The effect of the calcium antagonist nifedipine on peripheral nerve function in streptozotocin-diabetic rats

Diabetologia, Dec 1992

Summary Recent data suggests that reduced nerve blood flow is implicated in the aetiology of experimental diabetic neuropathy, which may be prevented by manipulations that reduce receptor-mediated vasoconstrictor activity. This investigation examines the effects of nifedipine, a voltage-sensitive calcium channel antagonist which has a direct vasodilatory effect on vessels, on nerve conduction, hypoxic resistance and capillary density in streptozotocin-induced diabetic rats. Treated and non-treated non-diabetic and diabetic groups were employed. Diabetes duration was 2 months. Treatment was preventive, groups received a nifedipine dietary supplement (40 mg · kg−1 · day−1) for 2 months from the start of the study. Conduction was measured in sciatic motor branches supplying tibialis anterior and gastrocnemius muscles, and sensory saphenous nerve. Diabetes resulted in a 23–28 % reduction in motor conduction velocity (p<0.001), and a 15% deficit for sensory saphenous nerve (p<0.001). In the nifedipine-treated diabetic group, motor and sensory conduction deficits were minimal compared with non-treated diabetes (p<0.001). Nifedipine treatment had no significant effect on conduction velocity in nondiabetic rats. In vitro measurement of sciatic nerve hypoxic resistance revealed a 60 % increase in the time taken for compound action potential amplitude to reach half its initial value with diabetes (p<0.001). This was not significantly affected by nifedipine treatment. Experimental diabetes or nifedipine treatment did not significantly alter sciatic nerve endoneurial capillary density. We conclude that nifedipine, a vasodilator which acts directly on vascular smooth muscle, prevents nerve conduction deficits in experimental diabetes.

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The effect of the calcium antagonist nifedipine on peripheral nerve function in streptozotocin-diabetic rats

Diabetologia T h e e f f e c t o f t h e c a l c i u m antagonist n i f e d i p i n e o n peripheral n e r v e f u n c t i o n in s t r e p t o z o t o c i n - d i a b e t i c rats S. Robertson 0 1 N. E. Cameron 0 1 M. A. Cotter 0 1 0 Department of Biomedical Sciences,University of Aberdeen , UK 1 Dr. N. E. Cameron Department of Biomedical Sciences Universityof Aberdeen Marischal College Aberdeen AB9 1AS , Scotland UK Summary. Recent data suggests that reduced nerve blood flow is implicated in the aetiology of experimental diabetic neuropathy, which may be prevented by manipulations that reduce receptor-mediated vasoconstrictor activity. This investigation examines the effects of nifedipine, a voltage-sensitive calcium channel antagonist which has a direct vasodilatory effect on vessels, on nerve conduction, hypoxic resistance and capillary density in streptozotocin-induced diabetic rats. Treated and non-treated non-diabetic and diabetic groups were employed. Diabetes duration was 2 months. Treatment was preventive, groups received a nifedipine dietary supplement (40 mg. kg-1 day<) for 2 months from the start of the study. Conduction was measured in sciatic motor branches supplying tibialis anterior and gastrocnemius muscles, and sensory saphenous nerve. Diabetes resulted in a 23-28 % reduction in motor conduction velocity (p < 0.001), and a 15 % deficit for sensory saphenous nerve Neuropathy; nerve conduction; ischaemia; capillary density; calcium antagonists; streptozotocin; diabetic rat - 9 Springer-Verlag1992 R e d u c e d nerve conduction velocity (NCV) and resistance to ischaemic conduction failure (RICF) are early indications of neuropathic dysfunction in b o t h diabetic patients and animals [ 1 ]. One view of the underlying aetiology suggests that chronically reduced blood flow, caused by microvascular and rheological changes, leads to endoneurial hypoxia sufficient to impair function [2]. A second hypothesis explains neuropathic changes in terms of a biochemical dysfunction and proposes that increased polyol pathway activity results in deficits in nerve myo-inositol, leading to altered phosphoinositide metabolism and a reduction in Na § +-ATPase activity [ 3 ]. T h e importance of vascular factors in the pathogenesis of diabetic n e u r o p a t h y has recently b e e n highlighted by studies which show that t r e a t m e n t with the oq blocker prazosin or chronic chemical sympathectomy with guanethidine [ 4, 5 ] result in improvements in b o t h nerve blood flow, N C V and R I C F in streptozotocin-diabetic rats. T h e rationale for these experiments was that there is increased reactivity to noradrenaline for resistance vessels in ex(p < 0.001). In the nifedipine-treated diabetic group, motor and sensory conduction deficits were minimal compared with non-treated diabetes (p < 0.001). Nifedipine treatment had no significant effect on conduction velocity in nondiabetic rats. In vitro measurement of sciatic nerve hypoxic resistance revealed a 60 % increase in the time taken for compound action potential amplitude to reach half its initial value with diabetes (p < 0.001). This was not significantly affected by nifedipine treatment. Experimental diabetes or nifedipine treatment did not significantly alter sciatic nerve endoneurial capillary density. We conclude that nifedipine, a vasodilator which acts directly on vascular smooth muscle, prevents nerve conduction deficits in experimental diabetes. perimental diabetes [6], and that sciatic nerve noradrenaline levels are reduced [ 5, 7 ], perhaps indicating greater release by vasa n e r v o r u m sympathetic nerves. Therefore, blockade of sympathetic vasoconstriction could compensate for vasa n e r v o r u m insufficiency, reduce endoneurial hypoxia and normalize nerve function. T h e beneficial effects of vasodilator t r e a t m e n t on diabetic nerve function may not be restricted to drugs that act on the noradrenergic system, as angiotensin converting enzyme inhibition also p r o v e d effective [8]. However, different receptormediated agonists exert a co-operative effect in the control of vascular responses, demonstrated, for example, by the use of angiotensin II to reveal postjunctional ~2-mediated contractions [ 9 ]. Thus, it is not clear whether vasodilators which exert relatively uncomplicated effects on m e m b r a n e ion channels in vascular smooth muscle, such as Ca 2+ antagonists, could give effective protection against diabetic vascular complications. The aim of the present study was to examine the efficacy of nifedipine, which blocks voltage-dependent Ca 2+ c h a n n e l s a n d is relatively specific for v a s c u l a r s m o o t h m u s c l e [ 10 ], in p r e v e n t i n g N C V deficits a n d the d e v e l o p m e n t of hypoxic resistance in s t r e p t o z o t o c i n - d i a b e t i c rats. C h r o n i c t r e a t m e n t with b o t h p r a z o s i n a n d an a n g i o t e n s i n c o n v e r t i n g e n z y m e i n h i b i t o r r e s u l t e d in e n d o n e u r i a l capillary growth, which c o r r e l a t e d with i m p r o v e d n e r v e f u n c t i o n [ 4, 8 ]. A s e c o n d a r y a i m of the s t u d y was to e x a m i n e w h e t h e r n i f e d i p i n e also c a u s e d vasa n e r v o r u m angiogenesis. Materials and m e t h o d s All experiments were carried out on mature male Sprague-Dawley rats (Aberdeen University colony), 19 weeks old and weighing 493 _+16 g at the start of the study. The animalswere randomlyallocated to four experimental groups. One group of non-treated nondiabetic rats acted as onset controls and were studied at 19 weeks. Another group of non-diabetic rats were given nifedipine (Sigma, Poole, Dorset, UK) in their diet at a concentrationof approximately 40 mg. kg 1.day-k Diabetes was induced in all other animals by a single injection of streptozotocin (45 mg. kg 1 in 20 mmol. 1-1 sodium citrate buffer, pH 4.5, i.p.). Diabetes was verified 24 h later by estimating hyperglycaemia and glycosuria (Visidex II and Diastix; Ames, Slough, Bucks, UK). Final plasma glucose levels were determined using a standard test kit (GOD-Period method; Boehringer Mannheim,Mannheim,FRG) on samples taken on the day of the experiments. Diabetic animals were divided into two groups. One group remained untreated for 2 months. The other preventivetreated group was fed a diet of normal rat chow to which nifedipine was added (Sigma; approximate dose 40 mg.kg -1. day-1, for the 2-month period). The dose of nifedipine used, and the method of treatment, is similar to that employed in chronic studies in nondiabetic rats [ 11 ], and was chosen to produce a near-maximal ( > 85 %) blockade of voltage-sensitiveCa2+-channelsin arteries of diabetic rats [ 12 ]. In final experiments, anaesthesia was initiallyinduced with 5 % halothane in air and maintained by i.p. urethane (1-1.5 g. kg-1). Animal core temperature was monitored throughout by a rectal temperature probe and maintained at 37-38~ by an electrically heated blanket. Nerve conductionmeasurementswere made in vivo as described previously [ 13 ]. For the sciatic motor branches innervating the tibialis anterior (peroneal division) and gastrocnemius (tibial division) muscles, bipolar stimulatingelectrodes were placed around the sciatic nerve at the notch and knee. A bipolar electrode placed in the relevant muscle recorded electromyograms. Sensory NCV was measured on the saphenous nerve between groin and ankle. NCV was calculated as the interelectrode distance divided by the latency difference between first inflectionsof potentials evoked at the stimulation sites. Nerve temperatures were monitored with a thermistor probe and regulated between 36.5 and 37.5~ by radiant heat. The in vitro measurement of sciatic nerve resistance to hypoxia (RICF) has previouslybeen described [ 14 ].Briefly, the contralateral sciatic trunk was mounted on bipolar stimulating(proximal) recording (distal) electrodes and left to equilibrate in a chamber filled with Krebs Ringer solution (144.0Na +, 5.0K § 2.5Ca +, 1.1Mg +, 25.0 HCO3-, 1.1 PO43-, 1.1 SO42-, in mmol. 1-1, at 35~ gassed with 95 % 02:CO2 for approximately30 min. Glucose concentration was 5.5mmol.1-1 for nerves of non-diabetic animals, and 40 mmol. 1-1 for nerves of diabetic animals. Previous experiments have shown that glucose concentrations over this range have no significant differential effects on RICF for control or diabetic nerves (Cameron, N.E., Cotter, M.A., Cox, D. unpublishedobservations). The chamber was then refilled with mineral oil which had been pregassed with 100 % N2 for i h, and N2bubblingwas continued. Compound actionpotentials were evoked byjust supramaximalelectrical stimulation (1 Hz, 0.05 ms pulse width, 10 mA) and their amplitude was monitored at 2-minintervalsuntil it was less than 10 % of the initial value. At the end of the experiments a length of sciatic nerve between the notch and knee was removed (2.5 cm), cleared of surrounding tissues and divided into approximately 0.5 cm pieces. These were then mounted on cork discs using skeletal muscle as support tissue, and frozen in isopentane which had been pre-chilled in liquid nitrogen. Three 10 ~tm thick transverse sections, each 90 grn apart, were cut on a cryostat at -20~ and capillary endothelium was stained for alkaline phosphatase using the method of Ziada et al. [ 15 ]. Capillaries in all nerve fascicles were counted with the assistance of a projection microscope. Fascicle areas were traced and areas measured using a digitizing pad linked to a microcomputer. Statistical analysis Results are expressed as mean + SEM. Data were subjected to oneway analysis of variance. Where statistical significance was attained (p < 0.05), Student's t-tests were performed between groups to assign probability levels and the Bonferroni correction for multiple comparisons was applied using a commercially available statistical package (Instat; GraphPad, San Diego, Calif., USA). Results A l l diabetic a n d t r e a t e d diabetic a n i m a l s s h o w e d persist e n t h y p e r p h a g i a , polydipsia a n d polyuria. P l a s m a glucose levels a n d b o d y weights are s u m m a r i s e d i n T a b l e 1. Plasm a glucose levels w e r e e l e v a t e d a p p r o x i m a t e l y five-fold b y diabetes, a n d w e r e u n a f f e c t e d by n i f e d i p i n e t r e a t m e n t . D i a b e t i c a n i m a l s lost weight, irrespective of t r e a t m e n t . B o d y weights w e r e r e d u c e d 3 1 % b e l o w o n s e t values at 2 m o n t h s in diabetic c o n t r o l animals. A similar r e d u c t i o n was o b s e r v e d i n the p r e v e n t i v e n i f e d i p i n e - t r e a t e d diabetic group. N i f e d i p i n e - t r e a t e d n o n - d i a b e t i c a n i m a l s i n c r e a s e d their weight b y 24 % , in line with the growth rate for n o n - t r e a t e d n o n - d i a b e t i c rats of c o m p a r a b l e age [ 13 ]. N C V d a t a for tibialis anterior, g a s t r o c n e m i u s a n d sap h e n o u s n e r v e s are illustrated i n F i g u r e 1. D i a b e t e s res u l t e d i n a n average 25 % r e d u c t i o n (p < 0.001) in m o t o r n e r v e c o n d u c t i o n c o m p a r e d w i t h o n s e t controls. C o n d u c t i o n deficits w e r e c o m p l e t e l y p r e v e n t e d b y n i f e d i p i n e t r e a t m e n t . S e n s o r y s a p h e n o u s N C V was 15 % (p < 0.001) r e d u c e d by diabetes. N i f e d i p i n e t r e a t m e n t p r e v e n t e d this r e d u c t i o n , the resulting v a l u e was n o t significantly differe n t f r o m t h a t of n o n - d i a b e t i c controls. T h e r e were n o significant differences b e t w e e n n o n - d i a b e t i c c o n t r o l a n d n o n - d i a b e t i c n i f e d i p i n e - t r e a t e d rats for a n y of the N C V KX~ 0 CF 6 5 45 C D DF C CF D OF C CF D DF A B % E 20 Hypoxia duration (min) 30 40 Fig.2. Percentage change in sciatic nerve compound action potential amplitude with duration of hypoxia in vitro. Symbols and error bars show group means _+ SEM. Controls ( 9 ), n - 22; nifedipinetreated controls (O), n = 5; diabetic controls ([]), n = 16; nifedipine-treated diabetic group (A), n =14. The inset histogram shows initial sciatic nerve compound action potential amplitudes before the period of hypoxia for controls (C), nifedipine-treated controls (CF), diabetic controls (D), nifedipine-treated diabetic group (DF). There were no statistically significant between-group differences in initial amplitude T h e results d e m o n s t r a t e t h a t t r e a t m e n t with t h e C a 2+ c h a n n e l b l o c k e r n i f e d i p i n e p r e v e n t s t h e d e v e l o p m e n t o f b o t h m o t o r a n d s e n s o r y N C V deficits in s t r e p t o z o t o c i n i n d u c e d d i a b e t i c rats. T h e c h a n g e s in n o n - t r e a t e d d i a b e t e s a r e u n l i k e l y to result f r o m a c y t o t o x i c a c t i o n of s t r e p t o z o t o c i n as t h e y are p r e v e n t a b l e b y insulin t r e a t m e n t [ 16 ]. I n c o n t r a s t to a r e c e n t s t u d y w h i c h u s e d t h e oqr e c e p t o r a n t a g o n i s t p r a z o s i n [ 4 ] to i m p r o v e e n d o n e u r i a l b l o o d flow, t h e effect o f n i f e d i p i n e o n N C V was f o u n d in the a b s e n c e o f c h a n g e s in n e r v e h y p o x i c r e s i s t a n c e o r cap i l l a r i z a t i o n . N i f e d i p i n e b l o c k s a v o l t a g e - s e n s i t i v e c o m p o n e n t of C a 2+ influx into v a s c u l a r s m o o t h m u s c l e , l e a d i n g to reduced vascular tone [ 17, 18 ], which would be expected to increase nerve blood flow [19]. A o r t a e f r o m diabetic rats show increased d e p e n d e n c e on extracellular Ca 2+ for contractile responses [ 20, 21 ]. Thus, nifedipine may be a m o r e effective vasodilator for diabetic than for non-diabetic rats. This should counteract the increased vascular reactivity seen in diabetes [ 6, 22 ], which depends on elevated c~-sensitivity [ 23, 24 ] and an e n h a n c e m e n t of the activity or n u m b e r of Ca 2§ channels in vascular smooth muscle or both [21]. Further contributions to the increased reactivity are m a d e by hypoinsulinaemia [ 25 ], r e d u c e d synthesis of prostacyclin by neural vessels [ 7 ] which m a y d e p e n d on defects in essential fatty acid metabolism [ 14 ], and impaired e n d o t h e l i u m - d e p e n d e n t relaxation [ 24, 26-29 ]. O t h e r rheological effects of diabetes include increased blood viscosity, platelet aggregation, reduced erythrocyte deformability, and decreased oxygen unloading f r o m haemoglobin [ 7, 30 ]. Together, these r e n d e r nerve endoneurium hypoxic [2], providing a plausible explanation for the basic disturbance underlying the aetiology of diabetic neuropathy. Nifedipine t r e a t m e n t did not affect R I C F in diabetic nerves, which contrasts with the effects on NCV. This could suggest that the mechanisms underlying N C V and R I C F are different, or that R I C F is a m o r e sensitive indicator of diabetic effects. Factors contributing to the develo p m e n t of hypoxic resistance are disputed. S o m e authors suggest that R I C F is a result of reduced metabolic demand, reflecting decreased Na § +-ATPase activity [ 31 ]. Whilst it is agreed that there is a deficit in N a + - K § Pase activity in nerve h o m o g e n a t e s f r o m diabetic rats [ 4, 32, 33 ], the physiological significance of this has yet to be established [ 4 ]. Others have p r o p o s e d that the developm e n t of hypoxic resistance reflects the capacity of nerve to adapt to endoneurial hypoxia, via greater reliance on anaerobic metabolism, [ 1 ]. T h e vascular hypothesis provides an explanation for differential effects on N C V and R I C E E n h a n c e d anaerobic metabolism in response to endoneurial hypoxia can be viewed as a protective mechanism to increase A T P production and limit nerve dysfunction [ 1 ]. Clearly, with non-treated diabetes this mechanism only provides partial protection. However, with nifedipine, an i m p r o v e m e n t in endoneurial oxygenation would be additive with R I C E allowing normal N C V without completely removing the stimulus for increased reliance on anaerobic metabolism. The relative degree of prevention of R I C F by vasoditator t r e a t m e n t could simply depend on the extent of the correction of endoneurial hypoxia. This would reflect the degree of smooth muscle relaxation obtainable for a particular vasodilator, and the dose used in treatment. Thus, in prazosin-treated (5 mg- k g - 1. d a y - 1) diabetic rats, N C V was completely corrected but the rate of increase in R I C F was only halved [4]. For the angiotensin converting enzyme inhibitor lisinopril ( 2 0 m g - k g - l . d a y - 1 ) , both N C V and R I C F were normalized [ 8 ]. As the dose of nifedipine used in this study was high, close to the top of the concentration-response curve for vessels f r o m diabetic rats in vitro [ 12 ], this suggests that the ability of nifedipine to produce vasodilation sufficient to completely p r e v e n t abnormalities in n e r v e function may be limited. O n e plausible explanation is that nifedipine does not block Ca 2+ release from intracellular stores or flux through ligand-gated channels and, therefore, will only partially reduce vasoconstriction p r o d u c e d by noradrenergic stimulation of the cz-adrenoceptors which control vasa n e r v o r u m perfusion [ 34 ]. E n d o n e u r i a l capillary density did not increase in nifedipine-treated diabetic or non-diabetic groups. For diabetic rats, prazosin treatment, omega-6 essential fatty acid dietary supplementation, and angiotensin converting enzyme inhibition all resulted in approximately 20 % increases in capillary density [ 4, 8, 14 ]. T h e stimulus for vasodilator-induced angiogenesis is the mechanical effect of increased blood flow on endothelium [ 14, 15, 35 ]. It is possible that nifedipine treatment did not produce a sufficient increase in blood flow to stimulate capillary growth, or that Ca 2§ channel blockade interfered with angiogenesis, for example, by disrupting Ca2+-dependent proteolysis [ 36, 37 ]. However, this does not rule out other effects on vasa nervorum, including increased vessel patency and size [38]. Regardless of the mechanism, the data demonstrate that neo-capillarization is not necessary to prevent N C V deficits in diabetic rats. In conclusion, nifedipine p r e v e n t e d N C V deficits in streptozotocin-diabetic rats. Given that other diabetic complications such as cardiomyopathy can also be improved by Ca 2§ antagonists [ 39 ], they could have a potential preventive therapeutic role. The lack of effect on R I C E even at the high dose of nifedipine e m p l o y e d could, however, suggest that actions on nerve may be m o r e limited in practice than those of some other pharmacologically distinct vasodilators [ 4, 8 ]. Acknowledgement. This work was supported by a grant from the British Diabetic Association. R e f e r e n c e s 1. Low PA , Tuck RR , Takeuchi M ( 1987 ) Nerve microenvironment in diabetic neuropathy . In: Dyck PJ , Thomas PK , Asbury AK , Winegrad AI , Porte D (eds) Diabetic neuropathy . Saunders , Philadelphia, pp 266 - 278 2. Tuck RR , Schmelzer JD , Low PA ( 1984 ) Endoneurial blood flow and oxygentension in the sciaticnerves of rats wi~ experimental diabetic neuropathy . 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S. Robertson, N. E. Cameron, M. A. Cotter. The effect of the calcium antagonist nifedipine on peripheral nerve function in streptozotocin-diabetic rats, Diabetologia, 1992, 1113-1117, DOI: 10.1007/BF00401363