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Anesth Analg 2000;91:1345-1350
© 2000 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

A Comparison of the Spasmolytic Effects of Olprinone and Aminophylline on Serotonin-Induced Pulmonary Hypertension and Bronchoconstriction With or Without ß-Blockade in Dogs

Yoshio Hashimoto, MD, Kazuyoshi Hirota, MD, Hideki Yoshioka, MD, Tsuyoshi Kudo, PhD, Hironori Ishihara, MD, and Akitomo Matsuki, MD

Department of Anesthesiology, University of Hirosaki School of Medicine, Hirosaki, Japan

Address correspondence to K. Hirota, MD, Department of Anesthesiology, University of Hirosaki School of Medicine, Hirosaki 036-8562, Japan. Address e-mail to masuika{at}cc.hirosaki-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
In the present study in dogs, we compared with aminophylline the spasmolytic effects of olprinone, a novel phosphodiesterase 3 inhibitor, on serotonin-induced pulmonary hypertension (PH) and bronchoconstriction. Mongrel dogs were anesthetized with pentobarbital. PH and bronchoconstriction were induced with serotonin: 10 µg/kg + 1 mg · kg-1 · h-1, and assessed as % changes in pulmonary vascular resistance and bronchial cross-sectional area (basal = 100%). Initially, the relaxant effects of olprinone (n = 8: 0–1000 µg/kg) and aminophylline (n = 8: 0–100 mg/kg) were compared. Pulmonary vascular resistance and bronchial cross-sectional area were assessed before and 30 min after serotonin 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, n = 6) or aminophylline (100 mg/kg, n = 6) compared with saline (n = 6 each). Olprinone and aminophylline dose-dependently attenuated both PH and bronchoconstriction (olprinone > aminophylline: -logED50[mean] for PH and bronchoconstriction 5.37 ± 0.35[4.24 µg/kg] vs 1.60 ± 0.23[25.4 mg/kg] and 4.06 ± 0.12[87.8 µg/kg] vs 1.51 ± 0.21[30.6 mg/kg], respectively). In addition, olprinone produced more potent pulmonary vasodilation than bronchodilation while aminophylline was equipotent. In addition, there was a significant increase in plasma catecholamines after olprinone (>=100 µg/kg) and aminophylline (>=10 mg/kg). With the exception of aminophylline-induced bronchodilation, propranolol did not reverse any of the other effects measured. Therefore, the spasmolytic effects of olprinone are independent of plasma catecholamines, while the bronchodilating effect of aminophylline may partially involve increased levels of circulating catecholamines.

Implications: We compared the relaxant effects of olprinone and aminophylline on serotonin-induced pulmonary hypertension and bronchoconstriction in dogs. Olprinone was a more potent pulmonary vasodilator and bronchodilator than aminophylline. In addition, olprinone may produce greater effects on phosphodiesterase-3 in pulmonary vascular than in airway smooth muscle.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Patients with coexisting cardiac and reactive airway diseases can experience severe circulatory depression or bronchospasm caused by mechanical stimulation, drugs, or fluid homeostatic imbalance during the perioperative period. Therefore, active prevention and treatment of these perioperative complications is indicated. Phosphodiesterase (PDE)3 inhibitors represent a sensible choice, as it has been reported that some PDE3 inhibitors are effective for treating the complications outlined above (1,2). In Japan, olprinone, a novel PDE3 inhibitor, is currently in clinical use along with milrinone for treating patients with heart failure (3).

Cyclic nucleotides are important in the regulation of vascular and airway smooth muscle function. The intracellular concentrations of cyclic nucleotides are regulated by the balance between the activities of adenylate or guanylate cyclase and cyclic nucleotide phosphodiesterases. Cyclic nucleotide PDEs are subdivided into seven families based on their genetic and functional characteristics (1,4). Inhibition of the PDE3 isoform promotes positive inotropism, vasodilation and bronchodilation via an inhibition of cyclic 3'5'-adenosine monophosphate (cAMP) hydrolysis (4).

Serotonin (5-hydroxytryptamine [5HT]) produces smooth muscle contraction via the 5HT receptor, especially 5HT2A, at small concentrations and the {alpha}-adrenoceptor at large concentrations (5).

In a previous study, we found that milrinone attenuated both 5HT-induced pulmonary hypertension and bronchoconstriction (6). However, the 50% effective dose of milrinone bronchoconstriction was significantly smaller than that for pulmonary hypertension. As pharmacological and substrate heterogeneity of PDE3 between vascular and airway smooth muscle has been suggested (7), other PDE3 inhibitors may exert different relaxant effects. In addition, we have previously found that prostaglandin E1 may produce potent spasmolytic effects on 5HT-induced bronchoconstriction, but not on pulmonary hypertension, even though prostaglandin E1 increases intracellular cAMP concentration in smooth muscle cells via EP2 receptors (8). In this study, using the same model as in previous reports (6,9), we compared the spasmolytic effects of olprinone, a novel PDE3 inhibitor, and aminophylline. The bronchodilating effect of aminophylline may partially result from increased levels of plasma catecholamines (10,11). As PDE3 inhibitors induce systemic vasodilation, this may increase plasma catecholamine levels via arterial baroreceptor reflexes. Therefore, we also determined whether the spasmolytic effects of olprinone and aminophylline were altered by ß-adrenoceptor blockade.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After the study protocol was approved by our Animal Experiment Committee, forty mongrel dogs (8–12 kg) were anesthetized with pentobarbital 30 mg/kg IV. Anesthesia was then maintained throughout the experiment with a continuous infusion of pentobarbital 10 mg · kg-1 · h-1 along with 0.2 mg · kg-1 · h-1 pancuronium for muscle paralysis. The trachea was intubated by using a special tracheal tube (inside diameter 7.0 mm) with an additional small lumen for insertion of a superfine fiberoptic bronchoscope (outside diameter 2.2 mm; AF type 22ATM; Olympus, Tokyo, Japan). The lungs were ventilated with a ventilator (Servo 900CTM; Siemens-Elema AB, Solna, Sweden) by using a fraction of inspired oxygen of 1.0, volume control mode, respiratory rate 20 breaths/min, inspiratory time 25%, pause time 10%, positive end-expiratory pressure 0 cm H2O and tidal volume adjusted to maintain the continuously measured end-tidal carbon dioxide concentration at 4.0%–4.5%. A pulmonary artery catheter (CCO thermodilution catheter Model 139H 7.5FTM; Baxter Healthcare Corporation, Irvine, CA) was inserted via the femoral vein through a sheath to monitor pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP), and cardiac output (CO) and to administer 5HT. CO was continuously measured by using a Vigilance monitor® (Model VGSSYS; Baxter Healthcare Corporation). The femoral artery was cannulated to monitor systemic arterial pressure and to withdraw blood samples. Lactated Ringer’s solution was infused at 4 mL · kg-1 · h-1, and drugs were administered via the pulmonary artery catheter sheath device.

Pulmonary artery and airway tone were assessed by changes in pulmonary vascular resistance (PVR) and bronchial cross-sectional area as previously reported (6,9). Briefly, PVR was calculated from CO, mean PAP, and PCWP. Bronchial cross-sectional area at the second-third bifurcation was monitored continuously by using the fiberoptic bronchoscope. Images were printed by using a videoprinter (Videoprinter VY-170TM; Hitachi, Tokyo, Japan) during the end-expiratory pause, and then measured by using image analyzing software (NIH Image program; written by Wayne Rasband at the United States National Institutes of Health and available from the Internet by anonymous ftp from zippy.nimh.nih.gov or on floppy disk from NTIS, 5258 Port Royal Rd., Springfield, VA 22161, part number PB93-504858). Measured bronchial cross-sectional area was expressed as a percentage of the basal (=100%).

Pulmonary hypertension and bronchoconstriction were elicited with 5HT 10 µg/kg IV followed by an infusion of 1 mg · kg-1 · h-1 via the pulmonary artery catheter. Thirty minutes later, when stable pulmonary hypertension and bronchoconstriction were achieved, drugs were administered. The dogs were allocated randomly to one of six groups: olprinone (n = 8), aminophylline (n = 8), olprinone-saline (n = 6), olprinone-propranolol (n = 6), aminophylline-saline (n = 6), and aminophylline-propranolol (n = 6). At the end of the experiment, all dogs were killed by thiopental overdose.

In the olprinone and aminophylline groups, dogs were given each dose of olprinone: 0 (saline), 1, 10, 100, 1000 µg/kg or aminophylline: 0, 0.1, 1.0, 10, 100 mg/kg IV, cumulatively. PVR and bronchial cross-sectional area were assessed before and 30 min after the start of 5HT infusion and 5 min after the administration of each dose of olprinone. At least 15 min elapsed between the administrations of each dose.

In olprinone-saline, olprinone-propranolol, aminophylline-saline and aminophylline-propranolol groups, dogs were given olprinone 1000 µg/kg or aminophylline 100 mg/kg. Five minutes later, the dogs received either saline or propranolol 0.4 mg/kg. PVR and bronchial cross-sectional area were assessed before and 30 min after the start of 5HT infusion, and 5 min after the administrations of olprinone, aminophylline, or propranolol.

Arterial blood (6 mL) was collected through the femoral artery catheter into an EDTA syringe simultaneously with measurement of PVR and bronchial cross-sectional area. Blood was immediately centrifuged at 3000 rpm for 10 min at -10°C. The plasma was separated and frozen at -70°C until assay. Plasma epinephrine and norepinephrine concentrations were determined by using high performance liquid chromatography with electrochemical detection. The intraassay coefficient of variation for epinephrine and norepinephrine was 3.31% and 2.93%, respectively. The lower limit of detection for epinephrine and norepinephrine was 9 pg/mL and 12.5 pg/mL, respectively.

All data were mean ± SD. Statistical analysis was by repeated measures two-way analysis of variance or unpaired t-test as appropriate, and P < 0.05 was considered significant. The doses of olprinone and aminophylline that attenuated increase in PVR and bronchial constriction by half (ED50) were calculated by using a computer-assisted curve fitting (GraphPad-PrismTM; GraphPad Software Inc., San Diego, CA) from individual curves.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
In all groups, 5-HT infusion produced approximately 100% augmentation in PVR and 50% reduction in bronchial cross-sectional area, respectively. Heart rate and CO did not change significantly, while mean arterial blood pressure and systemic vascular resistance (SVR) were decreased significantly (Table 1).


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  		Table 1. Effects of Olprinone and Aminophylline on Hemodynamics and Airway Tone
 
Olprinone reversed the 5HT-induced increase in PVR and decrease in bronchial cross-sectional area in a dose-dependent manner (Table 1, Figure 1). However, the -log ED50 (pED50) for PVR, 5.37 ± 0.35 (4.24 µg/kg), was significantly higher than that for bronchial cross-sectional area 4.06 ± 0.12 (87.8 µg/kg) (P < 0.05).



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  		Figure 1. Sigmoid dose-response curve for spasmolytic effects of olprinone (OP) and aminophylline (AP) in 5HT-induced pulmonary hypertension and bronchoconstriction (n = 8 each). All values are expressed as mean ± SEM. PVR = pulmonary vascular resistance, BCA = bronchial cross sectional area, PDE = phosphodiesterase.

 
Aminophylline also attenuated 5HT-induced pulmonary hypertension and bronchoconstriction in a dose-dependent manner (Table 1, Figure 1). The pED50 values of aminophylline for PVR and bronchial cross-sectional area were 1.60 ± 0.23 (25.4 mg/kg) and 1.51 ± 0.21 (30.6 mg/kg), and these did not differ significantly.

Olprinone (>100 µg/kg) and aminophylline (>10 mg/kg) significantly increased plasma catecholamine levels (Table 2).


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  		Table 2. Effects of Olprinone and Aminophylline on Plasma Catecholamine Concentrations
 
There were no significant differences in PVR and bronchial cross-sectional area at any measurement points between the olprinone-saline and olprinone-propranolol groups (Table 3). However, bronchial cross-sectional area after propranolol IV in the aminophylline-propranolol group was significantly smaller than that after saline IV in the aminophylline-saline group. There were no significant differences in PVR between these two groups (Table 3).


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  		Table 3. Effects of ß-Blockade on Olprinone- and Aminophylline-Induced Relaxation
 
Greater than 100 µg/kg olprinone significantly increased heart rate and decreased mean arterial pressure, SVR, and mean PAP compared with those at 30 min after the initiation of 5HT infusion (Table 1). However, CO did not significantly increase after any dose of olprinone, and similar hemodynamic changes were observed in the aminophylline group.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The present study demonstrates that olprinone attenuates both 5HT-induced pulmonary hypertension and a bronchial cross sectional area in a dose-related manner. PDE1–5 isoforms have been detected in vascular smooth muscle (12), and there is an abundance of PDE in the human pulmonary artery (PDE5 = PDE3 >> PDE4) (13). Haynes et al. (14) reported that PDE3 is important in the regulation of pulmonary vascular tone. Milrinone, another PDE3 selective inhibitor, is effective for treatment of pulmonary hypertension (15). Moreover, we also demonstrated in a previous study that milrinone attenuates 5HT-induced pulmonary hypertension (6). Therefore, the spasmolytic effects of olprinone on 5HT-induced pulmonary hypertension may be caused by an inhibition of PDE3.

In this study, olprinone also produced a dose-dependent attenuation of 5HT-induced bronchoconstriction. PDE1–5 isoforms have also been identified in airway smooth muscle (16,17), and PDE3 inhibitors produce airway relaxation (18,19). Torphy et al. (19) documented a relaxation of the canine trachealis muscle by SK & F94836 (a PDE3 inhibitor) caused by an increase in intracellular cAMP and activation of cAMP-dependent protein kinase. They also reported that SK & F94836 potentiated isoproterenol-induced relaxation and increased cAMP accumulation. In addition, we have reported relaxing effects of milrinone on 5HT-induced bronchoconstriction (6). It is likely therefore, that the bronchodilating effects of olprinone involve cAMP accumulation. However, the spasmolytic effect of olprinone on pulmonary hypertension is more potent than that for bronchoconstriction, as the ED50 of olprinone for pulmonary vasodilation was significantly smaller than that for bronchodilation. Interestingly, we previously found that the ED50 of milrinone, another PDE3 inhibitor, for bronchoconstriction was significantly smaller than that for pulmonary hypertension. Silver et al. (7) reported that there is pharmacological and substrate heterogeneity of PDE3 between aortic and tracheal smooth muscle in the same species, although cardiac and vascular smooth muscle PDE isozymes are pharmacologically similar. Therefore, the differences in relaxant effects of olprinone and milrinone may be the result of the heterogeneity of PDE3 between vascular and airway smooth muscles.

In clinical practice, aminophylline is infused at 5 mg/kg + 0.5–1.0 mg · kg-1 · h-1 (20) and olprinone at 10 µg/kg + 6–18 µg · kg-1 · h-1 (21) implying some 55–500 fold less potency of the former compared with the latter PDE3 inhibitor. In the present study, the ED50 values of olprinone for %bronchial cross-sectional area and PVR are about 349- and 6045-fold less than those of aminophylline, respectively. Therefore, our data suggest that olprinone may produce a much more potent spasmolytic effect on pulmonary hypertension, but similar effects on bronchoconstriction.

Pharmacokinetic data suggest that plasma concentration of olprinone and aminophylline 5 min after 100 µg/kg olprinone (22) and 10 mg/kg aminophylline (23) in dogs are approximately 100 ng/mL and 17 µg/mL, respectively. Clinically initial doses (10 µg/kg and 5 mg/kg) of olprinone and aminophylline followed by continuous infusion (6–18 µg · kg-1 · h-1 and 0.5–1.0 mg · kg-1 · h-1) produces plasma concentrations of 40–120 ng/mL (24) and 10–20 µg/mL (20) respectively. Therefore, the doses of olprinone (100 µg/kg) and aminophylline (10 mg/kg) used in our study may be similar to those encountered in clinical situations. In addition, the ED50 values of olprinone and aminophylline for PVR and %bronchial cross-sectional area would be within or close to their clinically relevant range.

Both olprinone (>=100 µg/kg) and aminophylline (>=10 mg/kg) stimulated endogenous catecholamine release. This release may result from baroreceptor reflexes as both PDE inhibitors produce vasodilation. Sympathetic influence on airway tone is mainly dependent on circulating catecholamines as direct sympathetic neural supply in the lung is limited (25). These data suggest that endogenous catecholamines might be involved in PDE inhibitor-induced bronchodilation. However, in this study, propranolol did not reverse olprinone-induced bronchodilation. In addition, several reports suggest that bronchodilation produced by selective PDE inhibitors does not involve endogenous catecholamines (26). Therefore, catecholamine release may not be responsible for olprinone-induced relaxation of bronchial smooth muscle. However, aminophylline-induced bronchodilation was partially reversed by propranolol. Moreover, plasma concentration of epinephrine after aminophylline was increased to a greater extent than after olprinone. Boldt et al. (10) reported that theophylline increased concentration of plasma epinephrine to a greater extent than plasma norepinephrine. Also, Ward and Tomlinson (11) 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 addition, it is well known that aminophylline induces life-threatening arrhythmias. In the present study, multifocal or short runs of ventricular premature contractions were observed in three dogs in the aminophylline group, compared with none in olprinone group. Therefore, even if aminophylline, at a dose equivalent to olprinone, produces similar bronchodilation, clinically olprinone may be a better choice.

PDE3 inhibitors have positive inotropic actions (3,27). However, in the present study, CO did not increase significantly even after 1000 µg/kg IV. As PDE3 inhibitors also produce vasorelaxant actions, SVR markedly decreased. PCWP decreased significantly after olprinone, and reduced venous return does not increase CO. Intravascular volume is expanded with adequate fluid administration to maintain venous return, CO may increase with olprinone as reported previously (3).

We used 5HT as a spasmogen for both pulmonary vasculature and the bronchus (5). The present data suggest that this agent may be suitable for simultaneous assessment of spasmolytic effects of some agents on the pulmonary vasculature and the bronchus because 5HT provides stable spasmogenic actions at both sites without circulatory depression.

In conclusion, we have demonstrated that olprinone may produce a direct relaxant effect on both pulmonary hypertension and bronchoconstriction elicited by 5HT infusion, whereas the relaxant effects of aminophylline on the airway but not pulmonary vasculature may partially result from endogenous epinephrine release. Moreover, the smooth muscle relaxant effects of olprinone on pulmonary hypertension and possibly airway constriction may be more potent than those of aminophylline. We suggest that olprinone may be effective for the treatment of pulmonary hypertension, and could be used safely in patients with hyperreactive airway.


   Acknowledgments
 
The authors thank Dr. D. G. Lambert (University Department of Anaesthesia and Pain Management, Leicester Royal Infirmary, UK) for his valuable comments.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication August 1, 2000.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2000 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press