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Pentoxifylline Effects on Nerve Conduction Velocity and Blood Flow in Diabetic Rats

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Pentoxifylline Effects on Nerve Conduction Velocity and Blood Flow in Diabetic Rats CORE Metadata, citation and similar papers at core.ac.uk Provided by PubMed Central Int. Jnl. Experimental Diab. Res., Vol. 1, pp. 49-58 (C) 2000 OPA (Overseas Publishers Association) N.V. Reprints available directly from the publisher Published by license under Photocopying permitted by license only the Harwood Academic Publishers imprint, part of The Gordon and Breach Publishing Group. Printed in Malaysia. Pentoxifylline Effects on Nerve Conduction Velocity and Blood Flow in Diabetic Rats HEATHER FLINT, MARY A. COTTER and NORMAN E. CAMERON* Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland UK (Received 16 September 1999; Revised 27 October 1999; In final form 29 October 1999) Pentoxifylline has several actions that improve INTRODUCTION blood rheology and tissue perfusion and may there- fore potentially be applicable to diabetic neuropathy. The aims of this study were to ascertain whether 2 The early neuropathic changes in experimental weeks of treatment with pentoxifylline could correct diabetes, such as diminished conduction velo- nerve conduction velocity and blood flow deficits in city (NCV), are believed to be largely attribu- 6-week streptozotocin-diabetic rats and to examine whether the effects were blocked by co-treatment table to a reduction in nerve perfusion (Tuck with the cyclooxygenase inhibitor, flurbiprofen, or et al., 1984; Cameron et al., 1991). Parallels the nitric oxide synthase inhibitor, NG-nitro-L-argi may be drawn with reduced sural nerve blood nine. Diabetic deficits in sciatic motor and saphen- ous sensory nerve conduction velocity were 56.5% flow and the presence of endoneurial hypoxia and 69.8% corrected, respectively, with pentoxifyl- in neuropathic patients (Tesfaye et al., 1994). line treatment. Sciatic endoneurial blood flow was Several vasodilators have been identified that approximately halved by diabetes and this deficit or correct nerve was 50.4% corrected by pentoxifylline. Flurbiprofen partially prevent dysfunction co-treatment markedly attenuated these actions of in diabetic rats (Cameron et al., 1994a), and pentoxifylline on nerve conduction and blood flow et al., 1994), by G patients (Tesfaye presumably whereas N-nitro-L-arginine was without effect. improving perfusion and oxygenation. Major Thus, pentoxifylline treatment confers neurovascu- lar ben.efits in experimental diabetic neuropathy, contributions to impaired nerve blood flow are which are linked at least in part to cyclooxygenase- made by decreased vasa nervorum prostacyclin mediated metabolism. and nitric oxide (NO) production or action, and elevated vasoconstrictor activity (Ward et al., Keywords: Diabetes, neuropathy, rat, blood flow, ischemia, 1989; Kihara and Low, 1995; Maxfield et al., nerve conduction, phosphodiesterase inhibitor, vasodilation *Corresponding author. Tel.: +44 1224 273013, Fax: +44 1224 273019, e-mail: [email protected] 49 50 H. FLINT et al. 1995, 1997; Cameron and Cotter, 1996a). In turn, MATERIALS AND METHODS these changes result from metabolic conse- quences of hyperglycemia, including increased Male Sprague-Dawley rats, 19 weeks of age at polyol pathway, elevated production of re- the start of the experiment, were used. Diabetes active oxygen species, advanced glycation was induced by intraperitoneal injection (40- and protein kinase C activation (Cameron et al., 45 mg kg-1) of streptozotocin (Zeneca, Maccles- 1994a, 1994b, 1996; Cameron and Cotter, 1996b; field, Cheshire, UK) freshly made up in sterile Cameron et al., 1999; Sima and Sugimoto, 1999). saline. Diabetes was verified 24 h later by esti- Diabetes also causes elevated blood viscos- mating hyperglycemia and glycosuria (Visidex ity, decreased red cell deformability, increas- II and Diastix; Ames, Slough, UK). Rats were test- ed platelet activation, a prothrombotic state, ed weekly, and weighed daily; they were rejected and phagocyte activation that may contribute if blood glucose was < 20 mM or if they showed to reduced nerve perfusion (Simpson, 1988; a consistent increase in body weight over 3 Ceriello, 1993). days. Samples for plasma glucose measurement Pentoxifylline is a methylxanthine deriva- (GOD-Perid method; Boehringer, Mannheim, tive possessing hemorheological actions that im- Germany) were taken from the tail vein before prove the microcirculation (Ward and Clissold, or from a carotid cannula after final experiments. 1987). It is a phosphodiesterase inhibitor that Experimental groups comprised non-diabetic can cause vasodilation in some vessels by endo- onset control rats (n=20), 8-week untreated thelium-dependent and independent mecha- diabetic rats (n 20), and 6-week untreated dia- nisms (Hansen, 1994; Kaputlu and Sadan, 1994). betic groups treated for a further 2 weeks with Pentoxifylline also inhibits production of plate- pentoxifylline (Sigma, Poole, Dorset, UK) at a let activating factor, reduces platelet aggrega- dose of 40 mg kg-1 day-1 p.o. (n 26) or pentoxi- tion, increases red cell membrane fluidity, fylline + N-nitro-L-arginine (Sigma; 10 mg kg-1 and reduces the production of inflammatory day-1, added to the drinking water) (n 22) or cytokines, particularly tumor necrosis factor, by pentoxifylline + flurbiprofen (Sigma; 5 mg kg-1 phagocytes and vascular endothelium (Adams day-1, added to the drinking water) (n=20). et al., 1995; Ambrus et al., 1995; Bernard et al., Doses of N-nitro-L-arginine and flurbiprofen 1995; Mandell, 1995). Thus, pentoxifylline has were chosen to have modest effects on neuro- vascular and rheological actions that may coun- vascular function in non-diabetic rats, but to be teract some of the changes in diabetes that con- effective in blocking effects of certain inter- tribute to nerve dysfunction. The aim of this ventions in diabetic rats, including aldose re- study was to determine whether pentoxifylline ductase inhibition and a;-6 essential fatty acid treatment corrects NCV and perfusion deficits treatment (Cameron et al., 1996, 1993). Separate in diabetic rats. As some putative actions of groups of rats were used to assess motor and pentoxifylline involve correction or potentia- sensory NCV (n 10-16), and sciatic nerve per- tion of the effects of prostacyclin and NO sys- fusion (n 9-10). tems, the outcomes of co-treatment with the At the end of the treatment period, rats were cyclooxygenase inhibitor, flurbiprofen, or the anesthetized with urethane (Sigma; 1-1.5mg NO synthase inhibitor, N-nitro-L-arginine, kg-1), or for the nerve perfusion experiments were examined to further elucidate underlying with thiobutabarbital (Zeneca; 50-100 mg kg-1), mechanisms. Preliminary data were presented at by intraperitoneal injection. The trachea was a meeting of the International Diabetes Federa- cannulated for artificial ventilation. A carotid tion (Cotter et al., 1997). cannula was used to monitor mean systemic PENTOXIFYLLINE AND NEUROVASCULAR DYSFUNCTION 51 blood pressure in rats undergoing blood flow another site of the sciatic nerve. After the ex- measurement. Motor NCV was assessed be- periment, clearance curves were digitized and tween the sciatic notch and the knee in the mono-exponential or bi-exponential curves were nerve branch innervating the tibialis anterior fitted to the data by computer using non-linear muscle as previously described (Cameron et al., regression software that employs the Marquardt 1989). This is representative of the whole sciatic algorithm and the least squares method for opti- nerve in terms of susceptibility to diabetes and mizing goodness-of-fit (Prism, Graphpad, San treatment effects. Sensory NCV was measured Diego, CA, USA). The slow exponent was tak- in saphenous nerve between the groin and the en to reflect nutritive (capillary) flow (Day et al., ankle as previously described (Cameron et al., 1989). Vascular conductance was calculated by 1989). Rectal and nerve temperatures were moni- dividing flow by the mean arterial blood pres- tored, and kept between 36.5 and 37.5C. sure during the recording period. The average Sciatic endoneurial blood flow was measured of the two determinations was taken as repre- by microelectrode polarography and hydrogen sentative for all measures of sciatic endoneurial clearance as previously described (Cameron blood flow. et al., 1991). Briefly, the core temperature of the rat was monitored and kept between 37 and Statistical Analysis 38C, using a rectal probe and radiant heat. The skin around the sciatic nerve incision was su- Data are presented as group means + SEM. They tured to a metal ring and used to form a pool, were given Bartlett's test for homogeneity of which was filled with mineral oil. Pool tempera- variances, followed by log transformation where ture was maintained between 35 and 37C by appropriate (nutritive vascular conductance and radiant heat during blood flow measurements. composite blood flow) before being subjected Rats were given neuromuscular blockade us- to one-way analysis of variance. When over- ing d-tubocurarine (Sigma, 2mg kg-1 via the all significance (P < 0.05) was attained, between- carotid cannula) and we.re artificially ventilated. group differences were established by post hoc The level of anesthesia was monitored by ob- analysis using the Student-Newman-Keuls test serving blood pressure reactions to manipula- which is corrected for multiple comparisons. tions and supplementary anaesthetic was given as necessary. A glass-insulated platinum micro- electrode was inserted into the middle portion RESULTS of the sciatic
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