The effect of vanadyl treatment on vascular responsiveness of streptozotocin-diabetic rats

Diabetologia, Jun 1994

Vanadyl sulphate has been demonstrated to possess insulin-like effects in streptozotocin (STZ) diabetic rats, including the normalization of hyperglycaemia and the prevention of diabetes-induced cardiac dysfunction. However, the effectiveness of vanadyl sulphate on diabetes-related vascular aberrations has not been questioned. Hence, in the present work, we have specifically addressed the question of whether chronic oral vanadyl sulphate treatment has any beneficial effect on diabetes-induced changes in vascular reactivity. Male albino rats were injected with a single intravenous dose of STZ (55 mg/kg). Vanadyl sulphate was administered in the drinking water at a concentration of 1 mg/ml from 7 days after the STZ injection and treatment was maintained for 10 weeks. Vanadyl intake was accompanied by decreased blood glucose and serum insulin levels. The effects of diabetes on vascular smooth muscle function were assessed by the responsiveness of aortae to noradrenaline and KCl. Contractile responses of the diabetic aortae were found to be significantly increased as compared with controls. However, there were no significant differences in pD2 values of the agonists in either of the groups. Treatment of diabetic rats with vanadyl sulphate completely prevented the increases in responsiveness of aortae to noradrenaline and KCl. The effect of diabetes on the fast and slow components of noradrenaline-induced contraction was also examined. Both components of the response to noradrenaline were significantly increased in diabetic aortae. These changes were also prevented by vanadyl sulphate treatment. The data demonstrate that 10-week vanadyl sulphate treatment results in improved vascular reactivity of diabetic rats.

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The effect of vanadyl treatment on vascular responsiveness of streptozotocin-diabetic rats

Diabetologia The effect of vanadyl treatment on vascular responsiveness of streptozotocin-diabetic rats A. T. 0 z~elikay 0 C. Pekiner ~ 0 N. Ari ~ 0 Y. Oztiirk 0 ziiari ~ 0 V. M. Altan ~ 0 0 1Department of Pharmacology,Faculty of Pharmacy,University of Ankara, Ankara, Turkey 2Department of Pharmacology,Faculty of Pharmacy,University of Anadolu , Eskisehir , Turkey Summary Vanadyl sulphate has been demonstrated to possess insulin-like effects in streptozotocin (STZ) diabetic rats, including the normalization of hyperglycaemia and the prevention of diabetes-induced cardiac dysfunction. However, the effectiveness of vanadyl sulphate on diabetes-related vascular aberrations has not been questioned. Hence, in the present work, we have specifically addressed the question of whether chronic oral vanadyl sulphate treatment has any beneficial effect on diabetes-induced changes in vascular reactivity. Male albino rats were injected with a single intravenous dose of STZ (55 mg/kg). Vanadyl sulphate was administered in the drinking water at a concentration of i mg/ml from 7 days after the STZ injection and treatment was maintained for 10 weeks. Vanadyl intake was accompanied by decreased blood glucose and serum insulin levels. The effects of diabetes on vascular smooth muscle function were assessed by the responsiveness of aortae Streptozotocin; diabetic rat; aorta; contraction; vanadyl treatment - 9 Springer-Verlag1994 The cardiovascular diseases that result from diabetes mellitus which are responsible for most of the diabetic morbidity and mortality have been described in various clinical and experimental settings [l, 2]. Several studies have indicated that a greater incidence of vascular disease is found in patients with insulin-dependent or noninsulin-dependent diabetes than in the general populaAbbrevations: STZ, streptozotocin; VST, vanadyl sulphate trihydrate. to noradrenaline and KC1. Contractile responses of the diabetic aortae were found to be significantly increased as compared with controls. However, there were no significant differences in pD2 values of the agonists in either of the groups. Treatment of diabetic rats with vanadyl sulphate completelyprevented the increases in responsiveness of aortae to noradrenaline and KC1. The effect of diabetes on the fast and slow components of noradrenaline-induced contraction was also examined. Both components of the response to noradrenaline were significantly increased in diabetic aortae. These changes were also prevented by vanadyl sulphate treatment. The data demonstrate that 10-week vanadyl sulphate treatment results in improved vascular reactivity of diabetic rats. [Diabetologia (1994) 37: 572-578] tion [ 3, 4 ]. Although the aetiology of vascular disorders in diabetes is not understood, it has been suggested that alterations in the sensitvity and/or responsiveness of vascular smooth muscle to neurotransmitters and circulating hormones may underlie the functional abnormalities of blood vessels in diabetes [ 5, 6 ]. In this regard, the responsiveness of isolated vascular preparations from STZ or alloxan-diabetic rats has been studied extensively [ 7-13 ]. Although the results of these studies are somewhat inconclusive, the discrepancies might be attributed to differences in experimental conditions such as techniques for measuring contractile force, expression of contractile force, gender, and severity and duration of diabetes. Nevertheless, in many of these studies, it was demonstrated that arteries from STZ-diabetic rats were more responsive to the contractile effects of noradrenaline [ 7, 8, 14-16 ]. The increased A. T. 0z~elikay et al.: The effect of vanadyl on aorta of diabetic rat 350 -A aoo 250 200 ~ 150 04" I I I I I i I I i I 0 1 2 3 4 5 6 7 6 9 1 0 Time (weeks) r e s p o n s i v e n e s s o f v a s c u l a r s m o o t h m u s c l e to n o r a d r e n a l i n e w a s also d e m o n s t r a t e d t o b e p r e v e n t e d f r o m occ u r r i n g , o r r e v e r s e d o n c e e s t a b l i s h e d , b y t r e a t m e n t o f d i a b e t i c rats w i t h insulin [ 8 ]. V a n a d i u m c o m p o u n d s h a v e b e e n s h o w n t o p o s s e s s s e v e r a l i n s u l i n - m i m e t i c a c t i o n s b o t h in v i v o a n d in vitro. T h e s e i n c l u d e e n h a n c e m e n t o f g l u c o s e t r a n s p o r t a n d o x i d a t i o n in rat a d i p o c y t e s [ 17, 18 ] a n d s k e l e t a l m u s c l e [ 19, 20 ], s t i m u l a t i o n o f p e n t o s e p h o s p h a t e p a t h w a y [ 21 ] a n d g l y c o g e n s y n t h a s e activity in r a t a d i p o c y t e s [ 22 ], e n h a n c e m e n t o f g l y c o g e n s y n t h e s i s in t h e liver a n d d i a p h r a g m [ 23 ], i n h i b i t i o n o f lipolysis [ 24 ] a n d a c t i v a t i o n o f l i p o g e n e s i s in rat a d i p o c y t e s [ 25 ] a n d red u c t i o n o f insulin r e q u i r e m e n t in s p o n t a n e o u s l y d i a b e t i c ( B B W i s t a r ) rats [ 26 ]. It has also b e e n s h o w n t h a t v a n a d i u m c o m p o u n d s , b o t h in t h e v a n a d a t e a n d v a n a d y l f o r m s , l o w e r p l a s m a g l u c o s e a n d p r e v e n t t h e d e c l i n e in c a r d i a c p e r f o r m a n c e [ 26-30 ] d u e t o d i a b e t e s w h e n a d m i n i s t e r e d to i n t a c t e x p e r i m e n t a l l y - i n d u c e d d i a b e t i c rats. T o o u r k n o w l e d g e , h o w e v e r , n o d a t a a r e a v a i l a b l e o n t h e e f f e c t o f v a n a d i u m t r e a t m e n t o n v a s c u lar a b e r r a t i o n s in d i a b e t e s . H e n c e , in t h e p r e s e n t study, t h e c o n t r a c t i l e effects o f n o r a d r e n a l i n e a n d KC1 o n a o r tic rings o b t a i n e d f r o m c o n t r o l a n d d i a b e t i c rats w e r e c o m p a r e d , a n d t h e e f f e c t o f c h r o n i c o r a l V S T t r e a t m e n t o n v a s c u l a r r e a c t i v i t y w a s i n v e s t i g a t e d . Materials and methods Induction of experimental diabetes. Male albino rats, weighing 150-200 g, were used in the present investigation. The rats were lightly anaesthetized with ether, and either STZ (55 mg/kg) in citrate buffer (pH 4.5) or citrate buffer alone was administered by injection into the lateral tail vein. After 3 days, blood glucose levels were determined using an Ames glucometer (Miles Laboratories Inc., Elkhart, Ind., USA), and rats with blood glucose levels of 14 retool/1 or above were considered to be diabetic. Vanadyl treatment. The control and diabetic rats were randomly divided from 7 days after the STZ injection into two subgroups: one group was given plain tap water (untreated control and untreated diabetic), and the other group was given drinking water containing VST (1 mg/ml; treated control and treated diabetic). The rats were maintained for 10 weeks with free access to food and water. The rats were weighed once per week and average fluid intake was recorded daily. The average vanadyl intake by each animal in the treated groups, on the other hand, was calculated by multiplying average fluid intake by the vanadyl concentration used. Blood glucose levels were also monitored at the end of weeks 1, 2 and 6. Final plasma glucose levels were measured on samples taken when the rats were killed. Isolation of aortic rings. Rats were killed by stunning followed by decapitation. The thoracic aorta was excised from each animal and placed in Krebs-Ringer bicarbonate buffer solution with the following composition (mmol/l): NaC1 (118), KC1 (4.7), CaCI2 (2.5), MgSO 4. 7H20 (1.2), KH2PO4 (1.2), NaHCO 3 (25) and glucose (11.1). The aorta was cleaned of adhering fat and connective tissue and cut into rings 5 mm long. In all experiments, the luminal surface of the preparation was rubbed to remove endothelium. The removal of the endothelium was confirmed by the inability of arteries precontracted with noradrenaline (10 -~ mol/1) to relax in response to acteylcholine (5.10 6mmol/1). Aortic rings were suspended in isolated tissue baths filled with 20 ml of Krebs solution continuously bubbled with a mixture of 5 % CO 2 95 % 02 (pH 7.4) at 37~ One end of the aortic ring was connected to a tissue holder and the other to an isometric force transducer (Ugo Basile, No. 7004, Varese, Italy) connected to a microdynamometer (Ugo Basile, Unirecord). The rings were equilibrated for 90 min under a resting tension of 2 g. During the equilibration period the solution in the tissue bath was replaced every 30 rain. At the end of this period, dose-response curves were obtained with noradrenaline and KC1. Noradrenaline (10- 8-10- s mol/1) and KC1 (10-50 mmol/1) were added in a cumulative manner until a maximal response was achieved. After the addition of each dose, a plateau response was obtained before the addition of a subsequent dose. At the end of each experiment, tissue was blotted dry, measured and weighed, and its cross-sectional area was calculated using the following formula: Cross-sectional area (mm2) = weight (mg) 9length (ram) -J - density (mg/mm3) -1 The density of the preparations was assumed to be 1.05 mg/mm3 [ 31 ]. Before starting the dose-response curves with noradrenaline and KC1, the aortic rings were exposed to 10-s mol/1 noradrenaline until the contraction reached the plateau (approximately 10 rain) in order to measure the fast and slow components of vascular response to noradrenaline. The fast component of the response was measured from the baseline to the point at which the rate of contraction started to decrease abruptly; the slow component, on the other hand, was measured from this point to the top of the contraction [ 32 ]. The total response was the sum of these two components. Determination of blood glucose and serum insulin. Glucose was determined from a drop of whole blood from a cut from the rat tail and measured with an Ames Glucometer and glucose-sensitive sticks. Blood was collected at the time of death and centrifuged at (2,000 g for 5 min). Resulting serum samples were analysed for insulin levels by standard radioimmunoassay techniques using a commercial kit available from DPC (Diagnostic Products Corporation, Los Angeles, Calif., USA). The drugs used came from the following sources: STZ and noradrenaline (Sigma, St Louis, Mo., USA), VST (Aldrich, Milwaukee, Wis., USA) and KC1 (Baker, Phillipsburg, N. J., USA). Data analysis. Contractile responses to noradrenaline and KC1 were calculated as the increase in tension (g) in response to the agonist per cross-sectional area of aorta (mm2). Agonist pD2 value (apparent agonist affinity constants; -log EDs0) were calculated from each agonist dose-response curve by linear regression analysis of the linear portion of the curve and taken as a measure of the sensitivity of the tissues to each agonist. All values are expressed as means + SEM. Statistical differences were evaluated using one-way analysis of variance (ANOVA) followed by Neuman-Keul's test. Results were considered to be significantly different at p less than 0.05. Results T h e b o d y weights of rats in e a c h e x p e r i m e n t a l g r o u p are s h o w n in F i g u r e 1 a n d T a b l e 1. T h e b o d y weights of u n t r e a t e d d i a b e t i c rats w e r e significantly less t h a n t h o s e o f u n t r e a t e d controls. T h e r a t e of g r o w t h in all g r o u p s was d e c r e a s e d relative to t h e u n t r e a t e d c o n t r o l group. H o w e v e r , t r e a t m e n t with V S T c a u s e d a slight increase in the g r o w t h of diabetic rats a l t h o u g h b o d y weights of diabetic rats w e r e still l o w e r t h a n t h o s e of c o n t r o l rats a f t e r t r e a t m e n t . Fluid a n d V S T i n t a k e b y t h e rats are s h o w n in T a b l e 1. Fluid i n t a k e , as e x p e c t e d , was m a r k e d l y i n c r e a s e d in d i a b e t i c rats given o n l y drinking w a t e r as c o m p a r e d with u n t r e a t e d c o n t r o l rats. D u r i n g t r e a t m e n t with VST, fluid i n t a k e was low e r e d in b o t h c o n t r o l a n d d i a b e t i c rats b e l o w the level of u n t r e a t e d controls. V S T i n t a k e ( e x p r e s s e d as average s e l f - a d m i n i s t e r e d d o s e p e r rat), on t h e o t h e r h a n d , was higher in diabetic t h a n in c o n t r o l rats. B l o o d glucose levels of c o n t r o l a n d diabetic rats at the e n d of t h e 10 w e e k s in t h e a b s e n c e or p r e s e n c e of V S T are d e m o n s t r a t e d in T a b l e 1. A s e x p e c t e d , b l o o d glucose levels w e r e e l e v a t e d in the u n t r e a t e d - d i a b e t i c rats. T h e b l o o d glucose c o n c e n t r a t i o n s of c o n t r o l rats t r e a t e d with V S T w e r e u n c h a n g e d while e l e v a t e d b l o o d glucose c o n c e n t r a t i o n s of d i a b e t i c rats w e r e c o m p l e t e l y n o r m a l i z e d a f t e r V S T t r e a t m e n t . A s s h o w n in F i g u r e 1, b l o o d glucose levels o f d i a b e t i c rats r e a c h e d n e a r to u n t r e a t e d c o n t r o l levels within 6 w e e k s of V S T t r e a t m e n t , a n d d u r i n g the r e m a i n i n g p e r i o d of s t u d y t h e y w e r e similar in the t w o groups. T h e induct i o n o f S T Z - d i a b e t e s , o n t h e o t h e r h a n d , also r e s u l t e d in r e d u c e d s e r u m insulin levels (Table 1). Interestingly, a significant d e c r e a s e in t h e insulin levels was also obs e r v e d in c o n t r o l rats a f t e r V S T t r e a t m e n t . T h e s e r u m insulin levels of diabetic rats t r e a t e d with V S T rem a i n e d d e c r e a s e d as well. T h e influence o f V S T t r e a t m e n t on t h e reactivity of t h o r a c i c a o r t a e f r o m rats with S T Z - i n d u c e d d i a b e t e s was also i n v e s t i g a t e d in this study. T h e cross-sectional A. T. Ozqelikay et al.: The effect of vanadyl on aorta of diabetic rat Values are mean + SEM of 5-20 observations in each group F a s t R. Slow R. Total R. Fig.3. Fast, slow and total responses of noradrenaline (10 mol/l) in aortas from untreated control (n = 20, solid bars), vanadyl treated control (n = 5, open bars), untreated diabetic (n = 17, hatched bars) and vanadyl treated diabetic rats (n = 11, diagonal crosshatch). Values are means + SEM areas of aortae from untreated diabetic rats w e r e significantly less than those of untreated controls (Table 1). However, as also shown in Table 1, treatment of diabetic rats with VST prevented this decrease. VST treatment also prevented the change in the reactivity of diabetic aortae to b o t h noradrenaline and KC1 (Fig.2). Contractile responses of aortae to noradrenaline (10-8-10-5mol/1/ are shown in Figure 2. Concentrations of noradrenaline greater than 10-8 mol/1 p r o d u c e d much greater increases in tension in aortae from untreated-diabetic rats than in aortae from untreated control rats. A o r t a e from untreated diabetic rats also responded to KC1 (10-50 mmol/1/ with much greater increases in tension than those from untreated control rats (Fig. 2). In contrast, response of aortae from VST-treated diabetic rats to b o t h noradrenaline and KC1 were very similar to those of aortae from controls (Fig. 2). However, no change in pD2 values for noradrenaline and KC1 from either untreated or VST-treated diabetic rats c o m p a r e d with controls was detected (Table 2). Since it has b e e n well established that vascular response to noradrenaline can b e divided from the mechanical point of view into fast and slow components, in the present work, the effects of S T Z diabetes and of VST treatment on the mechanical response to 10- 5 tool/1 noradrenaline were also characterized. As shown in Figure 3, either fast or slow components of total response to noradrenaline were found to be significantly greater in untreated-diabetic rats than untreated controls. VST treatment, on the other hand, normalized the increased fast and slow components of noradrenaline response in diabetic aortae. Discussion It is evident from the present study that treatment with oral VST restored the altered vascular reactivity to agonists in 10-week diabetic rats. The abilities of vanadium compounds to stimulate the insulin receptor kinase [ 33-35 ] as well as to prolong receptor activation [ 36 ] and also to exert post-receptor effects [ 37, 38 ] have all b e e n p r o p o s e d as possible mechanisms of action. Recognition of similarities b e t w e e n the physiological properties of vanadium and insulin raised the possibility that vanadium compounds may have a role in regulating both glucose metabolism and cardiac performance. A m o n g the many recognized physiologic changes associated with STZ-induced diabetes are a depression in working heart performance [ 27-29, 39 ], and an alteration in vascular reactivity to various vasoactive agents [ 7-9, 13, 14 ]. The defects in isolated heart functions of diabetic rats have b e e n demonstrated to be reversible following chronic daily insulin injections [ 39 ] and oral vanadium therapy [ 27 ]. The present investigation confirms previous reports that oral VST treatment normalizes the increased blood glucose levels of STZ-diabetic rats [ 26, 28, 29 ]. As expected, b l o o d glucose levels were elevated in diabetic rats but returned to normal following chronic (10-weeks) VST treatment. Blood glucose levels of control rats, however, were not affected by VST treatment. On the other hand, b o d y weights of diabetic animals treated with V S T were improved to a certain extent b u t they were still lower than those of untreated controls. The results of the present study also demonstrate that aortae from 10-week STZ-diabetic rats are m o r e responsive to the contractile effects of either noradrenaline or KC1 than are aortae from corresponding controls, while VST treatment prevented these changes in responsiveness. The increased vascular responsiveness of STZ-diabetic rats observed in our study is in agreement with previous reports [ 8, 14, 40 ] on noradrenaline contraction, and [ 7 ], for KC1 contraction. A m o n g the mechanisms that could have b e e n involved in the alterations of vascular smooth muscle function in diabetic rats are e n h a n c e d phosphoinositide metabolism [ 41 ], increased adrenergic stimulation [ 10, 15 ], enhanced sensitivity of calcium channels [ 10, 14, 40 ] and deficient endothelial activity [ 42, 43 ]. Since all experiments in the present investigation were carried out in aortae in which the endothelium had b e e n mechanically removed, the underlying mechanism does not appear to be due to a decrease in the release of endotheliumderived relaxing factors. It is also unlikely that a change in either the density or the affinity of the alpha-adrenoceptors took place in diabetic aortae, since the increases in tension of diabetic aortae in response to noradrenaline obtained in the present investigation occurred in the absence of any significant changes in sensitivity (pD2 value) to the catecholamine. Rather, it seems m o r e likely that there is an alteration in the coupling of alpha receptors to the mobilization of Ca 2+ . Recently, A b e b e et al. [ 14 ] have reported that enhanced contractile responses of aortae from rats with chronic STZ-diabetes to alpha-adrenoceptor agonists are largely dependent on the presence of extracellular Ca 2+. The enhanced responsiveness to KC1 observed in aortae from STZ-diabetic rats in the present study, also indicates an increased Ca 2+ entry. As is well known, the contraction of the rat aorta to noradrenaline occurs in two phases: a rapid initial contraction (fast response) is followed b y a slow further increase in tension (slow response) [ 44-46 ]. The slow response is d e p e n d e n t on the influx of extracellular Ca 2+ whereas Ca 2+ from intracellular sources is utilized for the fast response [ 44, 45 ]. Recently, Rinaldi and Cingolani [32] have shown that the fast component of noradrenaline-induced contraction was increased while the slow c o m p o n e n t was depressed in spontaneously diabetic rats. The total response to noradrenaline in Rinaldi and Cingolani's study, however, was found to be not significantly different in diabetic rats compared with controls. Contrary to the observation of these investigators [ 32 ], we found an enhanced total response to noradrenaline in which the fast and slow components were both significantly increased in 10-week STZ-diabetic rat aortas. Both phases of the response to noradrenaline, however, were normalized with VST treatment of diabetic rats. The differences between our results and those of Rinaldi and Cingolani [ 32 ] could be at least partly due to the species of diabetic rats and/or the duration of diabetes. It is apparent from the results of the present study that treatment of diabetic rats with VST prevented the increased responsiveness of aortae to noradrenaline and KC1, and also prevented the enhanced fast and slow components of noradrenaline response. The mechanism(s) responsible for the promoting effect of VST on vascular reactivity of STZ-diabetic rats in the present study remain unclear. Some possible explanations, however, might be deduced from the results obtained in the present study and from those obtained in previous studies demonstrating the glucose lowering effect of vanadium treatment of diabetic animals occurred in the absence of increases in the endogenous levels of insulin [ 28, 29 ]. In addition, in the present study, circulating insulin levels of non-diabetic control animals were demonstrated to be decreased with vanadium treatment while euglycaemia was being maintained as demonstrated in several other studies [ 27, 30 ]. These findings led to the suggestion that vanadium is able to substitute for insulin under in vivo conditions. On the other hand, vanadyl treatment has recently A. T. (gzgelikayet al.: The effect of vanadyl on aorta of diabetic rat b e e n shown to potentiate the in vivo glucose lowering effect of insulin in STZ-diabetic rats and to produce a decline in the dosage of insulin required for the maintenance of a non-glycosuric state in spontaneously diabetic BB rats [ 26 ]. Moreover, treatment of diabetic rats with insulin has b e e n demonstrated to prevent or reverse the increased responsinvess of aortae to noradrenaline [ 8 ]. The above-mentioned ability of insulin could be the result of a chronic effect of insulin treatment, either directly on vascular smooth muscle or indirectly via its action on glucose metabolism [ 8 ]. In a recent study by Mongold et al. [ 47 ], it was demonstrated that muscle vanadium levels of diabetic rats treated with vanadyl sulphate (up to i mg/ml in drinking water) were well below the in vitro active concentrations. It is, therefore, unlikely that VST at the concentration used in our experiments might have a direct effect on glucose metabolism in muscle, but might increase the sensitivity of vascular smooth muscle to the effects of insulin. These findings alternatively raise the possibility that vanadyl may be able to enhance the responsiveness of tissues to low circulating levels of insulin [ 28, 48-51 ]. Thus, it might be speculated that the effectiveness of endogenous insulin on vascular activity is then re-established in the STZ-diabetic rats treated with vanadyl although the present study has no direct evidence to support this possibility. In conclusion, the present findings demonstrate that 10-week VST treatment can be beneficial in restoring the changes in vascular reactivity of STZ-diabetic rats. The effectiveness of VST occurs b y its insulin-like actions. However, its mechanism(s) of action on vascular reactivity remain unclear and require further investigation. Acknowledgements. 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A. T. Özçelikay, C. Pekiner, N. Ari, Y. Öztürk, A. Özüari, Dr. V. M. Altan. The effect of vanadyl treatment on vascular responsiveness of streptozotocin-diabetic rats, Diabetologia, 1994, 572-578, DOI: 10.1007/BF00403375