiece by an infrared CO 2 analyzer (Beckman Medical Gas Analyzer, LB-2, Beckman Cardiopulmonary Instruments, Fullerton, CA) calibrated with gases of known CO2 concentration. Arterial oxygen saturation was measured by ear-oximetry (BTI Biox IIA, Bioximetry Technology, Inc., Boulder, CO). Actual measurements started after achievement of steady-state, as evidenced by a stable end-tidal Pco2. Resting ventilation was measured when the subject breathed room air during which a timed volume of exhaled gas was collected for calculation of 0 2 consumption (Vo2) and CO 2 production ('qco2). Mixed-expired CO 2 and 0 2 concentrations were measured by gas analyzers (Beckman Medical Gas Analyzers). Dead space was calculated using Bohr's equation, knowing arterial and mixed-expired Pco2. Alveolar ventilation (VA) was calculated form the equation "qA = RR (VT - VD). The hypercapnic ventilatory response (HCVR) was performed in duplicate using a modification of the rebreathing method of Read (1967). The test was performed using a bag containing a volume of gas (93 j°o 0 2 + 7~o CO2) equal to subject's vital capacity plus 1 L. The subject took three deep breaths from the bag to facilitate gas mixing; data points after appearance of mixed venous Pco_~ plateau were used for calculations. The HCVR was stopped when end-tidal CO 2 concentration was approximately 8 °,o. Linear
362
S. JAVAHERI AND L.F. GUERRA
regression was used in the equation : V = S (Pco2 - B), where S is the slope of HVCR, and B is the intercept on the Pco: axis. We also calculated the predicted ventilation for PEco ~, = 60 mm Hg (VI 60) for each subject. The isocapnic hypoxic ventilatory response (HVR) was performed in duplicate by the rebreathing method detailed by Rebuck and Slutsky (1981). The subject rebreathed from the same bag initially containing a small amount of gas (24~0 02, 7~, CO2, balance N2). Isocapnia was maintained by keeping end-tidal Pco2 at the prevailing levels by removing appropriate amount of CO2 from the circuit by two variable speed pumps which were connected to a CO 2 absorber. Nitrogen was added to the system and rebreathing was stopped when arterial 0 2 saturation reached 70~o. Data points between 90 to 70°~/o saturation were used for calculations by least squares regression analysis relating ventilation to saturation. A minimum of 10 rain was allowed between each response test. CO 2 production and 9o~ are expressed in STPD; all other volumes are expressed in BTPS.
Statistical analysis. Statistical significance was determined with one-way analysis of variance with repeated measures. In case of statistical significance, values during treatments were compared with placebo using two-tailed t-test with Bonferroni correction for three comparisons. P < 0.017 was considered significant. To determine synergism with DP + MPA, a two-way analysis of variance was used. The SAS computer system of the University of Cincinnati was used for calculations. Data are expressed in mean _+ SD.
Results
All eight subjects successfully completed the drug trials. Side effects occurred on two occasions in two subjects when taking MPA. The symptoms consisted of nonspecific feelings of tiredness and light-headedness. No side effects were noted with DP. Most physical and spirometric tests did not change significantly. Mean values for systolic and diastolic blood pressure were 105 + 12 and 66 _+ 4 mm Hg with P and did not change significantly during any of the drug trials. The mean values for body weight were 75.0 _+ 10, 74.5 _+ 10, 74.5 _+ 10, and 74.0 + 10 kg, respectively with P, MPA, DP, and MPA + DP. The mean values for oral temperature were 36.5 _+ 0.3, 36.8 + 0.1, 36.8 + 0.2 and 37.0 _+ 0.3 °C, respectively with P, MPA, DP, and MPA + DP. The rise in oral temperature with MPA + DP when compared to P was significant (P < 0.001). The mean values for FEVI(L), FVC(L), FEVI/FVC'/% and FRC(L) were respectively, 4.4 + 0.7, 5.2 _+ 0.7, 85 _+ 5, and 3.7 + 0.8 with P, and remained virtually constant during drug trials.
D O M P E R I D O N E AND P R O G E S T E R O N E
363
TABLE 1 Resting ventilation during various drug treatments. F (min P + P
')
12.7 -+3.7 14.7"* -+3.4 14.1 +3.0 15.6*** +3.6
MPA + P DP + P MPA + DP
VT (ml)
~)l (L.min
696.8 _+ 161.9 708.8 -+ 156.8 665.5 -+ 138.9 670.8 +117.7
8.39 _+ 1.47 10.0(;*** -+ 1.72 9.07 +_0.89 10.27"** -+1.6
i)
VD (L.min
VA (L'min
i)
2.83 _+0.99 3.47 -+0.49 3.24 -+0.49 3.32 -+0.91
VD/VT i)
5.56 -+0.78 6.48** -+0.81 5.79 -+0.60 6.89*** _+1.33
0.33 _+0.07 0.34 -+0.06 0.36 -+0.04 0.34 -+0.08
Mean + SD; N = 8; P = placebo; MPA = medroxyprogesterone acetate; DP = domperidone; ventilation is in BTPS; ** = P < 0.01; *** = P < 0.001. No synergism was found with DP + MPA.
Resting ventilation. duced
Medroxyprogesterone
acetate, when
compared
to placebo,
pro-
a s i g n i f i c a n t i n c r e a s e in r e s t i n g ~/t a n d ~/A ( t a b l e 1). B l o o d g a s a n a l y s i s w a s
consistent with this ventilatory change revealing significant hypocapnia reduction
in p l a s m a
( t a b l e 2). D o m p e r i d o n e
[HCO3
] with plasma
[H + ] remaining
and a significant
relatively unchanged
a l o n e d i d n o t r e s u l t in a n y s i g n i f i c a n t c h a n g e s
in r e s p i r a t o r y
f r e q u e n c y , VA o r P a c o ~ ( t a b l e s 1 a n d 2). When MPA
a n d D P w e r e g i v e n in c o m b i n a t i o n ,
f r e q u e n c y , ~/I a n d ~/A w a s n o t e d , p r o d u c i n g reduction
in p l a s m a
[HCO3
a s i g n i f i c a n t i n c r e a s e in r e s p i r a t o r y
a significant hypocapnia
] ( t a b l e s 1 a n d 2). S y n e r g i s m
between
and a significant MPA
and DP,
TABLE 2 Resting gas exchange and arterial blood acid-base variables during various drug treatments.
P + P MPA + P DP + P MPA + DP
Paco: (ram Hg)
[HCO; ] (mmol. L l)
[H ~ ] (nmol. L)
PaQ (ram Hg)
£Zco: (ml.min
40.0 _+ 1.8 34.6*** + 1.6 39.8 -+2.1 35.8*** +4.7
25.1 +0.8 22.1"* -+ 1.3 24.5 -+ 1.6 22.7* _+3.1
38.8 -+ 1.5 38.2 -+ 1.3 38.9 _+0.9 37.8 -+ 1.5
92.9 -+4.6 95.1 +4.5 91.8 -+7.4 94.8 + 7.9
167.6 _+28.6 182.5 -+ 15.9 177.9 -+26.5 180.3 -+ 25.1
l)
~Zo2 (ml.min 224.4 +32.7 227.4 +21.4 250.2 -+81.1 232.2 -+ 38.4
R 1) 0.75 +0.11 0.81 +0.11 0.75 -+0.16 0.78 ± 0.10
Mean _+ SD; N = 8; P = placebo; MPA = medroxyprogesterone acetate; DP = domperidone; Vco2 = CO2 production, '¢o~ = 02 consumption (STPD); R = respiratory exchange ratio; * = P < 0.017; ** = P < 0.01 ; • ** = P < 0.001. No synergism was found with DP + MPA.
364
S. JAVAHER[ AND L.F. GUERRA 7.0 6.5 ,
6.0
"1"
5.5
CD
E
E
s.o
,~
4.5
E.
4.0
[1~
3.5
>
0
3.o
~ m
2.5
:_:,-- . . . . : < : : - : 2 . . . . . . . . . . . . . . . .
2.0 1
1.5
DP
MPA
Fig. 1. Slopes (S) of hypercapnic vcntilatory responses (HCVR) fbr placebo (P), domperidone (DP) and medroxyprogesterone acetate (MPA). For clarity data of DP + MPA are not shown.
however, was not evident. There were no significant changes in Vco2, '¢o2, or respiratory exchange ratio (table 2) with the use of either drug.
Hypercapnic ventilator), response. F i g u r e 1 s h o w s c h a n g e s in t h e S o f H C V R o f e a c h subject for P, D P and MPA. The S of the H C V R was significantly increased with M P A (table 3). In addition, the response curve was significantly shifted to the left as indicated by a decrease in the X-intercept and an increase in "v'I(60). D o m p e r i d o n e increased the S of H C V R (fig. 1) and V](60) slightly but not significantly (table 3). When M P A and D P were used in combination an increase in the S of the H V C R (P = 0.02) and leftward shift in intercept were observed (table 3). This effect was not greater than when M P A was used alone.
4,0
7%¢, 3.S i
.--:-:'"~ . . . . . . . .
....
.
.c_
2.5
....
E
::2;';; ....
ft.
1.s
g" r
1.o
........ ::
0.5
.........................
0.0
""" 1
P
DP
MPA
Fig. 2. Slopes (S) ofhypoxic ventilatory responses (HVR) for placebo (P), domperidone (DP) and medroxyprogesterone acetate (MPA). For clarity data of DP + MPA are not shown.
+ 0.93
4.30 + 3.3
36.9***
39.3 + 2.8
4.13
+3.5
+ 1.25
_+ 1.23
37.0**
± 2.9
_+0.83
4.58**
39.8
3.38
X (mm Hg)
± 19.3
99.3***
_+ 19.8
82.8
_+25.1
102,2"**
i 11.7
66.5
V1 (60) (L'min 1)
± 1.30
- 1.99"**
+ 1.38
- 1.89"
+ 1.38
- 1.96"*
+ 0.74
- 1.22
S, H V R (L'min
l-~oSat
1)
± 120.1
192.4"*
+ 123.8
179.0"
_+ 121.4
185.7"*
± 67.0
118.7
Y (L.min
1)
r e s p o n s e ; VI (60) = ventilation at end-tidal P c o 2 o f 60 m m H g ; * = P < 0.017; ** = P < 0.01 ; *** = P < 0.001. T h e S o f H C V R with M P A + D P w a s significant at P = 0.02.
M e a n _+ S D ; N = 8. P = p l a c e b o ; M P A = m e d r o x y p r o g e s t e r o n e a c e t a t e ; D P = d o m p e r i d o n e ; S = slope; H C V R a n d H V R = h y p e r c a p n i c a n d h y p o x i c v e n t i l a t o r y
MPA + DP
DP + P
MPA + P
P + P
S, H C V R (L.min l'mmHg-l)
Hypercapnic and hypoxic ventilatory responses during various drug treatments.
TABLE 3
© z,'-m
,H
0
> Z
L; 0 Z
7z
©
366
s. JAVAHERI AND I..F. GUERRA
Hypoxic ventilatorv response. Figure 2 shows changes in the S of HVR of each subject for P, DP, MPA. The mean value for S of HVR (table 3) obtained with P was similar to that reported by Rebuck and Slutsky (1981). Both MPA and DP when used alone significantly increased the S of HVR (table 3). The increase in HVR noted after combination of MPA and DP was not significantly greater than when MPA or DP was used alone.
Discussion The conclusions of this study are: (1) orally administered DP increases HVR but does not significantly change resting ventilation and Paco2; (2)orally administered MPA increases "(/A and causes chronic respiratory alkalosis; MPA increases HCVR and HVR; and (3) surprisingly, combination of MPA and DP results in ventilatory stimulation essentially similar to MPA. Before we discuss the ventilatory effects of the drugs in detail, we emphasize that the experimental design of the study was placebo-controlled, cross-over, and double-blind. Furthermore, because of the short period of drug trials (one week each time), no known side effects which would be characteristic of a drug (e.g. impotence due to MPA) occurred,
Ventilatorv effects o f M P A . This study shows that MPA, at 20 mg TID, is a moderate respiratory stimulant. The mean Paco_~ dropped by 5 mm Hg as a result of an increase in VA, with Vc:o_~ (and Vow) remaining unchanged. MPA caused chronic respiratory alkalosis characterized by about 3 mmol/L drop in plasma [ H C O 3 ] with little change in plasma [H + ]. Changes in ventilation and P a c o 2caused by MPA noted in the present study are virtually identical to those observed by Skatrud and associates (1978) using a similar protocol. Furthermore, our finding that MPA increased the S of HCVR is in agreement with studies of Zwillich et al. (1978) and Schoene and associates (1980). This observation is important because it suggests that MPA may act centrally as a stimulant, increasing the sensitivity of the central structures to the existing afferent inputs. MPA also significantly increased the S of HVR as previously reported by Zwillich and associates (1980). This observation indicates that MPA stimulates either carotid bodies and/or the central structures involved in integration of chemoreception from PCR (central amplification). Although the mechanism of respiratory action of progesterone is not yet elucidated, it is known that progesterone acts on cytosolic, as well as nuclear receptors and induces synthesis of specific proteins (Kato, 1985). These biochemical events may conceivably be involved within the PCR and CNS network of control of ventilation as MPA and progesterone have been shown to cross the BBB (Dempsey et al., 1986; Kato, 1985), and specific intracranial progesterone receptors have been identified (Kato, 1985). The small rise in body temperature noted after MPA may have contributed to the
DOMPERIDONE AND PROGESTERONE
367
ventilatory responses to hypercapnia and hypoxemia; however, this is doubtful since DP, which equally increased body temperature, resulted in only minor augmentation of HCVR (table 3). Ventilatorv effects of DP. Dense-cored vesicles exist in the Type I (chief or principal) cells of the carotid body (Fidone et al., 1980). These vesicles contain catecholamines, primarily dopamine and norepinephrine and have been identified in the carotid bodies of all species so far studied (Fidone et al., 1980). Although there are species differences (Eyzaguirre and Monti-Bloch, 1980), there is growing evidence that in man exogenous dopamine has an inhibitory effect on the carotid bodies (Welsh et al., 1978; Ward and Bellville, 1982; Olson et al., 1982a). Studies of Welsh and associates (1978) showed that intravenous infusion of dopamine in man at therapeutic doses resulted in a small fall in ~/A and minimal rise in P a c o 2. Furthermore, dopamine infusion diminished the magnitude of the hyperventilatory response to hypoxic but not hypercapnic gas breathing, strongly suggesting that the site of action was in the carotid bodies. Similar observations were reported by Olson and associates (1982a), and Ward and Bellville (1982). However, Ward and Bellville (1982) demonstrated that dopamine infusion partially suppressed CO 2 sensitivity, and this was presumed to represent the portion contributed by carotid bodies. Because dopamine does not cross the BBB, its ventilatory effects cannot be attributed to central mechanisms. The studies of dopamine infusion in man strongly indicated the presence of inhibitory receptors outside CNS that respond to exogenous dopamine (Welsh et al., 1978; Ward and Bellville, 1982; Olson et al., 1982a). Yet these experiments provide no conclusive evidence as to the physiological role of endogenous dopamine, important information which is obtained from experiments using specific dopamine receptor antagonists. Dopamine receptors are divided into D-1 and D-2 receptors (Kohli et al., 1983); D-1 excitation activates adenyl-cyclase, whereas D-2 receptors inhibit cyclic AMP formation. Radioligand-binding studies have shown that dopamine receptors in carotid bodies are of subtype D-2 (Mir et al., 1984). Dopamine receptors also exist within the CN S and these may influence the central network ofventilatory control in a complicated manner (Hender et al., 1982). In addition, inhibition of dopamine in the CNS may also cause sedation which per se may influence ventilatory control. Ventilatory effects of dopamine antagonists have been reported in man. Bainbridge and Heistad (1980) used haloperidol, and Olson and associates (1982b) used prochlorperazine as dopamine antagonist. The two studies reported opposing results on baseline ventilation in man. Dopamine-receptor antagonists used in these studies (Bainbridge and Heistad, 1980; Olson et al., 1982b) react with both receptors to various degrees. These antagonists also cross the BBB and in addition may cause sedation. Domperidone, which has been used in Europe as an antiemetic for a long time is a specific dopamine D-2 receptor antagonist which does not cross the BBB (Champion etal., 1986; Brogden etal., 1982), and in contrast to other antagonists, has no ~-2 receptor blocking activity (Kohli et al., 1983). In the present study, DP was not associated with any side effects, and sedation was
368
S. JAVAHERI AND L.F. GUERRA
not noted by any subject. In contrast to the ventilatory effects of other dopamine antagonists used in previous studies (Bainbridge and Heistad, 1980; Olson et al., 1982b) in the present study DP had no significant effect on baseline ventilation, Vco2 and Paco ~. Domperidone, however, significantly augmented HVR. These data strongly suggest that dopamine D-2 receptor is involved in transduction of HVR in man. Because DP did not affect baseline ventilation during normoxemia, we also cautiously suggest that dopamine should not contribute to the tonic baseline carotid body activity in man. In the context of the latter conclusion, we emphasize that we did not perform dose-response studies, but used the maximum dose of DP which has been shown to affect other peripheral actions of dopamine such as those of gastrointestinal tract (Champion et al., 1986; Brogden et al., 1982). In a typical study (reviewed by Champion et al., 1986), DP 20 mg TID was compared to metoclopramide at the same dose for treatment of symptomatic endoscopically proven gastrointestinal disorders; with both drugs equally effective, metoclopramide resulted in some extrapyramidal side effects. It is emphasized that although DP lacks c~-2 receptor blocking activity, it acts as an ~-1 receptor inhibitor (Ennis and Cox, 1980). Therefore, contribution of c~-I receptor blockade by DP to changes in HVR observed in the present study cannot be quantitated. However, there is some evidence that ~-1 receptor stimulation does not play a major role in ventilatory response in man (Stone et al., 1973). While our study with 'chronic' oral administration of DP was in progress, results of two studies with acute intravenous administration of DP on HVR have been published (Ward, 1987; Delpierre et al., 1987) and confirm our observation. In the study reported by Delpierre and associates (1987), DP was given intravenously in a double-blind fashion, and it augmented HVR without changing baseline ventilation or arterial blood pressure. Hypercapnic ventilatory response was not measured in these two studies. In the present study, DP resulted in a small but insignificant augmentation of HCVR (table 3) and this may reflect the small contribution of the PCR to HCVR. Ventilatory effects of combined M P A and DP. An important aspect of the design of the present study was to combine a PCR respiratory stimulant with a (presumably) predominantly centrally-acting drug. We had hoped that if the drugs had different mechanisms of action, and if there was a central amplification of the PCR input, the combination would result in either an additive or synergistic ventilatory response which would prove useful in treatment of disorders with diminished respiratory drive. Both MPA and DP augmented HVR when given alone, but synergistic or additive effect was notably absent with combined MPA and DP therapy. These negative results, however, may have important implications in control of ventilation in man. Lack of additive effect suggests that the two drugs may share a common pathway in chemoreception in carotid bodies. Lack of synergistic effect between MPA and DP further suggests that in man afferent input from carotid bodies may not be amplified within the central network of breathing (central amplification), or else central amplification is not sensitive to progesterone. Although our study with combination drug therapy did not show any synergistic
DOMPERIDONE AND PROGESTERONE
369
v e n t i l a t o r y effect, it is still c o n c e i v a b l e t h a t o t h e r d r u g s w i t h d i f f e r e n t m e c h a n i s m s o f a c t i o n (e.g., a l m i t r i n e ) w h e n c o m b i n e d w i t h M P A m a y p o t e n t i a l l y h a v e s y n e r g i s t i c effect w h i c h m a y p r o v e t h e r a p e u t i c a l l y effective in t r e a t m e n t o f d i s e a s e s w i t h d i m i n i s h e d r e s p i r a t o r y drive.
Acknowledgement. This research was supported in part by grants from the Department of Veterans Affairs. The authors thank Janssen Pharmaceutica (Picataway, New Jersey) for their generous supply of domperidone and Ms Saundra K. Eversole for her secretarial assistance.
References Bainbridge, C.W. and D. D. Heistad (1980). Effect of haloperidol on ventilatory responses to dopamine in man. J. Pharmacol. Exp. Ther. 213: 13-17. Bonora, M. and H. Gautier (1988). Influence of dopamine and norepinephrine on the central ventilatory response to hypoxia in conscious cats. Respir. Physiol. 71:11-24. B rogden, R. N., A.A. Carmine and R.C. Heel (1982). Domperidone: a review of its pharmacologic activity, pharmacokinetics and therapeutics efficacy in the symptomatic treatment of chronic dyspepsia and as an anti-emetic. Drugs 24: 360-400. Champion, M.C., M. Hartnett and M. Yen (1986). Domperidone, a new dopamine antagonist. Can. Med. Assoc. J. 135: 457-461. Delpierre, S., M. Fornaris, C. Guillot and C. Grimaud (1987). Increased ventilatory chemosensitivity induced by domperidone, a dopamine antagonist, in healthy humans. Bull. Eur. Physiopathol. Respir. 23: 31-35. Dempsey, J.A., E.B. Olson, Jr. and J. B. Skatrud (1986). Hormones and neuro-chemicals in the regulation of breathing. In: Handbook of Physiology, edited by A.P. Fishman and N.S. Cherniack, Section 3, Vol. II. The Respiratory System. Control of Breathing. Bethesda, M.D.: American Physiological Society, pp. 181-222. Ennis, C. and B. Cox (1980). The dopamine receptor antagonist domperidone is also a competitive antagonist at a-adrenoceptors. J. Pharrn. Pharmacol. 32: 434-435. Eyzaguirre, C. and L. Monti-Bloch (1980). Similarities and differences in the physiology and pharmacology of cat and rabbit carotid bodies. Fed. Proc. 9: 2653-2656. Fidone, S.J., C. Gonzalez and K. Yoshizaki (1980). Putative neurotransmitters in the carotid body: the case for dopamine. Fed. Proc. 39: 2636-2640. Hender, J., T. Hender, S. Jonason and D. Lundberg (1982). Evidence for a dopamine interaction with the central respiratory control system in the rat. Eur. J. Pharmacol. 81: 603-615. Kato, J. (1985). Progesterone receptors in brain and hypophysis. In: Actions of Progesterone on the Brain, edited by D. Ganten and D. Pfaff, Berlin, Springer-Verlag, pp. 31-81. Kohli, J.D., D. Glock and L.I. Goldberg (1983). Selective DA 2 versus DA 1 antagonist activity of domperidone in the periphery. Eur. J. Pharm. 89: 137-141. Kressin, N. A., A. M. Nielsen, R. Laravuso and G. E. Bisgard (1986). Domperidone-induced potentiation of ventilatory responses in awake goats. Respir. Physiol. 65: 169-180. Mir, A.K., D.S. McQueen, D.J. Pallot and S.R. Nahorski (1984). Direct biochemical and neuropharmacological identification of dopamine D-2 receptors in the rabbit carotid body. Brain Res. 291: 273-283. Olson, L. G., M.J. Hensley and N.A. Saunders (1982a). Ventilatory responsiveness to hypercapnic hypoxia during dopamine infusion in humans. Am. Rev. Respir. Dis. 126: 783-787. Olson, L.G., M.J. Hensley and N.A. Saunders (1982b). Augmentation ofventilatory responses to asphyxia by prochlorperazine in humans. J. Appl. Physiol. 53: 637-643.
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Read, D.J.C. (1967). A clinical method for assessing the ventilatory response to CO 2. Aust. Ann. Med. 16: 22-32. Rebuck, A. S. and A. S. Slutsky ( 1981). Measurement of ventilatory responses to hypercapnia and hypoxia. In: Regulation of Breathing, Lung Biology in Health and Disease, edited by T. H. Hornbein. New York, Marcel Dekker, Inc., pp. 745-772. Schoene, R.B., D.J. Pierson and D.L. Lakshminarayan (1980). Effect of medroxyprogesterone acetate on respiratory drive and occlusion pressure. Bull. Physio-Pathol. Respir. 16: 645-653. Skatrud, J. B., J. A. Dempsey and G. D. Kaiser (1978). Ventilatory response to medroxyprogesterone acetate in normal subjects: time course and mechanism. J. Appl. Physiol. 44: 939-944. Stone, D.J., H. Keltz, T.K. Sarkar and J. Singzon (1973). Ventilatory response to alpha-adrenergic stimulation and inhibition. J. Appl. Physiol. 34: 619-623. Ward, D. S. and J.W. Bellville (1982). Reduction of hypoxic ventilatory drive by dopamine. Anesth. Analg. 61: 333-337. Ward, D. S. (1987). The role of the peripheral D-2 dopamine receptors in hypoxic ventilatory response. In: Concepts and Formalizations in the Control of Breathing, edited by G. Benchetrit, P. Baconnier and J. Demongeot. Manchester: Manchester University Press, pp. 157-163. Welsh, M.J., D.D. Heistad and F.M. Abboud (1978). Depression of ventilation by dopamine in man; evidence for an effect on the chemoreceptor reflex. J. Clin. Invest. 61: 708-713. Zwillich, C.W., M.R. Natalino, F.D. Sutton and J.V. Well (1978). Effects of progesterone on chemosensitivity in normal men. J. Lab. Clin. Med. 92: 262-269.
359
RESP 01690
Effects of domperidone and medroxyprogesterone acetate on ventilation in man Shahrokh Javaheri and Luis F. Guerra Pulmonao" Secthm and Medical Services, Veterans Affairs Medical Center. and Department of Medicine, University of Cincinnati College of Medicine. Cincinnati, Ohio, U.S.A.
(Accepted for publication 8 May 1990) Abstract. If endogenous dopamine acts as an inhibitory neurotransmitter in the carotid bodies in man, domperidone (DP), a selective dopamine D-2 receptor antagonist should stimulate carotid bodies and augment ventilation. Furthermore, the combination of a central ventilatory stimulant, medroxyprogesterone acetate (M PA), with a peripheral ventilatory stimulant, DP, may produce an additive/synergistic ventilatory effect. We conducted a double-blind, placebo-controlled (P), cross-over trial comparing MPA 20 mg three times daily (TID) and DP (20 mg TID) alone and together in 8 healthy male human subjects. Drug effects were measured after 7 days, and a two-week drug washout period was allowed. MPA significantly increased alveolar ventilation (~'.,x), and slopes of hypercapnic and hypoxic ventilatory responses. Domperidone alone significantly increased the slope of the hypoxic response; however, VA and Pa(.o, did not change significantly. The combination of MPA and DP resulted in ventilatory changes similar to MPA alone. We conclude that in man endogenous dopamine acts as a modulator of chemoreception during hypoxemia, but plays no major role tonically in control of ventilation during normoxemia and normocapnia. Lack of additive effect with combined DP and MPA suggests that these drugs may share the same final common pathway in the process of chemoreception.
Animal, man; Carotid bodies, and dopamine; Chemoreceptor, modulation by dopamine; Drug, domperidone, medroxyprogesterone acetate; Neurotransmitter, dopamine
T h e c a r o t i d b o d i e s m e d i a t e the v e n t i l a t o r y r e s p o n s e to h y p o x e m i a in h u m a n beings. W i t h i n the c a r o t i d b o d i e s (peripheral c h e m o r e c e p t o r s , P C R ) d o p a m i n e has b e e n f o u n d in large c o n c e n t r a t i o n s and m a y serve as a n e u r o t r a n s m i t t e r in the c h e m o r e c e p t i o n o f h y p o x e m i a ( F i d o n e et al., 1980). S u p p o r t i n g e v i d e n c e for this action c o m e s f r o m studies identifying the p r e s e n c e o f d o p a m i n e r e c e p t o r s within the c a r o t i d b o d i e s ( M i r et al., 1984), d e p r e s s i o n o f ventilation in a n i m a l s and h u m a n s with i n t r a v e n o u s a d m i n i s t r a t i o n o f d o p a m i n e ( W e l s h et al., 1978; W a r d a n d Bellville, 1982; O l s o n et al., 1982a), a n d a u g m e n t a t i o n o f v e n t i l a t i o n after a d m i n i s t r a t i o n o f d o p a m i n e r e c e p t o r a n t a g o n i s t s
Correspondence to: S. Javaheri, Director Sleep Laboratory, Pulmonary Section (111F), Veterans Affairs Medical Center Cincinnati, OH 45220, U.S.A.
0034-5687/90/$03.50 (c2 1990 Elsevier Science Publishers B.V. (Biomedical Division)
360
s JAVAIIERI AND L.F. GUERRA
(Olson et al., 1982b; Delpierre et al., 1987 ; Kressin et al., 1986; Bainbridge and Heistad, 1980). However, the role of endogenous dopamine in chemoreception in man still remains controversial. This is because the effects of dopamine receptor antagonists are difficult to interpret, considering the agents used in most studies cross the blood-brain barrier (BBB) which may exert an independent effect on ventilation (Bainbridge and Heistad, 1980; Olson et al., 1982a; Ward, 1987; Bonora et al., 1988; Ilender et al., 1982). Domperidone (DP) is a new, selective dopamine D-2 receptor antagonist which does not cross the BBB (Hender et al., 1982; Brogden et al., 1982; Champion et al., 1986). In animal studies, DP has been shown to augment resting ventilation and increase chemosensitivity to hypoxia and hypercapnia (Kressin et al., 1986). Medroxyprogesterone acetate (MPA) augments resting ventilation in man (Zwillich et al., 1978; Skatrud et al., 1978; Schoene et al., 1980) and it has been shown in some studies (Zwillich et al., 1978; Schoene et al., 1980) to increase chemosensitivity to hypercapnia. Although the exact site of action remains unclear, it is believed that MPA exerts its effect through central nervous system (CNS) stimulation (Dempsey et al., 1986; Kato, 1985). The purpose of this study was to investigate the ventilatory effects of DP in normal man after chronic oral administration and to compare its effect to MPA. Furthermore, the potential additive/synergistic effects of combining a peripheral ventilatory stimulant, DP, with a presumably central ventilatory stimulant, MPA, was evaluated.
Methods
Eight healthy male subjects, ages 28-42 years served as study subjects. All were nonsmokers and were free from any medical illnesses. Informed consent was given by all subjects, and the protocol was approved by the Institutional Review Board at the University of Cincinnati College of Medicine. Baseline spirometric and ventilatory parameters were obtained prior to drug trials and served as a training run. The ventilatory effects of DP and MPA were evaluated when used alone and in combination using a placebo (P) controlled, double-blind, crossover design. Identical capsules containing either P, 20 mg DP, or 20 mg MPA were made by the Pharmacy Department and were blinded to the investigators. Two capsules were taken three times daily (TID) for seven days such that each subject completed the following drug sequences in a random fashion: P + P, DP + P, MPA + P, and MPA + DP. The reason for the choice of MPA at 60 mg per day was that previous studies using MPA as a respiratory stimulant used this dose (Dempsey et al., 1986). In regard to DP, 60 mg per day also appears to be the maximal acceptable amount by most investigators who have used the drug and have dcmonstrated its efficacy in gastrointestinal disorders (Champion et al., 1986; Brogden el al., 1982). Spirometric and ventilatory measurements were obtained on day seven, followed by
D O M P E R I D O N E AND PROGESTERONE
361
a two-week washout period between drug runs. For each subject measurements were performed two hours postprandially and at the same time of day to eliminate the effects of diurnal variation. Measurements were obtained within 1 to 2 h after ingestion of the last doses of various drug regimens. All subjects refrained from beverages containing caffeine derivatives on the day of study. The sequence of measurements made at baseline and after drug runs were identical for all subjects. Weight, height, oral temperature (using a mercury thermometer) and blood pressure were measured after assuming the supine position for at least 5 minutes. Later, arterial blood samples were obtained anaerobically in the sitting position by radial artery puncture. The samples were obtained in 5 ml syringes whose dead space was filled with heparin solution. Care was exercised not to disturb steady state; skin was anesthetized with 2 °Jo lidocaine to eliminate pain and anxiety. The blood was collected over several breath cycles. Arterial blood gases and pH were measured in duplicate in appropriate electrodes (ABL 2, Acid-Base Laboratory, Radiometer, Copenhagen) at 37 °C. Functional residual capacity (FRC) was determined in a plethysmograph (Collins Body Plethysmograph System, W.E. Collins, Inc., Braintree, MA). Spirometric tests were performed in triplicate (Collins/DS, W.E. Collins, Inc., Braintree, MA) and the highest value for each measurement was used for calculations. The ventilatory tests were measured in the sitting position with a nose clip in place and breathing through a mouthpiece connected to a low resistance 2-way valve (Hans-Rudolph, Kansas City, MO). Subjects listened to their music of choice by radio-headphones. Inspiratory flow and volume were measured by a pneumoscan (S-301, K L Engineering Co., Sylmar, CA). Calibration were done by known flow rates from a pneumatic calibrator (Model 65-250, Penwalt Cor., Bellville, N J) and for volume by a 3 L syringe. End-tidal CO2 was sampled at the mouthpiece by an infrared CO 2 analyzer (Beckman Medical Gas Analyzer, LB-2, Beckman Cardiopulmonary Instruments, Fullerton, CA) calibrated with gases of known CO2 concentration. Arterial oxygen saturation was measured by ear-oximetry (BTI Biox IIA, Bioximetry Technology, Inc., Boulder, CO). Actual measurements started after achievement of steady-state, as evidenced by a stable end-tidal Pco2. Resting ventilation was measured when the subject breathed room air during which a timed volume of exhaled gas was collected for calculation of 0 2 consumption (Vo2) and CO 2 production ('qco2). Mixed-expired CO 2 and 0 2 concentrations were measured by gas analyzers (Beckman Medical Gas Analyzers). Dead space was calculated using Bohr's equation, knowing arterial and mixed-expired Pco2. Alveolar ventilation (VA) was calculated form the equation "qA = RR (VT - VD). The hypercapnic ventilatory response (HCVR) was performed in duplicate using a modification of the rebreathing method of Read (1967). The test was performed using a bag containing a volume of gas (93 j°o 0 2 + 7~o CO2) equal to subject's vital capacity plus 1 L. The subject took three deep breaths from the bag to facilitate gas mixing; data points after appearance of mixed venous Pco_~ plateau were used for calculations. The HCVR was stopped when end-tidal CO 2 concentration was approximately 8 °,o. Linear
362
S. JAVAHERI AND L.F. GUERRA
regression was used in the equation : V = S (Pco2 - B), where S is the slope of HVCR, and B is the intercept on the Pco: axis. We also calculated the predicted ventilation for PEco ~, = 60 mm Hg (VI 60) for each subject. The isocapnic hypoxic ventilatory response (HVR) was performed in duplicate by the rebreathing method detailed by Rebuck and Slutsky (1981). The subject rebreathed from the same bag initially containing a small amount of gas (24~0 02, 7~, CO2, balance N2). Isocapnia was maintained by keeping end-tidal Pco2 at the prevailing levels by removing appropriate amount of CO2 from the circuit by two variable speed pumps which were connected to a CO 2 absorber. Nitrogen was added to the system and rebreathing was stopped when arterial 0 2 saturation reached 70~o. Data points between 90 to 70°~/o saturation were used for calculations by least squares regression analysis relating ventilation to saturation. A minimum of 10 rain was allowed between each response test. CO 2 production and 9o~ are expressed in STPD; all other volumes are expressed in BTPS.
Statistical analysis. Statistical significance was determined with one-way analysis of variance with repeated measures. In case of statistical significance, values during treatments were compared with placebo using two-tailed t-test with Bonferroni correction for three comparisons. P < 0.017 was considered significant. To determine synergism with DP + MPA, a two-way analysis of variance was used. The SAS computer system of the University of Cincinnati was used for calculations. Data are expressed in mean _+ SD.
Results
All eight subjects successfully completed the drug trials. Side effects occurred on two occasions in two subjects when taking MPA. The symptoms consisted of nonspecific feelings of tiredness and light-headedness. No side effects were noted with DP. Most physical and spirometric tests did not change significantly. Mean values for systolic and diastolic blood pressure were 105 + 12 and 66 _+ 4 mm Hg with P and did not change significantly during any of the drug trials. The mean values for body weight were 75.0 _+ 10, 74.5 _+ 10, 74.5 _+ 10, and 74.0 + 10 kg, respectively with P, MPA, DP, and MPA + DP. The mean values for oral temperature were 36.5 _+ 0.3, 36.8 + 0.1, 36.8 + 0.2 and 37.0 _+ 0.3 °C, respectively with P, MPA, DP, and MPA + DP. The rise in oral temperature with MPA + DP when compared to P was significant (P < 0.001). The mean values for FEVI(L), FVC(L), FEVI/FVC'/% and FRC(L) were respectively, 4.4 + 0.7, 5.2 _+ 0.7, 85 _+ 5, and 3.7 + 0.8 with P, and remained virtually constant during drug trials.
D O M P E R I D O N E AND P R O G E S T E R O N E
363
TABLE 1 Resting ventilation during various drug treatments. F (min P + P
')
12.7 -+3.7 14.7"* -+3.4 14.1 +3.0 15.6*** +3.6
MPA + P DP + P MPA + DP
VT (ml)
~)l (L.min
696.8 _+ 161.9 708.8 -+ 156.8 665.5 -+ 138.9 670.8 +117.7
8.39 _+ 1.47 10.0(;*** -+ 1.72 9.07 +_0.89 10.27"** -+1.6
i)
VD (L.min
VA (L'min
i)
2.83 _+0.99 3.47 -+0.49 3.24 -+0.49 3.32 -+0.91
VD/VT i)
5.56 -+0.78 6.48** -+0.81 5.79 -+0.60 6.89*** _+1.33
0.33 _+0.07 0.34 -+0.06 0.36 -+0.04 0.34 -+0.08
Mean + SD; N = 8; P = placebo; MPA = medroxyprogesterone acetate; DP = domperidone; ventilation is in BTPS; ** = P < 0.01; *** = P < 0.001. No synergism was found with DP + MPA.
Resting ventilation. duced
Medroxyprogesterone
acetate, when
compared
to placebo,
pro-
a s i g n i f i c a n t i n c r e a s e in r e s t i n g ~/t a n d ~/A ( t a b l e 1). B l o o d g a s a n a l y s i s w a s
consistent with this ventilatory change revealing significant hypocapnia reduction
in p l a s m a
( t a b l e 2). D o m p e r i d o n e
[HCO3
] with plasma
[H + ] remaining
and a significant
relatively unchanged
a l o n e d i d n o t r e s u l t in a n y s i g n i f i c a n t c h a n g e s
in r e s p i r a t o r y
f r e q u e n c y , VA o r P a c o ~ ( t a b l e s 1 a n d 2). When MPA
a n d D P w e r e g i v e n in c o m b i n a t i o n ,
f r e q u e n c y , ~/I a n d ~/A w a s n o t e d , p r o d u c i n g reduction
in p l a s m a
[HCO3
a s i g n i f i c a n t i n c r e a s e in r e s p i r a t o r y
a significant hypocapnia
] ( t a b l e s 1 a n d 2). S y n e r g i s m
between
and a significant MPA
and DP,
TABLE 2 Resting gas exchange and arterial blood acid-base variables during various drug treatments.
P + P MPA + P DP + P MPA + DP
Paco: (ram Hg)
[HCO; ] (mmol. L l)
[H ~ ] (nmol. L)
PaQ (ram Hg)
£Zco: (ml.min
40.0 _+ 1.8 34.6*** + 1.6 39.8 -+2.1 35.8*** +4.7
25.1 +0.8 22.1"* -+ 1.3 24.5 -+ 1.6 22.7* _+3.1
38.8 -+ 1.5 38.2 -+ 1.3 38.9 _+0.9 37.8 -+ 1.5
92.9 -+4.6 95.1 +4.5 91.8 -+7.4 94.8 + 7.9
167.6 _+28.6 182.5 -+ 15.9 177.9 -+26.5 180.3 -+ 25.1
l)
~Zo2 (ml.min 224.4 +32.7 227.4 +21.4 250.2 -+81.1 232.2 -+ 38.4
R 1) 0.75 +0.11 0.81 +0.11 0.75 -+0.16 0.78 ± 0.10
Mean _+ SD; N = 8; P = placebo; MPA = medroxyprogesterone acetate; DP = domperidone; Vco2 = CO2 production, '¢o~ = 02 consumption (STPD); R = respiratory exchange ratio; * = P < 0.017; ** = P < 0.01 ; • ** = P < 0.001. No synergism was found with DP + MPA.
364
S. JAVAHER[ AND L.F. GUERRA 7.0 6.5 ,
6.0
"1"
5.5
CD
E
E
s.o
,~
4.5
E.
4.0
[1~
3.5
>
0
3.o
~ m
2.5
:_:,-- . . . . : < : : - : 2 . . . . . . . . . . . . . . . .
2.0 1
1.5
DP
MPA
Fig. 1. Slopes (S) of hypercapnic vcntilatory responses (HCVR) fbr placebo (P), domperidone (DP) and medroxyprogesterone acetate (MPA). For clarity data of DP + MPA are not shown.
however, was not evident. There were no significant changes in Vco2, '¢o2, or respiratory exchange ratio (table 2) with the use of either drug.
Hypercapnic ventilator), response. F i g u r e 1 s h o w s c h a n g e s in t h e S o f H C V R o f e a c h subject for P, D P and MPA. The S of the H C V R was significantly increased with M P A (table 3). In addition, the response curve was significantly shifted to the left as indicated by a decrease in the X-intercept and an increase in "v'I(60). D o m p e r i d o n e increased the S of H C V R (fig. 1) and V](60) slightly but not significantly (table 3). When M P A and D P were used in combination an increase in the S of the H V C R (P = 0.02) and leftward shift in intercept were observed (table 3). This effect was not greater than when M P A was used alone.
4,0
7%¢, 3.S i
.--:-:'"~ . . . . . . . .
....
.
.c_
2.5
....
E
::2;';; ....
ft.
1.s
g" r
1.o
........ ::
0.5
.........................
0.0
""" 1
P
DP
MPA
Fig. 2. Slopes (S) ofhypoxic ventilatory responses (HVR) for placebo (P), domperidone (DP) and medroxyprogesterone acetate (MPA). For clarity data of DP + MPA are not shown.
+ 0.93
4.30 + 3.3
36.9***
39.3 + 2.8
4.13
+3.5
+ 1.25
_+ 1.23
37.0**
± 2.9
_+0.83
4.58**
39.8
3.38
X (mm Hg)
± 19.3
99.3***
_+ 19.8
82.8
_+25.1
102,2"**
i 11.7
66.5
V1 (60) (L'min 1)
± 1.30
- 1.99"**
+ 1.38
- 1.89"
+ 1.38
- 1.96"*
+ 0.74
- 1.22
S, H V R (L'min
l-~oSat
1)
± 120.1
192.4"*
+ 123.8
179.0"
_+ 121.4
185.7"*
± 67.0
118.7
Y (L.min
1)
r e s p o n s e ; VI (60) = ventilation at end-tidal P c o 2 o f 60 m m H g ; * = P < 0.017; ** = P < 0.01 ; *** = P < 0.001. T h e S o f H C V R with M P A + D P w a s significant at P = 0.02.
M e a n _+ S D ; N = 8. P = p l a c e b o ; M P A = m e d r o x y p r o g e s t e r o n e a c e t a t e ; D P = d o m p e r i d o n e ; S = slope; H C V R a n d H V R = h y p e r c a p n i c a n d h y p o x i c v e n t i l a t o r y
MPA + DP
DP + P
MPA + P
P + P
S, H C V R (L.min l'mmHg-l)
Hypercapnic and hypoxic ventilatory responses during various drug treatments.
TABLE 3
© z,'-m
,H
0
> Z
L; 0 Z
7z
©
366
s. JAVAHERI AND I..F. GUERRA
Hypoxic ventilatorv response. Figure 2 shows changes in the S of HVR of each subject for P, DP, MPA. The mean value for S of HVR (table 3) obtained with P was similar to that reported by Rebuck and Slutsky (1981). Both MPA and DP when used alone significantly increased the S of HVR (table 3). The increase in HVR noted after combination of MPA and DP was not significantly greater than when MPA or DP was used alone.
Discussion The conclusions of this study are: (1) orally administered DP increases HVR but does not significantly change resting ventilation and Paco2; (2)orally administered MPA increases "(/A and causes chronic respiratory alkalosis; MPA increases HCVR and HVR; and (3) surprisingly, combination of MPA and DP results in ventilatory stimulation essentially similar to MPA. Before we discuss the ventilatory effects of the drugs in detail, we emphasize that the experimental design of the study was placebo-controlled, cross-over, and double-blind. Furthermore, because of the short period of drug trials (one week each time), no known side effects which would be characteristic of a drug (e.g. impotence due to MPA) occurred,
Ventilatorv effects o f M P A . This study shows that MPA, at 20 mg TID, is a moderate respiratory stimulant. The mean Paco_~ dropped by 5 mm Hg as a result of an increase in VA, with Vc:o_~ (and Vow) remaining unchanged. MPA caused chronic respiratory alkalosis characterized by about 3 mmol/L drop in plasma [ H C O 3 ] with little change in plasma [H + ]. Changes in ventilation and P a c o 2caused by MPA noted in the present study are virtually identical to those observed by Skatrud and associates (1978) using a similar protocol. Furthermore, our finding that MPA increased the S of HCVR is in agreement with studies of Zwillich et al. (1978) and Schoene and associates (1980). This observation is important because it suggests that MPA may act centrally as a stimulant, increasing the sensitivity of the central structures to the existing afferent inputs. MPA also significantly increased the S of HVR as previously reported by Zwillich and associates (1980). This observation indicates that MPA stimulates either carotid bodies and/or the central structures involved in integration of chemoreception from PCR (central amplification). Although the mechanism of respiratory action of progesterone is not yet elucidated, it is known that progesterone acts on cytosolic, as well as nuclear receptors and induces synthesis of specific proteins (Kato, 1985). These biochemical events may conceivably be involved within the PCR and CNS network of control of ventilation as MPA and progesterone have been shown to cross the BBB (Dempsey et al., 1986; Kato, 1985), and specific intracranial progesterone receptors have been identified (Kato, 1985). The small rise in body temperature noted after MPA may have contributed to the
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ventilatory responses to hypercapnia and hypoxemia; however, this is doubtful since DP, which equally increased body temperature, resulted in only minor augmentation of HCVR (table 3). Ventilatorv effects of DP. Dense-cored vesicles exist in the Type I (chief or principal) cells of the carotid body (Fidone et al., 1980). These vesicles contain catecholamines, primarily dopamine and norepinephrine and have been identified in the carotid bodies of all species so far studied (Fidone et al., 1980). Although there are species differences (Eyzaguirre and Monti-Bloch, 1980), there is growing evidence that in man exogenous dopamine has an inhibitory effect on the carotid bodies (Welsh et al., 1978; Ward and Bellville, 1982; Olson et al., 1982a). Studies of Welsh and associates (1978) showed that intravenous infusion of dopamine in man at therapeutic doses resulted in a small fall in ~/A and minimal rise in P a c o 2. Furthermore, dopamine infusion diminished the magnitude of the hyperventilatory response to hypoxic but not hypercapnic gas breathing, strongly suggesting that the site of action was in the carotid bodies. Similar observations were reported by Olson and associates (1982a), and Ward and Bellville (1982). However, Ward and Bellville (1982) demonstrated that dopamine infusion partially suppressed CO 2 sensitivity, and this was presumed to represent the portion contributed by carotid bodies. Because dopamine does not cross the BBB, its ventilatory effects cannot be attributed to central mechanisms. The studies of dopamine infusion in man strongly indicated the presence of inhibitory receptors outside CNS that respond to exogenous dopamine (Welsh et al., 1978; Ward and Bellville, 1982; Olson et al., 1982a). Yet these experiments provide no conclusive evidence as to the physiological role of endogenous dopamine, important information which is obtained from experiments using specific dopamine receptor antagonists. Dopamine receptors are divided into D-1 and D-2 receptors (Kohli et al., 1983); D-1 excitation activates adenyl-cyclase, whereas D-2 receptors inhibit cyclic AMP formation. Radioligand-binding studies have shown that dopamine receptors in carotid bodies are of subtype D-2 (Mir et al., 1984). Dopamine receptors also exist within the CN S and these may influence the central network ofventilatory control in a complicated manner (Hender et al., 1982). In addition, inhibition of dopamine in the CNS may also cause sedation which per se may influence ventilatory control. Ventilatory effects of dopamine antagonists have been reported in man. Bainbridge and Heistad (1980) used haloperidol, and Olson and associates (1982b) used prochlorperazine as dopamine antagonist. The two studies reported opposing results on baseline ventilation in man. Dopamine-receptor antagonists used in these studies (Bainbridge and Heistad, 1980; Olson et al., 1982b) react with both receptors to various degrees. These antagonists also cross the BBB and in addition may cause sedation. Domperidone, which has been used in Europe as an antiemetic for a long time is a specific dopamine D-2 receptor antagonist which does not cross the BBB (Champion etal., 1986; Brogden etal., 1982), and in contrast to other antagonists, has no ~-2 receptor blocking activity (Kohli et al., 1983). In the present study, DP was not associated with any side effects, and sedation was
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not noted by any subject. In contrast to the ventilatory effects of other dopamine antagonists used in previous studies (Bainbridge and Heistad, 1980; Olson et al., 1982b) in the present study DP had no significant effect on baseline ventilation, Vco2 and Paco ~. Domperidone, however, significantly augmented HVR. These data strongly suggest that dopamine D-2 receptor is involved in transduction of HVR in man. Because DP did not affect baseline ventilation during normoxemia, we also cautiously suggest that dopamine should not contribute to the tonic baseline carotid body activity in man. In the context of the latter conclusion, we emphasize that we did not perform dose-response studies, but used the maximum dose of DP which has been shown to affect other peripheral actions of dopamine such as those of gastrointestinal tract (Champion et al., 1986; Brogden et al., 1982). In a typical study (reviewed by Champion et al., 1986), DP 20 mg TID was compared to metoclopramide at the same dose for treatment of symptomatic endoscopically proven gastrointestinal disorders; with both drugs equally effective, metoclopramide resulted in some extrapyramidal side effects. It is emphasized that although DP lacks c~-2 receptor blocking activity, it acts as an ~-1 receptor inhibitor (Ennis and Cox, 1980). Therefore, contribution of c~-I receptor blockade by DP to changes in HVR observed in the present study cannot be quantitated. However, there is some evidence that ~-1 receptor stimulation does not play a major role in ventilatory response in man (Stone et al., 1973). While our study with 'chronic' oral administration of DP was in progress, results of two studies with acute intravenous administration of DP on HVR have been published (Ward, 1987; Delpierre et al., 1987) and confirm our observation. In the study reported by Delpierre and associates (1987), DP was given intravenously in a double-blind fashion, and it augmented HVR without changing baseline ventilation or arterial blood pressure. Hypercapnic ventilatory response was not measured in these two studies. In the present study, DP resulted in a small but insignificant augmentation of HCVR (table 3) and this may reflect the small contribution of the PCR to HCVR. Ventilatory effects of combined M P A and DP. An important aspect of the design of the present study was to combine a PCR respiratory stimulant with a (presumably) predominantly centrally-acting drug. We had hoped that if the drugs had different mechanisms of action, and if there was a central amplification of the PCR input, the combination would result in either an additive or synergistic ventilatory response which would prove useful in treatment of disorders with diminished respiratory drive. Both MPA and DP augmented HVR when given alone, but synergistic or additive effect was notably absent with combined MPA and DP therapy. These negative results, however, may have important implications in control of ventilation in man. Lack of additive effect suggests that the two drugs may share a common pathway in chemoreception in carotid bodies. Lack of synergistic effect between MPA and DP further suggests that in man afferent input from carotid bodies may not be amplified within the central network of breathing (central amplification), or else central amplification is not sensitive to progesterone. Although our study with combination drug therapy did not show any synergistic
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v e n t i l a t o r y effect, it is still c o n c e i v a b l e t h a t o t h e r d r u g s w i t h d i f f e r e n t m e c h a n i s m s o f a c t i o n (e.g., a l m i t r i n e ) w h e n c o m b i n e d w i t h M P A m a y p o t e n t i a l l y h a v e s y n e r g i s t i c effect w h i c h m a y p r o v e t h e r a p e u t i c a l l y effective in t r e a t m e n t o f d i s e a s e s w i t h d i m i n i s h e d r e s p i r a t o r y drive.
Acknowledgement. This research was supported in part by grants from the Department of Veterans Affairs. The authors thank Janssen Pharmaceutica (Picataway, New Jersey) for their generous supply of domperidone and Ms Saundra K. Eversole for her secretarial assistance.
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