Spasmolytic effects of prostaglandin E1 on serotonin-induced bronchoconstriction and pulmonary hypertension in dogs

Y. Hashimoto, K. Hirota, H. Yoshioka, E. Hashiba, T. Kudo, H. Ishihara and A. Matsuki

Department of Anesthesiology, University of Hirosaki School of Medicine, Hirosaki 036–8562, Japan*Corresponding author

Accepted for publication: March 15, 2000


    Abstract
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 Abstract
 Introduction
 Methods and Results
 Comments
 References
 
In this study, we simultaneously evaluated the spasmolytic effects of prostaglandin E1 (PGE1) on serotonin-induced bronchoconstriction and pulmonary hypertension. Eleven mongrel dogs (8–12 kg) anaesthetized with pentobarbital were assigned to two groups: saline (n=4) and PGE1 (n=7). Bronchoconstriction and pulmonary hypertension were elicited with serotonin 10 µg kg–1 + 1 mg kg–1 h–1 and assessed as the percentage change in bronchial cross-sectional area (BCA) measured by bronchoscopy and pulmonary vascular resistance (PVR), respectively. Thirty minutes after starting the serotonin infusion, saline or PGE1 0 (saline), 0.01, 0.1, 1.0 or 10 µg kg–1 i.v. was given. %BCA and %PVR (basal=100%) were assessed before and 30 min after serotonin, and 30 and 60 min after saline (saline group) or 5 min after each dose of PGE1 (PGE1 group). In the saline group, pulmonary hypertension and bronchoconstriction were stable. In the PGE1 group, PGE1 at >=0.1 µg kg–1 significantly decreased %BCA and 10 µg kg–1 almost fully reversed the constriction (from mean (SEM) 56.2% (4.9%) to 94.4% (3.7%)). %PVR was significantly decreased at 10 µg kg–1 (from 230% (24%) to 176% (11%)) only. We suggest that PGE1 may produce bronchodilation rather than pulmonary vasodilation.

Br J Anaesth 2000; 85: 460–2

Keywords: airway, resistance; lung, bronchus; lung, respiratory resistance; equipment, bronchoscope; serotonin (5-hydroxytryptamine)


    Introduction
 Top
 Abstract
 Introduction
 Methods and Results
 Comments
 References
 
Prostaglandin E1 (PGE1) relaxes not only vascular smooth muscle but also airway smooth muscles.1 It has been reported that 60–90% of PGE1 is inactivated after one passage through the pulmonary circulation in dogs, cats, rabbits and humans.2 Its rapid metabolism in the lung may limit its clinical use, so previous investigators have examined inhalational administration of PGE1 (see reference 2 for details): it has been found that (i) this may be more effective than i.v. administration for antagonizing airway constriction; (ii) PGE1 has bronchodilating effects in asthmatic patients but not in healthy volunteers, but it was concluded that inhalation of PGE1 is unsuitable for therapeutic use in asthmatic patients as airway irritation occasionally induced bronchoconstriction; (iii) inhalation of PGE1 per se sometimes produces bronchial constriction, as coughing and bronchospasm were observed in one of six asthmatic volunteers, but bronchodilation was observed in the remaining volunteers.

We have previously demonstrated that PGE1 reverses histamine-induced bronchoconstriction dose-dependently.2 A multicentre clinical trial has shown that liposomal PGE1 improved oxygenation, increased lung compliance and decreased ventilator dependency in patients with acute respiratory distress syndrome (see reference 2). These findings suggest that i.v. PGE1 may be effective in airway constriction.

PGE1 has been reported to be useful for treating pulmonary hypertension.3 In addition, several reports suggest that it may reduce experimental pulmonary hypertension4. However, Priebe reported that PGE1 had no beneficial cardiopulmonary effects in a canine model of acute pulmonary hypertension.5 The spasmolytic effects of PGE1 in pulmonary hypertension thus remain controversial.

Serotonin (5-hydroxytryptamine, or 5HT) increases smooth muscle tone via 5HT receptors at low concentrations and via {alpha}-adrenoceptors at high concentrations.6 Hence it simultaneously produces bronchoconstriction and pulmonary hypertension.

In this study, we examined whether PGE1 reversed 5HT-induced bronchoconstriction and pulmonary hypertension.


    Methods and Results
 Top
 Abstract
 Introduction
 Methods and Results
 Comments
 References
 
Following approval of our study protocol by the Animal Experiment Committee of the University of Hirosaki, 11 mongrel dogs (8–12 kg) were anaesthetized with i.v. pentobarbital 30 mg kg–1 + 10 mg kg–1 h–1 and paralysed with pancuronium 0.2 mg kg–1 h–1. The trachea was intubated using a special tracheal tube (Univent tube; Fuji System, Tokyo, Japan) with an additional small lumen for insertion of a superfine fibreoptic bronchoscope (outer diameter 2.2 mm; OES Angiofibrescope AF type 22A; Olympus, Tokyo, Japan). The lungs were mechanically ventilated with oxygen using a respirator (Servoventilator 900C; Siemens AB, Elema, Sweden) and the end-tidal carbon dioxide concentration maintained at 4.0–4.5%. A pulmonary artery catheter (CCO thermodilution catheter Model 139H 7.5F; Baxter Healthcare Corporation, CA, USA) was inserted through a sheath into the femoral vein to monitor pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP) and cardiac output and to administer drugs and fluid (lactate Ringer’s solution at 4 ml kg–1 h–1). Cardiac output was measured continuously using a Vigilance monitor (Model VGSSYS; Baxter Healthcare, Corporation, Irvine, CA, USA). The femoral artery was cannulated to monitor systemic arterial pressure.

Airway tone was evaluated as bronchial cross-sectional area (BCA) determined by our bronchoscopic method as previously reported.2 7 Briefly, the BCA at the third bifurcation of the right lung was continuously monitored through the bronchoscope, and the area during the end-expiratory pause was measured using image analysis software (NIH Image program written by Wayne Rasband at the US National Institutes of Health). Pulmonary vascular tone was assessed as pulmonary vascular resistance (PVR). Changes in BCA and PVR were expressed as a percentage of the basal value before 5HT infusion.

Bronchoconstriction and pulmonary hypertension were elicited with 5HT infusion (10 µg kg–1 +1 mg kg–1 h–1) via the pulmonary artery catheter. Thirty minutes later, when stable pulmonary hypertension and bronchoconstriction was achieved, seven dogs were subsequently given each dose of PGE1 in the following order: 0 (saline), 0.01, 0.1, 1.0 and 10 µg kg–1 (PGE1 group) and four dogs were given saline only (saline group). BCA and PVR were assessed before and 30 min after the 5HT infusion started and 5 min after administration of each dose of PGE1 in the PGE1 group. At least 15 min elapsed between each administration. In the saline group, these variables were assessed before and 30 min after the 5HT infusion started, and 30 and 60 min after saline i.v.

Arterial blood (6 ml) was collected through the femoral artery catheter into syringes containing EDTA simultaneously with BCA and PVR assessment, immediately centrifuged at 3000 r.p.m. (1700 g) for 10 min at –10°C and then the plasma was separated and kept frozen at –70°C until catecholamine assay. Plasma catecholamine concentrations were determined by high performance liquid chromatography with electrochemical detection. The assay coefficients of variation for epinephrine and norepinephrine were 3.31% and 2.93%, respectively.

Data are shown as mean (95% confidence interval) except in Figure 1. Statistical analyses were performed by repeated measure ANOVA followed by Fisher’s protected least significant difference test. P<0.05 was considered significant.



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Fig 1 Effects of prostaglandin E1 on 5HT-induced pulmonary hypertension (A) and bronchoconstriction (B). Application of 5HT (10 µg kg–1 + 1.0 mg kg–1 h–1) is indicated by the solid bar. *, #, $ and + indicate P<0.05 and **, ##, $$ and ++ indicate P<0.01 compared with 0 (saline) and PGE1 0.01, 0.1 and 1.0 µg kg–1, respectively. All values are expressed as mean±SEM.

 
5HT decreased %BCA by 40–60% and increased %PVR to about 230% (Figure 1). In the saline group, these values persisted until the end of the experiment. In the PGE1 group, PGE1 10 µg kg–1 produced a significant reduction in %PVR (Figure 1A). In contrast, %BCA increased dose-dependently, such that PGE1 10 µg kg–1 almost fully reversed the constriction produced by 5HT (Figure 1B). Plasma epinephrine increased significantly from 165 (104–227) to 277 (50–503) pg ml–1 after PGE1 10 µg kg–1 i.v.

5HT did not significantly change systemic haemodynamic variables, while PAP was significantly increased. PGE1 10 µg kg–1 significantly decreased the following haemodynamic variables during 5HT infusion: systematic vascular resistance from 4274 (3345–5202) to 3338 (2608–4067, P<0.01) dynes•s cm–5 and mean arterial pressure from 127 (90–164) to 110 (78–143, P<0.01) mm Hg, whereas mean PAP did not change significantly (decreasing from 34 (28–39) to 31 (24–37) mm Hg).


    Comments
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 Abstract
 Introduction
 Methods and Results
 Comments
 References
 
Our results data show that PGE1 attenuated 5HT-induced bronchoconstriction. Similarly, we have previously observed that PGE1 also antagonized histamine-induced bronchoconstriction.2 As PGE1 is a an EP2 receptor agonist, adenylate cyclase is activated to increase intracellular cAMP concentrations which produces airway smooth muscle relaxation.1 Therefore, increased intracellular cAMP may contribute to the observed spasmolytic effects.

In the present study, plasma epinephrine slightly but significantly increased after administration of PGE1 10 µg kg–1. This suggests that PGE1-induced systemic vasodilation increases sympathetic activity although PGE1 attenuates arterial baroreceptor reflexes.8 As circulating catecholamine concentration is one of the most important factors controlling airway tone,9 catecholamine release may also be involved in the observed bronchodilation. However, as PGE1 0.1 and 1.0 µg kg–1 produced significant bronchodilation without increases in plasma catecholamines, PGE1 may have direct bronchodilatory effects.

PGE1 has been used clinically for the treatment of pulmonary hypertension.3 Fullerton and colleagues10 have also shown a direct relaxant effect of PGE1 on isolated rat pulmonary artery rings. In the present study, PGE1 10 µg kg–1 significantly attenuated pulmonary hypertension although at <=1.0 µg kg–1 PGE1 was ineffective. However, as the catabolism of PGE1 in the lungs of dogs is about six times that in humans,2 clinically relevant doses may not attenuate pulmonary hypertension. Consistent with this, several reports5 suggest that PGE1 does not attenuate pulmonary hypertension by pulmonary vasodilation.

In conclusion, the present study indicates that clinically relevant doses of PGE1 may produce direct bronchodilation, but not pulmonary vasodilation.


    Acknowledgement
 
This work was supported, in part, by a grant-in-aid from Ono Pharmaceutical Company, Japan.


    References
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 Abstract
 Introduction
 Methods and Results
 Comments
 References
 
1 Cambell WB, Halushka PV. Lipid-derived autacoids. In: Hardman JG, Limbird LE eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 9th edn. New York: McGraw-Hill, 1996; 601–16

2 Hashimoto Y, Otomo N, Hirota K et al. Prostaglandin E1 produces spasmolytic effects on histamine-induced bronchoconstriction in dogs. Crit Care Med 1999; 27: 2755–59[ISI][Medline]

3 Kunimoto F, Arai K, Isa Y et al. A comparative study of the vasodilator effects of prostaglandin E1 in patients with pulmonary hypertension after mitral valve replacement and with adult respiratory distress syndrome. Anesth Analg 1997; 85: 507–13[Abstract]

4 Leeman M, Lejeune P, Mélot C, Naeije R. Pulmonary vascular pressure-flow plots in canine oleic acid pulmonary edema. Am Rev Respir Dis 1998; 138: 362–7

5 Priebe HJ. Efficacy of vasodilator therapy in canine model of acute pulmonary hypertension. Am J Physiol 1988; 255: H1232–9

6 Sanders-Bush E, Mayer S. 5-Hydroxytryptamine (serotonin) receptor agonists and antagonists. In: Hardman JG, Limbird LE eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 9th edn. New York: McGraw-Hill, 1996; 249–63

7 Otomo N, Hirota K, Hashimoto Y et al. Measurement of bronchodilation using a superfine fibreoptic bronchoscope. Br J Anaesth 1997; 78: 583–5[Abstract/Free Full Text]

8 Taneyama C, Goto H, Goto K et al. Attenuation of arterial baroreceptor reflex response to acute hypovolemia during induced hypotension. Anesthesiology 1990; 73: 433–40[ISI][Medline]

9 Gal TJ. Bronchial hyperresponsiveness and anesthesia: physiologic and therapeutic perspectives. Anesth Analg 1994; 78: 559–73[ISI][Medline]

10 Fullerton DA, Agrafojo J, McIntyre RC Jr. Pulmonary vascular smooth muscle relaxation by cAMP-mediated pathways. J Surg Res 1996; 61: 444–8[ISI][Medline]