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From the Department of Anesthesiology Institute of Clinical Medicine University of Tsukuba, Tsukuba, Japan.
Address correspondence to: Dr. Masayuki Miyabe, Department of Anesthesiology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba 305-8575, Japan. Phone: 81-298-53-3088; Fax: 81-298-53-3092; E-mail: miyabe{at}md.tsukuba.ac.jp
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Abstract |
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Methods: Rabbits were anesthetized and ventilated mechanically. The pial arteriolar diameter was determined using a cranial window and intravital microscopy. Hypoxia was induced twice in the same animal by reducing FIO2 to 0.1. The first episode was induced during an infusion of saline, and the second during an infusion of saline (saline group; n = 8) or olprinone (1 µg•kg-1•min-1, OLP1 group; n = 8 or 10 µg•kg-1•min-1, OLP10 group; n = 8). The pial arteriolar responses to hypoxia were recorded and compared between the two episodes of hypoxia in each group.
Results: Blood gas data in the first hypoxic challenge were identical to those in the second challenge in each group. Pial arteriolar diameter increased significantly during hypoxia. In arterioles between 50–100 µm diameter, first and second hypoxia-induced pial arteriolar dilatation in OLP1 were 13 ± 6% and 10 ± 7% respectively (P = 0.574 ) and those in OLP10 were 16 ± 6% and 15 ± 7% respectively (P = 0.606). In arterioles between 25–50 µm, the results were the same as in arterioles between 50–100 µm.
Conclusion: Olprinone does not affect the hypoxia-induced dilatation of pial arterioles in pentobarbital anesthetized rabbits.
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Introduction |
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TOPAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Materials and methods |
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The rabbits were anesthetized with pentobarbital (50 mg iv). A tracheostomy was then performed, and the lungs were ventilated mechanically with an inspired oxygen concentration of 30–35%. End-tidal CO2 was monitored continuously (Datex Normocap CO2 monitor, Datex Instrumentarium Co., Helsinki, Finland), and tidal volume and respiratory rate were adjusted to maintain the end-expiratory CO2 level between 30–40 mmHg. Additional doses of pentobarbital (25 mg each) were administered when it was necessary during the tracheostomy, and anesthesia was then maintained with a continuous iv infusion of pentobarbital sodium (10 mg•hr-1) and pancuronium (0.4 mg•hr-1).
A catheter was placed in a femoral artery to measure mean arterial blood pressure (MAP) and obtain arterial blood samples. A femoral vein was cannulated for infusion of drugs. Arterial blood pH, PCO2, and PO2 were measured with a blood gas analyzer (288 Blood Gas System, Ciba Corning Diagnostics Co., MA, USA) and maintained at normal levels, except during the experimental induction of hypoxia.
Each animal was immobilized in a stereotactic frame, and a closed cranial window was placed over the right parietal cortex for visualization of the pial microcirculation as reported elsewhere.9 The scalp was incised and retracted, and the temporal muscle was removed. A hole approximately 8 mm in diameter was made in the parietal bone. The dura was reflected and removed and a plastic ring with a glass coverslip was placed over the hole and secured with dental acrylic. Two ports served as an inlet and an outlet for artificial cerebrospinal fluid (CSF). The composition of artificial CSF was Na+ 151, K+ 4, Ca2+ 3, Cl- 110 mEq•dl-1, and glucose 100 mg•dl-1.
We studied two arterioles (diameters between 25–50 µm and 50–100 µm) in each animal. Diameters of pial arterioles were observed with intravital microscopy (Olympus BX50WI, Olympus Optical Co., Ltd., Tokyo, Japan). The image was projected by a charge-coupled device video camera (model CS 900; Sony Co., Tokyo, Japan) onto a colour high-resolution video monitor (model CPDE220; Sony Co., Tokyo, Japan) by use of a recording lens (PE 2.5x; Olympus Optical Co., Ltd., Tokyo, Japan) and an objective lens (UP lanFl 4x; Olympus Optical Co., Ltd, Tokyo, Japan). The images were stored in a personal computer system for subsequent analysis. The diameters of pial arterioles were measured using CanvasTM (Deneba Systems Inc., Miami, Florida, USA).8
Experimental protocol
After surgery, we waited a minimum of 30 min before initiating the experimental protocol. At each measurement time, the arteriolar diameters, MAP, heart rate (HR), and blood gas data (pH, PaCO2, PaO2) were obtained.
Hypoxia was induced by administering 10% O2 in nitrogen to the animals during five minutes. In each experiment hypoxia was induced twice. The first hypoxic episode served as control and was induced during saline infusion (5 mL•hr-1). The second was induced during olprinone infusion. We waited a minimum of 30 min between hypoxic episodes. Two different concentrations of olprinone in saline were infused at a rate of 1 µg•kg-1•min-1 (OLP1 group; n = 8) or 10 µg•kg-1•min-1 (OLP10 group; n = 8), and hypoxia was induced 20 min after infusion of olprinone. In the saline time control group (saline group; n = 8), hypoxia was induced twice during saline infusion (5 mL•hr-1).
We also examined the effects of olprinone on pial arterioles by comparing diameters before and ten minutes after infusion of olprinone.
Statistical analysis
Data are presented as a mean ± SD. Hemodynamic and blood gas data under control conditions and during interventions were compared using analysis of variance (ANOVA), and post-hoc testing by the Scheffe’s F test. The change in diameter from baseline after olprinone infusion was compared using a paired t test. The percent changes in diameter during first and second hypoxia were compared using Wilcoxon test. A value of P < 0.05 was considered significant.
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Results |
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). In arterioles between 50–100 µm diameter, first and second hypoxia-induced pial arteriolar dilatation in saline group were 12 ± 6% and 14 ± 6% (P = 0.292) , those in OLP1 were 13 ± 6% and 10 ± 7% (P = 0.574 ), and those in OLP10 were 16 ± 6% and 15 ± 7% respectively (P = 0.606). In arterioles between 25–50 µm, the results were similar (Figure). Olprinone did not affect dilatation of pial arterioles in response to hypoxia (Figure).
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). Hypoxia increased MAP and decreased HR significantly (Table I).
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). Olprinone did not change PaO2, PaCO2, and pH (Table I). Both infusion rates of olprinone produced dilatation of pial arterioles of 25–50 µm diameter (Table II).
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Discussion |
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Olprinone, a PDE III inhibitor, has positive inotropic and vasodilator effects and has been used to treat patients with heart failure.10–13 Recently, it also has been reported that olprinone has a bronchodilator effect, and that bronchial asthma may be treated by iv olprinone in humans7 and animals,8 and by inhalation of olprinone in humans.14 Although the role of olprinone in the treatment of asthma remains to be established, it has more potent spasmolytic effect on the pulmonary vasculature and is less arrythmogenic compared to aminophylline.8 As we have shown, olprinone has few effects on cerebral arterioles during hypoxia, a possible additional benefit.
Although theophylline has been used widely to treat bronchial asthma, it has been shown to attenuate cerebral vasodilatation in response to hypoxia.1–4 Since the vasodilator response during hyoxia helps maintain blood supply to the brain,5,6 theophylline may not be recommended for hypoxic patients.4 From this point of view, olprinone may be a better choice than theophylline to treat severe asthma in hypoxic patients.
Theophylline is a phosphodiestrase inhibitor and also an adenosine receptor antagonist.15,16 Theophylline affects the cerebral vasodilatory response to hypoxia by blocking the adenosine receptor.1–3 The effect of olprinone or other PDE III inhibitors on the adenosine receptor of the cerebral vessels remains unclear. Based on our results, we speculate that olprinone does not antagonize the adenosine receptor in the cerebral arteriole.
In this study the animals were each exposed to hypoxia twice and results compared between the first and second hypoxic episode. Since the reduction of FIO2 to 0.1 does not necessarily result in the same level of PaO2 in each animal, variations in cerebral vasodilatation may have been important. However, by exposing each animal to hypoxia twice, we were able to compare vasodilatation in the same vessel before and after the infusion of olprinone.
In this study we tested 1 and 10 µg•kg-1•min-1 doses of olprinone. It remains possible that larger doses of olprinone may affect cerebral vasodilatation during hypoxia. However the doses of olprinone which produce bronchodilatation in humans7 and in animals8 were similar or smaller than the doses administered in this study.
The dilatory effect of olprinone was significant in arterioles of 25–50 µm diameter. The effect of olprinone on pial vessels of different diameters remains unclear and might be related to differences in the distribution of PDE III in the cerebral arterioles.
In summary, olprinone does not affect hypoxia-induced dilatation of pial arterioles in pentobarbital anesthetized rabbits. This characteristic of the drug, if documented in humans, may prove to be beneficial when treating heart failure or asthma in hypoxic patients.
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Acknowledgments |
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Revision received November 4, 2002. Accepted for publication August 20, 2002.
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References |
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2 Morii S, Ngai AC, Ko KR, Winn HR. Role of adenosine in regulation of cerebral blood flow: effects of theophylline during normoxia and hypoxia. Am J Physiol 1987; 253: H165–75.
3 Bowton DL, Haddon WS, Prough DS, et al. Theophylline effect on the cerebral blood flow response to hypoxemia. Chest 1988; 94: 371–5.
4 Nishimura M, Yoshioka A, Yamamoto M, Akiyama Y, Miyamoto K, Kawakami Y. Effect of theophylline on brain tissue oxygenation during normoxia and hypoxia in humans. J Appl Physiol 1993; 74: 2724–8.
5 Miyabe M, Jones MD Jr, Koehler RC, Traystman RJ. Chemodenervation does not alter cerebrovascular response to hypoxic hypoxia. Am J Physiol 1989; 257: H1413–8.
6 Duong TQ, Iadecola C, Kim SG. Effect of hyperoxia, hypercapnia, and hypoxia on cerebral interstitial oxygen tension and cerebral blood flow. Magn Reson Med 2001; 45: 61–70.[Medline]
7 Hirota K, Kabara S, Hashimoto H, Ishihara H, Matsuki A. Use of olprinone, a phosphodiesterase III inhibitor, in an asthmatic patient. Acta Anaesthesiol Scand 2001; 45: 510–2.[Medline]
8 Hashimoto Y, Hirota K, Yoshioka H, Kudo T, Ishihara H, Matsuki A. A comparison of the spasmolytic effects of olprinone and aminophylline on serotonin-induced pulmonary hypertension and bronchoconstriction with or without ß-blockade in dogs. Anesh Analg 2000; 91: 1345–50.
9 Miyabe M, Fukuda T, Saito S, Tajima K, Toyooka H. Effect of intravenous prostaglandin E1 on pial vessel diameters and intracranial pressure in rabbits. Acta Anesthesiol Scand 2001; 45: 1271–5.[Medline]
10 Takaoka H, Takeuchi M, Odake M, et al. Comparison of the effects on arterial-ventricular coupling between phosphodiesterase inhibitor and dobutamine in the diseased human heart. J Am Coll Cardiol 1993; 22: 598–606.[Abstract]
11 Orime Y, Shiono M, Hata H, et al. Effects of phosphodiesterase inhibitors after coronary artery bypass grafting. Jpn Circ J 1999; 63: 117–22.[Medline]
12 Murakami R, Sano K, Murakami Y, Shimada T, Morioka S. 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.[Medline]
13 Adachi H, Tanaka H. Effects of a new cardiotonic phosphodiesterase III inhibitor, olprinone, on cardiohemodynamics and plasma hormones in conscious pigs with heart failure. J Cardiovasc Pharmcol 1997; 29: 763–71.[Medline]
14 Myou S, Fujimura M, Kamio Y, et al. Bronchodilator effect of inhaled olprinone, a phosphodiesterase 3 inhibitor, in asthmatic patients. Am J Respir Care Med 1999; 160: 817–20.
15 Fredholm BB. Are methylxanthine effects due to antagonism of endogenous adenosine? Trends Pharmacol Sci 1980; 1: 129–32.
16 Fredholm BB, Persson CCA. Xanthine derivatives as adenosine receptor antagonists. Eur J Pharmacol 1982; 81: 673–6.[Medline]
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