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Vasodilative effects of prostaglandin E1 derivate on arteries of nerve roots in a canine model of a chronically compressed cauda equina
- Masayoshi Shirasaka†1,
- Bunji Takayama†2,
- Miho Sekiguchi†2Email author,
- Shin-ichi Konno†2 and
- Shin-ichi Kikuchi†2
© Shirasaka et al; licensee BioMed Central Ltd. 2008
Received: 15 October 2007
Accepted: 08 April 2008
Published: 08 April 2008
Reduction of blood flow is important in the induction of neurogenic intermittent claudication (NIC) in lumbar spinal canal stenosis. PGE1 improves the mean walking distance in patients with NIC type cauda equina compression. PGE1 derivate might be effective in dilating blood vessels and improving blood flow in nerve roots with chronically compressed cauda equina. The aim of this study was to assess whether PGE1 derivate has vasodilatory effects on both arteries and veins in a canine model of chronic cauda equina compression.
Fourteen dogs were used in this study. A plastic balloon inflated to 10 mmHg was placed under the lamina of the 7th lumbar vertebra for 1 week. OP-1206-cyclodextrin clathrate (OP-1206-CD: prostaglandin E1 derivate) was administered orally. The blood vessels of the second or third sacral nerve root were identified using a specially designed surgical microscope equipped with a video camera. The diameter of the blood vessels was measured on video-recordings every 15 minutes until 90 minutes after the administration of the PGE1 derivate.
We observed seven arteries and seven veins. The diameter and blood flow of the arteries was significantly increased compared with the veins at both 60 and 75 minutes after administration of the PGE1 derivate (p < 0.05). Blood flow velocity did not change over 90 minutes in either the arteries or veins.
The PGE1 derivate improved blood flow in the arteries but did not induce blood stasis in the veins. Our results suggest that the PGE1 derivate might be a potential therapeutic agent, as it improved blood flow in the nerve roots in a canine model of chronic cauda equina compression.
Compression of the cauda equina by spinal stenosis is a major clinical problem associated with neurogenic intermittent claudication (NIC). A reduction in blood flow is considered an important factor in inducing NIC in lumbar spinal canal stenosis [1–5], and improving blood flow is expected to prevent NIC and leg symptoms. PGE1 leads to vasodilation in both arterioles and venules . In patients with NIC type cauda equina compression, intravenous PGE1 has been shown to improve mean walking distance . During myeloscopic observation of lumbar spinal canal stenosis, blood vessels on the cauda equina have been shown to dilate during NIC; thus microcirculatory disturbance of vessels on the cauda equina may play an important role in NIC . In addition, as seen on myeloscopic examination, dilation of vessels is observed after administration of Lipo PGE1 in patients with lumbar spinal stenosis . However, even if vasodilatory effects are achieved in both arteries and veins, it would lead to blood stasis, which may subsequently induce a reduction in blood flow. In the experimental study of the porcine cauda equina compression, blood flow in veins on spinal nerve is stopped by lower compression pressure than the one in arteries . Therefore, it is important to investigate not only changes in the diameter of blood vessels but also changes in blood flow in both arteries and veins in the same model. The aim of this study was to assess the effect of a PGE1 derivate on nerve blood flow in both arteries and veins in a canine model of chronic cauda equina compression.
A total of 14 dogs (average body weight 11.1 ± 0.4 kg) were used in this study. The experimental protocol was approved by the local animal ethics committee and conformed to Fukushima Medical University Guidelines, the Japanese Government Animal Protection and Management Law (No. 15), and the Japanese Government Notification on Feeding and Safekeeping of Animals (No. 6). All dogs were anesthetized with an intramuscular injection of 25 mg/kg ketamine hydrochloride (50 mg/ml Ketalar, Parke-Davis, Morris Plains, New Jersey) and 10 mg/kg pentobarbital sodium (50 mg/ml Nembutal, Abbott Laboratories, North Chicago, Illinois). After endotracheal intubation, anesthesia was maintained by inhalation of nitrous oxide (3 l/min), oxygen (3 l/min), and halothane (1%, SIC Chemicals Ltd, Bristol England).
The dogs were placed prone, and a partial laminectomy of the caudal part of the sixth and seventh lumbar vertebras was performed. Compression balloons were made by welding thin polyethylene sheaths together. The width of the balloon was 20 mm. The balloon was folded into three layers and gently placed under the lamina of the seventh lumbar vertebra. An ATS-1000 compressed-air system (Aspen Laboratories, Littleton, Colorado) was used to infuse a substance called "konnyaku" into the balloon at a slow rate of 10 mmHg infusion pressure. This was based on a clinical study that showed that epidural pressure at the stenotic level is approximately 10 mmHg in spinal stenosis patients in the prone position . Konnyaku, which is starch from the plant Amorphophalus rivieri, becomes liquid after being mixed with water. Water at room temperature was sufficient for konnyaku to become viscous, which occurred in approximately 10 minutes. There was no injury to the nerve tissue when the konnyaku in the balloon became viscous. When there was no further flow of konnyaku into the balloon, the infusion pressure was maintained for 30 minutes to compensate for the pressure loss caused by displacement of the tissues in the spinal canal. The diameter of each balloon exceeded that of the spinal canal and a reliable pressure transmission was provided to the cauda equina, as confirmed in separate calibration experiments. The inflated balloon, still under infusion, was then ligated at the carnial and caudal borders of the lamina of the seventh lumbar vertebra. Parts of the balloon located dorsally to the lamina were cut and removed. The balloon was then secured in place between the cauda equina and the lamina of the seventh lumbar vertebra.
One week after this procedure, 3 μg/kg with 10 ml normal saline OP-1206 OP-1206α-CD cyclodextrin clathrate (OP-1206α-CD), a prostaglandin E1 derivative, was administrated orally and the studies described below were performed. Dosing was based on the following findings of other studies: Ninety to 95% of OP-1206 a-CD is absorbed through the stomach in a rat, and the half-life of this drug is 7 hours . There are no data regarding absorption rates in a canine model. In the clinical setting, oral therapy with 15 to 30 μg per day OP1206 a-CD is used for an adult patient. In rat studies [15, 16], oral administration of 30–300 μg/kg OP-1206α-CD has been used; however, these concentrations are higher than those used in the clinical setting. In a rat model, the blood concentration of OP1206α-CD is approximately 2 to 2.5% of the total amount of drug administered. In a previous canine model, 3–30 ng/kg/min OP-1206α-CD was administered intravenously . According to the clinical setting, 30 μg was chosen orally in this study. Because the mean weight of dogs in this study was 11.1 kg, 3 μg/kg OP-1206α-CD was chosen as the best dose.
Studies were conducted 1 week after the initial operation for the model construction, applying the same surgical procedures (e.g., animal posture and anesthesia) as the initial operation.
Comparisons of the difference in diameters of the blood vessels and blood flow index among each group were performed by repeated measure ANOVA. P values of less than 0.05 were considered significant. Intra-observer reliability (R) was evaluated by one-way ANOVA. R values of more than 0.8 were considered to be "good" and more than 0.9 be "excellent". The R value was more than 0.9 in all groups; thus, the average data of each time point was used for the graphs.
Throughout the observation period, neither paralysis nor bladder dysfunction was observed in any dog. There was no wound infection. At the second operation, all balloons were found to be intact in the inserted position. The blood pressure did not change significantly before or after administration of OP-1206α-CD. A total of 14 blood vessels were observed (7 arteries and 7 veins).
1) Diameter of blood vessels
2) Blood flow velocity
3) Blood flow index
NIC is a characteristic symptom among patients with lumbar spinal canal stenosis. It is aggravated by walking and leads to reductions in walking distance. Reduced intraneural blood flow is one cause of NIC [3, 7]. Administration of PGE1 derivate and calcitonin, which are thought to improve blood flow, has been reported to improve walking distance of patients with NIC [1, 20]. Intravenous administration of PGE1 increases nerve root blood flow velocity after lumbar diskectomy in spinal stenosis patients . Experimental studies of PGE1 treatments have also been reported. Compression of cauda equina reduced blood flow in spinal nerve roots [4, 5] and PGE1 increased blood flow and prevented the reduction in nerve conduction velocity in acute cauda equina compression . In addition, intravenous injection of PGE1 derivative increased blood flow in chronic cauda equina compression . In this study, the diameter of the arteries, but not the veins, increased after administration of PGE1 derivative under cauda equina compression. In addition, blood flow in the arteries increased after administration of PGE1 derivative. These results suggest that the PGE1 derivative has a vasodilatory effect and increases blood flow in arteries. No changes in blood pressure were observed following administration of the PGE1 derivate, and blood flow velocity was maintained during vasodilation. These findings indicate that the vasodilatory effect of the PGE1 derivate on arteries enables increased blood flow without inducing blood stasis. In veins, the PGE1 derivate did not cause vasodilation or increases in blood flow. In clinical practice, PGE1 derivative will be given orally or as an intravenous bolus. In the present study, PGE1 derivative was administrated orally and the duration of the vasodilatory effect was 90 minutes. In this experimental setting, it was difficult to investigate the duration of the effect of the PGE1 derivative after oral administration; however, because the half-life of this drug is 7 hours through the stomach in a rat and the increased of vasodilatation was approximately 9% at 90 minutes, we can assume that the duration of vasodilatation was more than 90 minutes in this model.
The actions of PGE1 are mediated primarily by the IP receptor, and include a vasodilatory effect as well as a platelet aggregation inhibition effect mediated by PGI2. The IP receptor is expressed in smooth muscle cells of various organs such as the aorta, coronary arteries, pulmonary arteries, and cerebral arteries, whereas no expression is found in veins . However, PGE1 is known to dilate both arterioles and venules . In addition, cyclic GMP is associated with smooth muscle relaxation, which is a different mechanism of vasodilation mediated by the IP receptor . PGE1 also inhibits aggregation of platelets  and increases peripheral venous pressure  in experimental studies. In a clinical study, PGE1 administration at a low infusion rate of 0.02 μg/kg/min increased cardiac output without altering mean arterial blood pressure and blood volume . In a canine model, from 3.8 to 5.6 ng/kg/min PGE1 intravenously did not influence systemic mean arterial pressure. Therefore, PGE1 may change arterial blood flow in the nerve roots due to both primary and secondary effects.
In this study, the arteries reacted to the administration of PGE1 derivative whereas the veins did not. However, one limitation of this study was that the changes in the diameter and blood flow in arteries and veins were observed for only 90 minutes. Another limitation of this study was that walking capacity could not be investigated before and after administration of the PGE1 derivative. However, in a rat model, orally administered PGE1 improved walking dysfunction and blood flow . The increase of nerve root blood flow may improve function of the nerve root and lead to an improvement in walking capacity. According to the previous clinical reports, PGE1 derivative may be a potential therapeutic agent for lumbar spinal stenosis with NIC.
The PGE1 derivate may have effects of vasodilation on arteries and improve blood flow of nerve roots in chronic cauda equina compression.
The authors would like to thank Mr. Akira Sato and Ms. Rie Shibuya for expert technical assistance.
- Murakami M, Takahashi K, Sekikawa T, Yasuhara K, Yamagata M, Moriya H: Effects of intravenous lipoprostaglandin E1 on neurogenic intermittent claudication. J Spinal Disord. 1997, 10: 499-504. 10.1097/00002517-199712000-00007.View ArticlePubMedGoogle Scholar
- Baker AR, Colins TA, Porter RW, Kidd C: Laser doppler study of porcine cauda equina blood flow. The effect of electrical stimulation of the rootlets during single and double site, low pressure compression of the cauda equina. Spine. 1995, 20: 660-664. 10.1097/00007632-199503150-00005.View ArticlePubMedGoogle Scholar
- Joffe R, Appleby A, Arjona V: 'Intermittent ischemia' of the cauda equina due to stenosis of the lumbar canal. J Neurol Neurosurg Psychiat. 1996, 29: 315-318.View ArticleGoogle Scholar
- Olmarker K, Rydevik B, Holm S, Bagge U: Effects of experimental graded compression blood flow in spinal nerve roots. A vital microscopic study on the porcine cauda equina. J Orthop Res. 1989, 7: 817-823. 10.1002/jor.1100070607.View ArticlePubMedGoogle Scholar
- Olmarker K, Rydevik B, Hansson T, Holm S: Compression-induced changes of the nutritional supply to the porcine cauda. J Spinal Disord. 1990, 1: 25-29.Google Scholar
- Muller B, Schmidtke M, Witt K: Action of the stable prostacyclin analogue iloprost on microvascular tone and permability in the hamster cheek pouch. Prostaglandins Leukot Medic. 1987, 29: 187-198. 10.1016/0262-1746(87)90008-4.View ArticleGoogle Scholar
- Ooi Y, Mita F, Satoh Y: Myeloscopic study on lumbar spinal canal stenosis with special reference to intermittent claudication. Spine. 1990, 15: 544-549. 10.1097/00007632-199006000-00021.View ArticlePubMedGoogle Scholar
- Yone K, Sakou T, Kawaguchi Y: The effect of Lipo prostaglandin E1 on cauda equina blood flow in patients with lumbar spinal canal stenosis: myeloscopic observation. Spinal cord. 1999, 37: 269-274. 10.1038/sj.sc.3100780.View ArticlePubMedGoogle Scholar
- Sekiguchi M, Konno S, Kikuchi S: Effects on improvement of blood flow in the chronically compressed cauda equina. Comparison between a selective prostaglandin E receptor (EP4) agonist and a prostaglandin E1 derivate. Spine. 2006, 31: 869-872. 10.1097/01.brs.0000209256.96186.a7.View ArticlePubMedGoogle Scholar
- Kikuchi S, Konno S, Kayama S, Sato K, Olmarker K: Increased resistance to acute compression injury in chronically compressed spinal nerve roots: An experimental study. Spine. 1996, 21: 2544-2550. 10.1097/00007632-199611150-00003.View ArticlePubMedGoogle Scholar
- Konno S, Yabuki S, Sato K, Olmarker K, Kikuchi S: A model for acute, chronic, and delayed graded compression of the dog cauda equina. Presentation of the gross, microscopic, and vascular anatomy of the dog cauda equina and accuracy in pressure transmission of the compression model. Spine. 1995, 20: 2758-2764. 10.1097/00007632-199512150-00019.View ArticlePubMedGoogle Scholar
- Mao GP, Konno S, Arai I: Chronic double-level cauda equina compression. An experimental study on the dog cauda equina with analyses of nerve conduction velocity. Spine. 1998, 23: 1641-1644. 10.1097/00007632-199808010-00004.View ArticlePubMedGoogle Scholar
- Takahashi K, Miyazaki T, Takino T, Matsui T, Tomita K: Epidural pressure measurements Relationship between epidural pressure and posture in patients with lumbar spinal stenosis. Spine. 1995, 20: 650-653.View ArticlePubMedGoogle Scholar
- Miyamoto S, Taniguchi K, Kajiwara I, Okada K, Kida J, Hosoya M, Ninagawa K: Effect of OP-1206 alpha-CD. Gendai iryo. 1986, 18: 56-69.Google Scholar
- Nakai K, Takenobu Y, Takimizu H, Akimura S, Ito H, Maegawa H, Marsala M, Katsube N: Effects of OP-1260 alpha-CD on walking dysfunction in the rat neuropathic intermittent claudication model: comparison with nifedipine, ticlopidine and cilostazol. Prostaglandins Other Lipid Mediat. 2003, 71: 253-63. 10.1016/S1098-8823(03)00044-3.View ArticlePubMedGoogle Scholar
- Nakai K, Takenobu Y, Eguchi K, Takimizu H, Honjo K, Akimaru S, Maegawa H, Marsala M, Katsube N: The effects of OP1206alpha-CD on walking dysfunction in the rat neuropathic intermittent claudication model. Anesth Analg. 2002, 94: 1537-41. 10.1097/00000539-200206000-00030.PubMedGoogle Scholar
- Konno S, Kayama S, Kikuchi S: Effects of OP-1206 (Prostaglandin E1) on nerve conduction velocity in the dog cauda equina subjected to acute experimental compression. J Spinal Disord. 1996, 9: 103-106. 10.1097/00002517-199604000-00003.View ArticlePubMedGoogle Scholar
- Otani K, Kikuchi S, Konno S, Olmarker K: Blood flow measurement on experimental chronic cauda equina compression in dogs: Changes in blood flow at various conditions. J Spinal Disord. 2001, 14: 343-346. 10.1097/00002517-200108000-00011.View ArticlePubMedGoogle Scholar
- Sekiguchi M, Konno S, Anzai H, Kikuchi S: Nerve vasculature changes induced by serotonin under chronic cauda equina compression. Spine. 2002, 27: 1634-1639. 10.1097/00007632-200208010-00008.View ArticlePubMedGoogle Scholar
- Porter RW, Hibbert C: Calcitonin treatment for neurogenic claudication. Spine. 1983, 8: 585-592. 10.1097/00007632-198309000-00004.View ArticlePubMedGoogle Scholar
- Fukusaki M, Miyako M, Miyoshi H, Takada M, Terao Y, Konishi H, Sumikawa K: Prostaglandin E1 but not corticosteroids increase nerve root blood flow velocity after lumbar diskectomy in surgical patients. J Neurosurg Anesthesiol. 2003, 15: 76-81. 10.1097/00008506-200304000-00002.View ArticlePubMedGoogle Scholar
- Oida H, Namba T, Sugimoto Y, Ushikubi Fm Ohishi H, Ichikawa A, Narumiya S: In situ hybridization studies of prostacyclin receptor mRNA expression in various mouse organs. Br J Pharmacol. 1995, 116: 2828-2837.View ArticlePubMedPubMed CentralGoogle Scholar
- Murad F: Cyclic granosine monophosphate as a mediator of vasodilation. J Clin Invest. 1986, 78: 1-5. 10.1172/JCI112536.View ArticlePubMedPubMed CentralGoogle Scholar
- Tsuboi T, Hatano N, Nakatsuji K, Fujitani B, Yoshida K, Shimizu M, Kawasaki A, Sakata M, Tsuboshima M: Pharmacological evaluation of OP a prostaglandin E1 derivative, as an antianginal agent. Arch Int Pharmacolodyn Ther. 1206, 247: 89-102.Google Scholar
- Maixner W, Wright CB, Jaffe BM, Jaffe BM, Gall WE, Schoepfle WJ: The peripheral hemodynamics of exogenously administered prostaglandin E1 during major venous occlusion in the dog. J Surg Reser. 1981, 30: 563-568. 10.1016/0022-4804(81)90014-7.View ArticleGoogle Scholar
- Fukuda H, Kawamoto M, Yuge O: Small doses of prostaglandin E(1) increase cardiac output without altering blood volume. J Clin Anesth. 2001, 13: 330-334. 10.1016/S0952-8180(01)00281-1.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/9/41/prepub
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