Metformin Attenuates Salt-Induced Hypertension in Spontaneously Hypertensive Rats

Abstract

Abstract-Metformin, an antihyperglycemic agent used for treatment of type 2 diabetes mellitus, lowers blood pressure in humans and experimental animals. We recently demonstrated that short-term administration of metformin may lower blood pressure by reducing sympathetic neural outflow. The present studies were initiated to determine whether long-term administration of metformin blunts salt-induced hypertension, a condition characterized by elevated sympathetic activity. Male spontaneously hypertensive rats, in which radiotelemeters had been implanted for continuous monitoring of heart rate and blood pressure, were randomly assigned to groups that received vehicle (drinking water) or metformin (500 mg/kg per day) and ate a normal 0.3% NaCl diet and to groups that received vehicle or metformin and ate a high 8.0% NaCl diet for a period of 4 weeks. Although metformin did not affect blood pressure in the animals that ate the normal-salt diet (vehicle, 130Ϯ3 mm Hg; metformin, 133Ϯ5 mm Hg; meanϮSEM), drug treatment blunted the rise in pressure caused by a high-salt diet (vehicle, 153Ϯ4 mm Hg; metformin, 140Ϯ5 mm Hg; PϽ0.001). In agreement, during direct pressure recordings in anesthetized rats, the animals that ate the high-salt diet had higher pressures (136Ϯ13 mm Hg) than those in the control (98Ϯ5 mm Hg, PϽ0.01), metformin (100Ϯ7 mm Hg, PϽ0.01), and metformin/high-salt groups (92Ϯ3 mm Hg, PϽ0.01). Finally, metformin lowered heart rate in rats that ate the normal-and high-salt diets (310Ϯ3 and 305Ϯ4 bpm) compared with rats that ate normal-and high-salt diets given vehicle (332Ϯ3 and 324Ϯ2 bpm, PϽ0.01). These data indicate that the chronic depressor actions of metformin are enhanced in animals with hypertension exacerbated by a high-salt diet. (Hypertension. 1999;33:1135-1140.)

Metformin reduces blood pressure and restores endothelial function in aorta of streptozotocin-induced diabetic rats

“…Metformin is reported to lower blood pressure in various animal models-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). In this study, metformin had no significant effect on blood glucose levels in nondiabetic and diabetic rats.…”

“…Metformin lowers blood pressure in 0024-3205/$ -see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.lfs.2005.10.020 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).…”

Protection from vascular risk in diabetic hypertension

“…In experimental models of hypertension, agents that reverse insulin resistance, such as metformin, can reduce blood pressure [14]. Therefore, the combined disorders in glucose and insulin have major independent but perhaps additive effects that contribute to the abnormal blood pressure regulation, especially in patients with type 2 DM.…”

Use of Metformin in Patients with Kidney and Cardiovascular Diseases

“…The observed impaired diastolic relaxation in diabetes is related to diminished removal of intracellular ionized calcium ([Ca 2+ ] i ) from cardiomyocytes after systolic contraction [31,32,33]. Treatment of diabetic rats with metformin corrects these functional cardiac abnormalities [33,34,35,36], probably through improvement of tyrosine kinase-dependent increases in [Ca 2+ ] i removal after systole [33]. This myocardial protective action of metformin was shown to be insulin independent.…”

“…This myocardial protective action of metformin was shown to be insulin independent. Moreover, treatment of spontaneously hypertensive rats with metformin has been reported to decrease heart rate (a sympatho-inhibitory effect) more than placebo [36,37]. Although these findings are of interest, there is little direct clinical evidence of the effect of metformin on the development and course of congestive heart failure in diabetic and CRS patients.…”