Effects of Fenoterol on Ventilatory Responses to Hypoxia And

Thorax 1995;50:139-142 139 Effects of fenoterol on ventilatory responses to

hypoxia and hypercapnia in normal subjects Thorax: first published as 10.1136/thx.50.2.139 on 1 February 1995. Downloaded from

Yasuhiro Yoshiike, Shunsuke Suzuki, Yuuji Watanuki, Takao Okubo

Abstract Lahiri et al' directly measured the carotid Background - The effects of P2 adrenergic chemoreceptor activity and showed that agonists on chemoreceptors remain con- isoprenaline excited the carotid body. Thus, troversial. This study was designed to ex- isoprenaline acts on the P adrenergic receptors amine whether fenoterol, a P2 adrenergic of the carotid body and increases ventilation. agonist, increases the ventilatory re- The effects of 12 adrenergic agonists on the sponses to hypercapnia (HCVR) and hyp- central chemoreceptors remain controversial. oxia (HVR) in normal subjects. Some studies78 showed that 2 adrenergic agon- Methods - HCVR was tested with a re- ists potentiate ventilatory chemosensitivity, but breathing method and HVR was examined this was not a universal finding9 and this dis- with a progressive isocapnic hypoxic crepancy may result from a species difference. method in 11 normal subjects. Both HCVR Furthermore, little is known about the effects and HVR were assessed by the slope of of P2 adrenergic agonists on the ventilatory occlusion pressure (P0.1) or ventilation response to hypoxia. It may be necessary to (VE) plotted against end tidal carbon di- consider the effects of 12 agonists on ventilatory oxide pressure and arterial oxygen sat- control when treating patients with airways uration, respectively. Respiratory muscle obstruction. The purpose of the present study strength, spirometric values and lung vol- was to investigate the quantitative effects of ume were measured. After a single oral fenoterol, a 12 adrenergic agonist, on ventilatory administration of 5mg fenoterol or pla- responses to hypercapnia and hypoxia in nor- cebo HCVR and HVR were evaluated. mal subjects. Results - Fenoterol treatment did not change the specific airway conductance or forced expiratory volume in one second. Methods Respiratory muscle strength did not

SUBJECTS http://thorax.bmj.com/ change. Fenoterol increased the slope of Eleven healthy non-smoking men whose mean the HCVR of both Po., (from 0-251 (0.116) (SD) age was 29-0 (6-2) years (range 24-46 to 0-386 (0.206) kPalkPa, average increase years) participated in the study. All were med- 71%) and VE (from 10-7 (3.4) to 15-1 (4-2) ical personnel and had no history of chronic l/min/kPa, average increase 52%), and respiratory or circulatory diseases. All gave in- shifted the response curves to higher val- formed consent and the study was approved ues. For the HVR fenoterol increased the by the institution's committee on investigation slopes of both Po., and VE (from - 4-06 in humans. (2.00) x 10-3 to -7*99 (4.29) x 10-' kPa/ on September 23, 2021 by guest. Protected copyright. %, an average increase of 83%, and from -0-221 (0.070) to -0-313 (0.112) IIminP/o, a 44 5% increase, respectively), and shifted PULMONARY FUNCTION TESTS the response curves to higher values. Spirometric measurements (forced expiratory Conclusion - Acute administration offen- volume in one second (FEVI) and vital capacity oterol increases the ventilatory responses (VC)) were performed using a dry seal spiro- to both hypercapnia and hypoxia in normal meter (OST-80, Chest Co, Tokyo) and body subjects. plethysmography (Autobox 2800, Gould, (Thorax 1995;50:139-142) USA) was used to measure specific airway The First Department conductance (sGaw) and functional residual of Internal Medicine, Keywords: fenoterol, 3 adrenergic agonist, hypercapnic capacity (FRC). Yokohama City ventilatory response, hypoxic ventilatory response. University School of Medicine, 3-9 Fukuura, Kanazawa-ku, VENTILATORY RESPONSES TO HYPERCAPNIA AND Yokohama 236, Japan Isoprenaline, a potent 13 adrenergic agonist, is HYPOXIA Y Yoshiike S Suzuki known to induce hyperpnoeal although the Chemical control of breathing was assessed by Y Watanuki mechanisms underlying this are disputed. measuring minute ventilation (VE) and oc- T Okubo Heistad et all and Winn et al' showed that clusion pressure (PO.,) responses to hypercapnia Reprint requests to: intravenous isoprenaline increased ventilation or hypoxia. Response to hypercapnia (HCVR) Dr S Suzuki. by stimulation of the peripheral chemo- was measured by a modification of the Read Received 21 January 1994 receptors and ventilation was augmented by technique.'0 The circuit used was similar to that Returned to authors 26 April 1994 moderate hypoxia. Wasserman et al' found that of Whitelaw et al." A two way non-rebreathing Revised version received bilateral sectioning of the carotid sinus nerves valve (Hans-Rudolph no. 1400, Kansas City, 6 July 1994 Accepted for publication substantially decreased the ventilatory response USA) was attached to the mouthpiece; both 2 November 1994 to isoprenaline. Eldridge and Gill-Kumar5 and inspiratory and expiratory sides of the valve 140 Yoshiike, Suzuki, Watanuki, Okubo

were connected to the rebreathing bag. Mouth P1., and Sao2 (AVE/ASao2 and AP0.,/ASao2, pressure was measured from the side tap of respectively). the mouthpiece using a differential pressure transducer (MP-45 Validyne, Northridge, Thorax: first published as 10.1136/thx.50.2.139 on 1 February 1995. Downloaded from USA). Airflow was measured with a Fleisch RESPIRATORY MUSCLE STRENGTH pneumotachograph (Fleisch no. 1, Lausanne, As we had previously found that fenoterol in- Switzerland) placed between the mouthpiece creased the strength of the fatigued canine and the two way valve. The volume was ob- diaphragm,'3 respiratory muscle strength was tained from electrical integration of the flow assessed by measuring mouth pressures during signal. The inspiratory side of the two way maximal static inspiratory (PImax) and ex- valve was connected with a solenoid valve which piratory (PEmax) efforts against a closed valve was capable of occluding the side of the valve. with a small air leak to prevent glottic closure.'4 The solenoid valve was closed during expiration Pimax was measured at FRC and residual vol- and opened no later than 200 ms after the ume (RV) and PEmax was measured at FRC beginning of inspiration using an analog elec- and total lung capacity (TLC) with a differ- trical circuit, by which a breathing cycle for ential pressure transducer (Validyne MP -45 measurement of occlusion pressure was manu- + 250 mm Hg). The determinations of Pimax ally selected. Occlusion pressure (PO.,) was ob- and PEmax were repeated until three meas- tained from the pressure measured 100 ms after urements varying by <5% and sustained for >2 the onset of inspiration, as defined by the ap- seconds were recorded; the highest value thus pearance of a negative mouth pressure. The obtained was reported. expiratory side was sampled continuously by a mass spectrometer (WSMR-1400; Westron, Chiba, Japan). The resistance ofthe inspiratory PROTOCOL side was 0 059 kPa/l/s, while that of the ex- The study was performed at the same time of piratory circuit was 0 049 kPa/l/s. Subjects day on two different days at least two days wearing nose clips were seated comfortably in apart and within a seven day interval. Subjects front of the rebreathing circuit and held the were instructed to refrain from caffeine-con- mouthpiece in position. Initially they breathed taining beverages, alcohol, and other drugs air by a bypass of the rebreathing bag to room for 24 hours before the study. HCVR was air until the circuit was equilibrated. They then examined in all subjects while HVR was meas- rebreathed a gas mixture of 7% carbon dioxide ured in seven of the 11 subjects. On each test and 93% oxygen from a six litre bag. During day the baseline measurements of pulse rate rebreathing the inspiratory side of the circuit (PR), blood pressure (BP), ventilation and was occluded randomly every 4-6 breaths. Re- PETCO2 were performed at rest. Either 5 mg was continued until the breathing end tidal fenoterol (Boehringer Ingelheim of Japan, http://thorax.bmj.com/ partial pressure of carbon dioxide (PETCO2) Kawanishi, Japan) or placebo was then reached about 8-7 kPa or the subject com- administered orally in a randomised, double plained of dyspnoea. The test was usually blind, crossover design on the first or second terminated within 3-4 minutes. Minute vent- day. Two hours after fenoterol or placebo ad- ilation (VE) was calculated as the average of ministration, pulmonary function tests, res- the two successive breaths preceding the one piratory muscle strength, heart rate, blood used for occlusion. Simultaneously the PETCO2 pressure, ventilation, and PETCO2 were meas- was measured. Hypercapnic response was as- ured and HCVR and HVR were then cal- sessed by the slopes of linear regressions be- culated. For HVR PETCO2 was controlled at on September 23, 2021 by guest. Protected copyright. tween VE and PETCO2 and between Po., and the baseline level before administration of fen- PETCO2 (AVE/APETCO2 and AP0 1/APETCO2, re- oterol or placebo because fenoterol could de- spectively), calculated by the least squares crease PETCO2. The order of the tests (HCVR method. Fifteen to 20 breath pairs were used and HVR) was randomised and at least 10 for analysis. minutes was allowed between tests. Hypoxic ventilatory response (HVR) was measured by a modification of the progressive isocapnic hypoxia method of Rebuck and DATA ANALYSIS Campbell. 12 Subjects rebreathed using the HCVR and HVR varied by approximately 20% same rebreathing circuit as for the hypercapnic and the sample size required to discern a sig- response, except the rebreathing bag contained nificant difference from the drug was 10. All eight litres of a gas mixture of 3-5% carbon values are expressed as the mean (SD). Stat- dioxide, 23% oxygen, and 73-5% nitrogen and istical analysis was performed using the a bypass carbon dioxide absorber was used. Wilcoxon signed rank test and the two way During the test arterial oxygen saturation analysis of variance (ANOVA). A p value of (Sao2) was monitored with a pulse oximeter <0 05 was considered significant. (Biox 3700, Ohmeda, Boulder, USA). During rebreathing PETCO2 was kept constant at the baseline resting level by removal of carbon Results dioxide from the circuit with a variable AC Fenoterol did not affect FEVI, VC, FRC, or motor fan connected to a bypass carbon dioxide sGaw. Heart rate was increased by 8-0 (10-5)% absorber. Rebreathing was continued until Sao, (ANOVA, p<0 05) although systemic blood decreased to 75-80%. The hypoxic response pressure did not change. Baseline minute vent- was obtained from the slopes of linear re- ilation while breathing air and VT/TI were both gressions between VE and Sao2 and between increased by 15% with fenoterol (p<0-01). Effect offenoterol on HCVR and HVR 141 A B However, after drug treatment PETCO, did not 60 E 30 r differ between those given placebo and those given fenoterol (5 05 (0 38) v 489 (0 62) kPa). Further, the P0.1 during breathing air did not Thorax: first published as 10.1136/thx.50.2.139 on 1 February 1995. Downloaded from 50 [- differ between treatments (0-197 (0-105) v I- -P /7 0-243 (0 153) kPa). There was no difference 40 H 20 0 in Pimax or PEmax between the two treatments. For HCVR fenoterol increased the slope of Placeb O - 30 i- VE to PETCO2 (AVE/APETCo2) by 52 (43)% (p<0 01) and that of Po.1 to PETCO, (APO.,/ w APETCO2) by 71 (104)% compared with placebo in L 20 F- 1n 1 (p<0 05) (figs 1 and 2). VE at PETCO2 of 60 mm Hg (-8 kPa) was 39-6 (12-6) 1/min with fen- 10 |- oterol, which was higher than the value with placebo (31-2 (7-6) 1/min) (p<001). P0., at PETCO2 of 8 kPa (0 70 (0 35) kPa) after fen- O l 0 I I 6.0 7.0 8-0 9-0 80 90 100 oterol was higher than after placebo (0-54 (0-21) kPa) (p<0 05). PETCO2 (kPa) Sao2 (%) For HVR fenoterol increased the slope ofVE Figure 1 Mean (A) hypercapnic and (B) hypoxic ventilatory responses (HCVR and to Sao2 (AVE/ASao2) by 445 (53 4)%; p<005 HVR). Fenoterol treatment (dashed line) increased both HCVR and HVR compared (fig 1). It also increased the slope of Po. to with placebo (solid line). Average response curves were calculatedfrom slope means (A VEI Sao2 (AP0.,/ASao2) (-4-1 (2 0) x 10-3 with APETCO2 and A VE/ASao2), and mean VE values (at PETCO2 of 8 kPa with HCVR and x with at 80% Sao2 with HVR, respectively). Mean responses and 95% confidence intervals are placebo v -8&0 (4.3) 10-3 kPa/% represented by thick and thin lines, respectively. fenoterol, p<0 05) (fig 3). The position of the VE v Sao2 curve at Sao2 of 80% was higher than that of placebo (16-7 (1-8) v 19-5 (3 5) 1/ p<005). Similarly, fenoterol shifted the A B min, PO., curve to a higher Po.1 at Sao2 of 80% (0-29 25 E 1*0 (0-17) v 0-38 (0 20) kPa, p<002).

Cu 20 0.8 CL -e - Discussion E 15 0.6 ///A We have demonstrated that a single oral dose CL CN 0 of 5 mg fenoterol enhanced the ventilatory re- 0 0

sponses to both hypercapnia and hypoxia in http://thorax.bmj.com/ 10 0.4 CL normal muscle 0~ subjects. Respiratory strength

w conductance were not 6L and specific airway 5 02 changed. These data suggest that fenoterol stimulates both central and peripheral chemoreceptors, although it is unknown whether its o 0 Placebo Fenoterol Placebo Fenoterol action is direct or indirect. We measured the ventilatory response two Figure 2 Hypercapnic ventilatory response (HCVR). (A) Sl1 ope of VE versus PETCO2 hours after oral administration of the drug to on September 23, 2021 by guest. Protected copyright. curve (A VE/APETcoz) with placebo andfenoterol. (B) Slope XofP0., versus PETCO2 curve allow the plasma concentration of fenoterol to (AP0.,/APETCo2) with placebo andfenoterol. Open boxes and bars represent the 95% confidence interval and mean value, respectively. Fenoterol increased the slopes of the reach a maximum.'5 Since VE reflects the neural response curve of VE by 56% (p<001) and that of Po., by 104% (p<0 01). output to inspiratory muscles poorly when thoracic mechanics change,'6 we used occlusion pressure (P0.1) as a reflection of respiratory output. " Occlusion pressure may be affected by A B inspiratory muscle strength or lung volume.'7 -0.6 -40020 Fortunately, in this study neither FRC nor inspiratory muscle strength was affected by fenoterol treatment. Therefore, it is possible zo:! 18- 4-0.015 that both occlusion pressure and minute ventilation reflected the neural output of the res- centre - piratory in this study. E ~-0001~~ ~ ~ ~ ~ ~ ~ ~ ~ ~ 0 o w.o1o / s Fenoterol is a potent bronchodilator and may increase FEVy and sGaw even in normal

w-02 subjects. Resistive unloading with helium/oxygen breathing decreased but inhalation of

2 Keltz H, Samortin T, Stone DJ. Hyperventilation: a ma- Fenoterol increased the slopes of VE and nifestation of exogenous f-adrenergic stimulation. Am Rev Po., in HVR. The activity of the carotid body Respir Dis 1972;105:637-40. chemoreceptors increases with decreasing 3 Wasserman K, Mitchell RA, Berger AJ, Casaburi R, Davis

JA. Mechanism of isoproterenol hyperpnea in the cat. Thorax: first published as 10.1136/thx.50.2.139 on 1 February 1995. Downloaded from Pao2.'9 Isoprenaline is known to stimulate the Respir Physiol 1979;38:359-76. 4 Win R, Hildebrandt JR, Hildebrandt J. Cardiorespiratory carotid body through a i adrenergic responses following isoproterenol injection in rabbits. J mechanism.'`356 Fenoterol is a selective ad- Appl Physiol 1979;47:352-9. P2 5 Eldridge FL, Gill-Kumar P. Mechanisms of hyperpnea renergic agonist but also has weak , activity.20 induced by isoproterenol. Respir Physiol 1980;40:349-63. In the present study fenoterol did not affect 6 Lahiri S, Pokorski M, Davies RO. Augmentation of carotid body chemoreceptor responses by isoproterenol in the cat. the resting level of PETCO2 so that the level of Respir Physiol 1981;44:351-64. carbon dioxide did not affect HVR. It is there- 7 Leitch AG, Clancy U, Costello JE, Flenley D. 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