Metformin reduces blood pressure and restores endothelial function in aorta of streptozotocin-induced diabetic rats
Introduction
Cardiovascular disease is one of the leading causes of death in the western world and diabetes mellitus, which alters the vascular responsiveness to several vasoconstrictors and vasodilators, is a major factor underlying its development (Senses et al., 2001). Most of the complications in diabetes are due to increased serum glucose and increased generation of oxygen-derived free radicals, which lead to endothelium dysfunction. It has been shown that vessels from diabetic animals, exhibited abnormal endothelium-dependent vascular relaxation to acetylcholine (Oyama et al., 1986, Kamata et al., 1989).
Metformin belongs to bigunide insulin-sensitizing class of anti-diabetic drugs, widely used for the treatment of type 2 diabetes. The exact mechanisms of action of metformin, is poorly understood (Moller, 2001), but it includes suppression of endogenous glucose output by liver and increased sensitivity in skeletal muscle (Matthaei et al., 2000). Metformin lowers blood pressure in certain human patients (Landin et al., 1991, Giugliano et al., 1993) but not in others (Calle-Pascual et al., 1995, Gudbjo¨Rnsdottir et al., 1994, Campbell et al., 1987). Metformin lowers blood pressure in fructose fed rats (Verma et al., 1994), OLETF rats (Kosegawa et al., 1996), SHR (Bhalla et al., 1996, Muntzel et al., 1999) and insulin-resistant rats (Katakam et al., 2000). Metformin also has antioxidant activity which is independent of its effect of insulin activity (Faure et al., 1999). Recently Sartoretto et al. (2005) has reported that metformin increases nitric oxide activity but not expression and that it improves microvascular reactivity in n- STZ-diabetic rats (Type 2). There are no reports on effect of metformin on STZ-diabetic model (Type I) wherein free radical generation is one of the main causes of endothelial dysfunction (Kobayashi and Kamata, 1999, Zanetti et al., 2001). We have previously shown that administration of STZ causes a significant increase in blood pressure and oxidative stress (Majithiya et al., 2005). The current study investigates the effect of chronic metformin treatment on blood pressure, endothelial function and oxidative stress in streptozotocin-induced diabetic rats. Moreover, in vitro effects of metformin on aortic rings of STZ-diabetic and nondiabetic rats are also studied.
Section snippets
Drugs
Metformin hydrochloride and glybenclamide were obtained as a gift sample from Alembic Ltd, Baroda. Streptozotocin, phenylephrine, acetylcholine, Nω-nitro-l-arginine-methyl ester (l-NAME), indomethacin, 4-aminopyridine, tetraethylammonium (TEA), epinephrine, 1,1,3,3,-tetra ethoxy propane, superoxide dismutase, catalase and glutathione standard were obtained form SIGMA, St. Louis, MO, USA. All other chemicals and reagents used in the study were of analytical grade. The composition of the Krebs
Blood glucose, body weight and systolic blood pressure
All streptozotocin-injected animals developed diabetes. The changes in blood glucose levels are shown in Table 1. Blood glucose levels remained unchanged in nondiabetic animals (N and N-MET groups). There was significant (p < 0.05) increase in blood glucose levels in streptozotocin injected animals. Metformin treatment did not have any significant effect on blood glucose level and body weight of diabetic rats (Table 1). There was a significant (p < 0.05) increase in systolic blood pressure in
Discussion
The blood pressure of 8-week STZ-diabetic rats was significantly higher as compared to nondiabetic control. The results are in concurrence with our previous study where the blood pressure was increased after 8 weeks of STZ administration and Ach-induced relaxation was impaired in aortic rings (Majithiya et al., 2005). Administration of metformin for 4 weeks restored the elevated blood pressure, reduced the enhanced contractibility to PE- and Ach-induced relaxation was restored. In
Acknowledgement
Financial assistance provided by The M.S. University of Baroda to Mr. Jayesh B Majithiya is highly acknowledged.
References (42)
- et al.
Anti-ulcer and antioxidant activity of DHC-1, a herbal formulation
Journal of Ethnopharmacology
(2004) - et al.
Vascular effects of metformin: possible mechanisms for its antihypertensive action in the spontaneously hypertensive rat
American Journal of Hypertension
(1996) - et al.
An intracellular modulation of free radical production could contribute to the beneficial effects of metformin towards oxidative stress
Metabolism
(2003) - et al.
Determination of nitrite/nitrate in human biological material by the simple Griess reaction
Clinica Chimica Acta
(1998) - et al.
Relationship among cholesterol, superoxide anion and endothelium-dependent relaxation in diabetic rats
European Journal of Pharmacology
(1999) - et al.
Effect of metformin on nitric oxide synthase in genetically obese (ob/ob) mice
Life Sciences
(2001) - et al.
Improved endothelial function with metformin in type 2 diabetes mellitus
Journal of the American College of Cardiology
(2001) - et al.
Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver
Biochimca and Biophysica Acta
(1979) - et al.
Attenuation of endothelium-dependent relaxation in aorta from diabetic rats
European Journal of Pharmacology
(1986) - et al.
Disparate effects of antidiabetic drugs on arterial contraction
Metabolism
(1997)
Metformin treatment restores the altered microvascular reactivity in neonatal streptozotocin-induced diabetic rats increasing NOS activity, but not NOS expression
Life Science
Decreased vascular reactivity in metformin-treated fructose-hypertensive rats
Metabolism
Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo: role of mitochondrial reactive nitrogen species
Journal of Biological Chemistry
Oxidoreductases acting on groups other than CHOH: catalase
Comparison between acarbose, metformin, and insulin treatment in type 2 diabetic patients with secondary failure to sulfonylurea treatment
Diabetes & Metabolism
The effect of metformin on glycaemic control, intermediary metabolism and blood pressure in non-insulin-dependent diabetes mellitus
Diabetes & Metabolism
An insulin sensitizer improves the free radical defense system potential and insulin sensitivity in high fructose-fed rats
Diabetes
Metformin prevents glucose-induced protein kinase c-β2 activation in human umbilical vein endothelial cells through an antioxidant mechanism
Diabetes
Metformin improves glucose lipid metabolism, and reduces blood pressure in hypertensive, obese women
Diabetes Care
Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor
Nature
The effect of metformin and insulin on sympathetic nerve activity, norepinephrine spillover and blood pressure in obese, insulin resistant, normoglycemic, hypertensive men
Blood Pressure
Cited by (98)
Effect of metformin treatment on memory and hippocampal neurogenesis decline correlated with oxidative stress induced by methotrexate in rats
2021, Biomedicine and PharmacotherapyVasorelaxant Activity and Its Mechanisms of Momordica charantia Fruit Extract in Diabetic Rat Aorta
2024, Malaysian Journal of Medicine and Health SciencesInfluence of rutin and its combination with metformin on vascular functions in type 1 diabetes
2023, Scientific ReportsMetformin relaxes rat thoracic aorta via nitric oxide, AMPK, potassium channels, and PKC
2023, Iranian Journal of Basic Medical Sciences