Anesth Analg 2001;93:230-233
© 2001 International Anesthesia Research Society
GENERAL ARTICLES
A Comparison of the Relaxant Effects of Olprinone and Aminophylline on Methacholine-Induced Bronchoconstriction in Dogs
Kazuyoshi Hirota, MD,
Hideki Yoshioka, MD,
Shizuko Kabara, MD,
Tsuyoshi Kudo, PhD,
Hironori Ishihara, MD, and
Akitomo Matsuki, MD
Department of Anesthesiology, University of Hirosaki School of Medicine, Hirosaki, Japan
Address correspondence and reprint requests to Dr. K. Hirota, Department of Anesthesiology, University of Hirosaki School of Medicine, Hirosaki 036-8562, Japan. Address e-mail to masuika@ cc.hirosaki-u.ac.jp.
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Abstract
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IV aminophylline, a nonselective phosphodiesterase (PDE) inhibitor, is often used to treat an asthma attack during anesthesia. However, in some instances, aminophylline-resistant attacks are observed. Selective PDE3 inhibitors are now clinically available and have been reported to produce bronchodilation. Thus, we compared the relaxant effects of olprinone, a novel PDE3 inhibitor, and aminophylline on methacholine-induced bronchoconstriction. Dogs were anesthetized with pentobarbital. Bronchoconstriction was elicited with methacholine (0.5 µg/kg + 5.0 µg · kg-1 · min-1) and assessed as percentage of changes in the bronchial cross-sectional area (BCA; basal = 100%) monitored by bronchoscope. Initially, the relaxant effects of olprinone (n = 8; 0–1000 µg/kg) and aminophylline (n = 8; 0–50 mg/kg) were compared. The bronchial cross-sectional areas were assessed before and 30 min after methacholine infusion began and 5 min after each dose of olprinone or aminophylline. We then determined whether propranolol (0.4 mg/kg) reversed the relaxation induced by olprinone (1000 µg/kg) and aminophylline (50 mg/kg). Olprinone and aminophylline dose-dependently antagonized bronchoconstriction by 56.2% ± 21.3% (SD) and 68.0% ± 30.3% with -log 50% effective dose (mean) of 4.80 ± 0.38 (15.8) µg/kg and 1.96 ± 0.42 (10.9) mg/kg, respectively. Aminophylline 50 mg/kg significantly increased plasma epinephrine, whereas olprinone did not. In addition, propranolol significantly reduced aminophylline-induced relaxation, but not olprinone-induced relaxation. Therefore, the relaxant effects of olprinone are independent of plasma epinephrine, whereas aminophylline effects may partially result from increased circulating concentrations of epinephrine.
Implications: We compared the relaxant effects of olprinone and aminophylline onmethacholine-induced bronchoconstriction in dogs. The relaxant effects ofolprinone are independent of plasma epinephrine, whereas the aminophyllineeffects may be partly caused by an increase in plasmaepinephrine.
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Introduction
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Cyclic nucleotides are important in the regulation of airway smooth muscle tone. The intracellular cyclic nucleotide level is dependent on the balance between the activities of adenylate or guanylate cyclase and cyclic nucleotide phosphodiesterases (PDEs). The PDE1–5 isoforms have also been identified in airway smooth muscle (1,2), and PDE3 inhibitors relax airway smooth muscle by an inhibition of cyclic 3'5'-adenosine monophosphate (cAMP) hydrolysis (3).
We previously reported that PDE3 inhibitors such as milrinone (4) and olprinone (5) attenuated 5-hydroxytryptamine-induced bronchoconstriction and that the relaxant effects may be independent of plasma catecholamines, whereas the effects of aminophylline, a nonselective PDE inhibitor, could be partially dependent on plasma catecholamines (5). Similarly, Lenox and Hirshman (6) reported that amrinone, another PDE3 inhibitor, attenuates methacholine-induced airway constriction. In addition, several reports have suggested that the bronchodilating effect of aminophylline may partially result from increased plasma catecholamines (7,8).
Muscarinic receptors play an important role for cholinergic influence on the airway (9), and there are muscarinic receptor subtypes M1, M2, and M3 on the human airway (10). M1 receptors facilitate neurotransmission through parasympathetic ganglia and enhance cholinergic reflexes. M3 receptor stimulation produces airway smooth muscle contraction. M2 activation inhibits the release of acetylcholine and also counteracts ß-agonist-induced bronchodilation (10). Methacholine is a nonselective muscarinic receptor agonist (11) and has been clinically used to quantify airway responsiveness in asthmatic patients (12). In addition, dogs have M1–M3 receptors (13,14) and show similar airway responses to muscarinic receptor agonists. Thus, this animal is often used to study muscarinic receptors in the airway (15).
We therefore compared the relaxant effects of olprinone and aminophylline on methacholine-induced bronchoconstriction. In addition, we also determined whether the relaxant effects of olprinone and aminophylline are caused by an increase in plasma catecholamine concentrations; PDE inhibitor-induced vasodilation may increase plasma catecholamines via arterial baroreceptor reflexes.
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Methods
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The study protocol was approved by the Animal Experiment Committee of University of Hirosaki. Sixteen mongrel dogs (8–12 kg) were anesthetized with a pentobarbital 30 mg/kg IV bolus followed by continuous IV infusion at 10 mg · kg-1 · h-1. Muscle relaxation was facilitated with 0.2 mg · kg-1 · h-1 pancuronium. The trachea was intubated with a special tracheal tube (inner diameter 7.0 mm; Fuji Systems, Tokyo, Japan) with an additional small lumen for insertion of a superfine fiberoptic bronchoscope (outer diameter 2.2 mm, AF type 22A; Olympus, Tokyo, Japan). The lungs were ventilated with a ventilator (Servo 900C; Siemens-Elema AB, Solna, Sweden). The ventilator was set to a fraction of inspired oxygen = 1.0; volume-control mode; respiratory rate, 20 breaths/min; inspiratory time, 25%; pause time, 10%; and positive end-expiratory pressure, 0 cm H2O. Tidal volume was adjusted to maintain the end-tidal carbon dioxide concentration at 4.0%–4.5%. A double-lumen catheter was inserted via the femoral vein. The femoral artery was cannulated to monitor systemic arterial pressure and to draw blood samples. Lactated Ringer’s solution was infused at 4 mL · kg-1 · h-1, and drugs were administered via the femoral vein.
Airway tone was assessed by changes in bronchial cross-sectional area as previously reported (16). Briefly, bronchial cross-sectional area at the second/third bifurcation was monitored continuously with the fiberoptic bronchoscope. Images were printed with a videoprinter (Videoprinter VY-170; Hitachi, Tokyo, Japan) during the end-expiratory pause and then measured with image analyzing software (MacSCOPE 2.56; Mitani Co, Fukui, Japan). Measured bronchial cross-sectional area was expressed as a percentage of the basal (100%). The coefficient of variation for the measurement was 2.36%.
Bronchoconstriction was elicited with IV infusion of methacholine (0.5 µg/kg + 5 µg · kg-1 · min-1) until the end of the experiment. Thirty minutes later, when stable bronchoconstriction was achieved, PDE inhibitors were administered. The dogs were allocated randomly to two groups: the Olprinone group (n = 8) and the Aminophylline group (n = 8).
The dogs were given each dose of IV olprinone (0 [saline], 1, 10, 100, and 1000 µg/kg) or aminophylline (0, 0.05, 0.5, 5, and 50 mg/kg) cumulatively. Then, propranolol 0.4 mg/kg was administered. The bronchial cross-sectional area was assessed before and 30 min after the start of methacholine infusion and 5 min after the administration of each dose of olprinone, aminophylline, or propranolol. At least 15 min elapsed between the administration of each dose of olprinone and aminophylline, but propranolol IV was given immediately after printing the bronchial cross-sectional area at the largest dose of olprinone and aminophylline.
Arterial blood (6 mL) was collected through the femoral artery catheter into an EDTA syringe simultaneously with measurement of the bronchial cross-sectional area. The plasma was separated by centrifugation at 3000 rpm for 10 min at -10°C and kept frozen at -70°C until assay. Plasma epinephrine and norepinephrine concentrations were determined by high-performance liquid chromatography with electrochemical detection. The intraassay coefficients of variation for epinephrine and norepinephrine were 3.31% and 2.93%, respectively. The lower limits of detection for epinephrine and norepinephrine were 9 and 12.5 pg/mL, respectively.
All data are expressed as mean (95% confidence intervals). Data were analyzed with repeated-mea-sures analysis of variance followed by Fisher’s protected least significant difference test or unpaired t-test with StatView II (Abacus Concepts, Berkeley, CA) on a Macintosh computer (Apple, Cupertino, CA). P < 0.05 was considered significant. In addition, to obtain the dose-response curve of PDE inhibitor-induced bronchodilation, the relaxation is expressed as a percentage: peak constriction by methacholine = 0%, and full relaxation (baseline)=100%. The sigmoid dose-response curve was fitted with GraphPad Prism 1.03, (GraphPad, San Diego, CA) and the maximal relaxation and log (the dose producing half of maximal effects) (pED50) of PDE inhibitors were obtained from each dose-response curve.
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Results
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In all groups, methacholine infusion produced approximately a 50% reduction in bronchial cross-sectional area. Olprinone and aminophylline dose-dependently reversed the methacholine-induced decrease in bronchial cross-sectional area (Table 1). The maximal relaxation and pED50 (mean ED50) of olprinone and aminophylline obtained from each sigmoid dose-response curve were 56.2% (38.4%–74.1%) and 68.0% (42.7%–93.3%) and 4.80 µg/kg (4.48–5.12 µg/kg) (15.8 µg/kg) and 1.96 mg/kg (1.61–2.31 mg/kg) (10.9 mg/kg), respectively (Fig. 1). There were no significant differences of maximal relaxation between groups.
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Figure 1. Sigmoid dose-response curve for spasmolytic effects of olprinone and aminophylline in methacholine-induced bronchoconstriction (n = 8 each). All values are expressed as mean ± SEM. PDE = phosphodiesterase.
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Olprinone did not significantly increase plasma catecholamines, and the bronchodilation was not reversed by propranolol. In contrast, aminophylline (50 mg/kg) significantly increased the plasma epinephrine level, and the relaxation was partially reversed by propranolol (Table 1).
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Discussion
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In this study, both olprinone and aminophylline attenuated methacholine-induced bronchoconstriction in a dose-related manner. Similarly, other investigators have reported that PDE3 inhibitors produce airway relaxation (6,17,18). Lenox and Hirshman (6) and Miyazawa (18) showed that amrinone also antagonized methacholine-induced bronchoconstriction. In addition, we have reported the relaxing effects of milrinone (4) and olprinone (5) on 5-hydroxytryptamine-induced bronchoconstriction. It is likely, therefore, that PDE3 inhibitors have a bronchodilating effect.
In clinical practice, aminophylline and olprinone are infused at 5 mg/kg + 0.5–1.0 mg · kg-1 · h-1 (19) and 10 µg/kg + 6–18 µg · kg-1 · h-1 (20), respectively. This suggests that aminophylline may have a 55–500-fold lower potency than olprinone. This study showed that the ED50 values of aminophylline were 690-fold higher than those of olprinone, with no significant differences in maximal relaxation between the two drugs. Thus, these results suggest that olprinone may produce similar relaxant effects. However, previous pharmacokinetic data in dogs suggest that plasma concentrations five minutes after olprinone 100 µg/kg (21) and aminophylline 10 mg/kg (22) were about 100 ng/mL and 17 µg/mL, respectively. The above clinical doses of olprinone and aminophylline produce plasma concentrations of 40–120 ng/mL (23) and 10–20 µg/mL (19) respectively. Therefore, the doses of olprinone 100 µg/kg and aminophylline 10 mg/kg may be equivalent to those encountered in clinical situations. Therefore, olprinone might be more potent clinically. Indeed, we previously reported that olprinone (10 µg/kg + 0.3 µg · kg-1 · min-1, total five milligrams) improved an asthmatic attack in a patient who was medicated with theophylline 400 mg/day, including on the day of surgery (24).
In the previous study, both olprinone and aminophylline induced endogenous catecholamine release by baroreceptor reflexes. Because sympathetic influence on airway tone is mainly dependent on circulating catecholamines, the plasma catecholamine level may strongly affect the in vivo airway tone (25). Thus, we measured plasma catecholamine levels. In this study, olprinone did not increase either epinephrine or norepinephrine, whereas aminophylline (50 mg/kg) significantly increased the epinephrine level. In addition, propranolol did not reverse olprinone-induced bronchodilation, whereas aminophylline-induced relaxation was reversed. These data suggest that the relaxant effects of olprinone may be independent of plasma catecholamines but that those of aminophylline may be dependent. Several reports also suggest that bronchodilation produced by selective PDE3 inhibitors does not involve endogenous catecholamines (4–6,26). In addition, Torphy et al. (17) have shown that relaxation of the canine trachealis muscle by SK&F 94836 (a PDE3 inhibitor) is caused by an increase in intracellular cAMP and activation of the cAMP-dependent protein kinase. Therefore, the relaxant effects of olprinone may be caused by intracellular cAMP accumulation. However, several reports suggest that aminophylline effects may be involved in the induction of plasma catecholamines (7,8). Boldt et al. (7) reported that theophylline increased plasma epinephrine more than plasma norepinephrine. Also, Ward and Tomlinson (8) found that propranolol completely blocked the relaxant effects of aminophylline on histamine-induced airway constriction in guinea pigs. Therefore, the bronchodilating effects of aminophylline may partially result from endogenous epinephrine release.
In conclusion, we have demonstrated that olprinone may produce a direct relaxant effect on methacholine-induced bronchoconstriction, whereas the relaxant effects of aminophylline may partially result from endogenous epinephrine release. We suggest that olprinone could be used safely in patients with a hyperreactive airway.
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References
|
|---|
-
Beavo JA. Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev 1995; 75: 725–48.[Abstract/Free Full Text]
-
Rabe KF, Tenor H, Dent C, et al. Phosphodiesterase isozymes modulating inherent tone in human airways: identification and characterization. Am J Physiol 1993; 264: L458–64.[Abstract/Free Full Text]
-
Kelly RA, Smith TW. Pharmacological treatment of heart failure. In: Hardman JG, Limbird LE, eds. Goodman & Gilman’s The pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill, 1996: 809–39.
-
Hashiba E, Hirota K, Yoshioka H, et al. Milrinone attenuates serotonin-induced pulmonary hypertension and bronchoconstriction in dogs. Anesth Analg 2000; 90: 790–4.[Abstract/Free Full Text]
-
Hashimoto Y, Hirota K, Yoshioka H, et al. Comparison of the spasmolytic effects of olprinone and aminophylline on serotonin-induced pulmonary hypertension and bronchoconstriction with or without ß-blockade in dogs. Anesth Analg 2000; 91: 1345–1350.[Abstract/Free Full Text]
-
Lenox WC, Hirshman CA. Amrinone attenuates airway constriction during halothane anesthesia. Anesthesiology 1993; 79: 789–94.[ISI][Medline]
-
Boldt J, Adams HA, Zickman B, et al. Comparative effects of enoximone and theophylline on plasma catecholamines and haemodynamics in cardiosurgical patients. Eur J Clin Pharmacol 1990; 38: 431–6.[ISI][Medline]
-
Ward MJ, Tomlinson DR. Pulmonary responses of salbutamol tolerant guinea-pigs to aminophylline and ipratropium bromide. Eur J Pharmacol 1984; 99: 97–102.[ISI][Medline]
-
Costello RW, Fryer AD. Cholinergic mechanisms in asthma. In: Barnes PJ, Grunstem MM, Leff AR, Woolcock AJ, eds. Asthma. Philadelphia: Lippincott-Raven, 1997: 965–84.
-
Barnes PJ. Muscarinic receptor subtypes in airways. Life Sci 1993; 52: 521–7.[ISI][Medline]
-
Brown JH, Taylor P. Muscarinic receptor agonists and antagonists. In: Hardman JG, Limbird LE, eds. Goodman & Gilman’s The pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill, 1996: 141–60.
-
LeSouëf PN. Lung function in asthma in early life. In: Barnes PJ, Grunstem MM, Leff AR, Woolcock AJ, eds. Asthma. Philadelphia: Lippincott-Raven, 1997: 1301–18.
-
Shioya T, Kagaya M, Sano M, et al. Antimuscarinic effect of tiquizium bromide in vitro and in vivo. Eur J Clin Pharmacol 1996; 50: 375–80.[ISI][Medline]
-
Yang CM. Characterization of muscarinic receptors in dog tracheal smooth muscle cells. J Auton Pharmacol 1991; 11: 51–61.[ISI][Medline]
-
Alabaster VA. Discovery and development of selective M3 antagonists for clinical use. Life Sci 1997; 60: 1053–60.[ISI][Medline]
-
Otomo N, Hirota K, Sato T, et al. Measurement of bronchodilation using a superfine fibreoptic bronchoscope. Br J Anaesth 1997; 78: 583–5.[Abstract/Free Full Text]
-
Torphy TJ, Burman M, Huang LBF, Tucker SS. Inhibition of the low Km cyclic AMP phosphodiesterase in intact canine trachealis by SK&F 94836: mechanical and biochemical responses. J Pharmacol Exp Ther 1988; 246: 843–50.[Abstract/Free Full Text]
-
Miyazawa N. Effect of amrinone and vagotomy on airway constriction in dogs: analysis by respiratory system impedance method. Masui 1997; 46: 31–41.[Medline]
-
Stoelting RK. Pharmacology and physiology in anesthetic practice: sympathomimetics. 2nd ed. Philadelphia: JB Lippincott Co, 1991: 264–84.
-
Yusa H, Futagawa K, Shiokawa Y, et al. Anesthetic management of a patient with dilated cardiomyopathy using olprinone. Masui 1998; 47: 221–4.[Medline]
-
Kaneko K, Tadano K, Nakajima K, et al. Studies on the metabolic fate of loprinone hydrochloride. III. Blood level, distribution, metabolism, excretion after a single intravenous administration to dogs. Xenob Metab Dispos 1994; 9: 171–83.
-
Stirt JA, Berger JM, Ricker SM, Sullivan SF. Aminophylline pharmacokinetics and cardiorespiratory effects during halothane anesthesia in experimental animals. Anesth Analg 1980; 59: 186–91.[Abstract/Free Full Text]
-
Murakami R, Sano K, Murakami Y, et al. Effects of intracoronary infusion of an inotropic agent, E-1020 (loprinone hydrochloride), on cardiac function: evaluation of left ventricular contractile performance using the end-systolic pressure-volume relationship. Int J Cardiol 1995; 51: 57–63.[ISI][Medline]
-
Hirota K, Kabara S, Hashimoto H, et al. Use of olprinone, a phosphodiesterase III inhibitor, in an asthmatic patient. Acta Anaesthesiol Scand. In press.
-
Gal TJ. Bronchial hyperresponsiveness and anesthesia: physiologic and therapeutic perspectives. Anesth Analg 1994; 78: 559–73.[Free Full Text]
-
Heaslip RJ, Buckley SK, Sickels BD, Grimes D. Bronchial vs. cardiovascular activities of selective phosphodiesterase inhibitors in the anesthetized beta-blocked dog. J Pharmacol Exp Ther 1991; 257: 741–7.[Abstract/Free Full Text]
Accepted for publication February 14, 2001.
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Abstract
Introduction
