Metformin normalizes endothelial function by suppressing vasoconstrictor prostanoids in mesenteric arteries from OLETF rats, a model of type 2 diabetes

Abstract

We previously reported that in mesenteric arteries from aged Otsuka Long-Evans Tokushima fatty (OLETF) rats (a type 2 diabetes model) endothelium-derived hyperpolarizing factor (EDHF)-type relaxation is impaired while endothelium-derived contracting factor (EDCF)-mediated contraction is enhanced (Matsumoto T, Kakami M, Noguchi E, Kobayashi T, Kamata K. Am J Physiol Heart Circ Physiol 293: H1480-H1490, 2007). Here we investigated whether acute and/or chronic treatment with metformin might improve this imbalance between the effects of the above endothelium-derived factors in mesenteric arteries isolated from OLETF rats. In acute studies on OLETF mesenteric arteries, ACh-induced relaxation was impaired and the relaxation became weaker at high ACh concentrations. Both metformin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside [AICAR, an AMP-activated protein kinase (AMPK) activator that is also activated by metformin] 1) diminished the tendency for the relaxation to reverse at high ACh concentrations and 2) suppressed both ACh-induced EDCF-mediated contraction and ACh-stimulated production of prostanoids (thromboxane A2 and PGE2). In studies on OLETF arteries from chronically treated animals, metformin treatment (300 mg.kg(-1).day(-1) for 4 wk) 1) improved ACh-induced nitric oxide- or EDHF-mediated relaxation and cyclooxygenase (COX)-mediated contraction, 2) reduced EDCF-mediated contraction, 3) suppressed production of prostanoids, and 4) reduced superoxide generation. Metformin did not alter the protein expressions of endothelial nitric oxide synthase (eNOS), phospho-eNOS (Ser1177), or COX-1, but it increased COX-2 protein. These results suggest that metformin improves endothelial functions in OLETF mesenteric arteries by suppressing vasoconstrictor prostanoids and by reducing oxidative stress. Our data suggest that within the timescale studied here, metformin improves endothelial function through this direct mechanism, rather than by improving metabolic abnormalities.

Activation and Signaling by the AMP-Activated Protein Kinase in Endothelial Cells

“…The latter is certainly possible because metformin treatment decreases the production of an endothelium-derived vasoconstrictor prostanoid in a rat model of type 2 diabetes. 130 Endothelium-dependent relaxation, however, is not exclusively regulated by NO and on the basis of the available literature it is tempting to speculate a link between the AMPK and relaxation linked to the generation of epoxyeicosatrienoic acids by cytochrome P450 epoxygenases. Indeed, LKB1 and the AMPK can be activated by stimulation of the constitutive androstane receptor and pregnane X receptor, using pheno-…”

“…Metformin and AICAR are able to redress this balance and to decrease oxidative stress without altering the expression of eNOS or cyclooxygenase-1 but by increasing the expression of cyclooxygenase-2 protein. 130 Because vascular complications are the leading cause of death in subjects with diabetes, a therapeutic approach that activates the AMPK should be able to improve glycemic control at the same time as maintaining or restoring endothelial function.…”

Dissociation of Hyperglycemia from Altered Vascular Contraction and Relaxation Mechanisms in Caveolin-1 Null Mice

“…Although cav-1 has been linked to regulation of both vascular and glycemic control mechanisms, the relation between hyperglycemia and altered vascular function and BP in cav-1 deficiency states is poorly defined. For example, whereas insulin-sensitizing compounds such as metformin are the first-line therapy for type 2 diabetes and glycemic control in prediabetic states and metformin improves hyperglycemia in several experimental models (Heishi et al, 2006;Matsumoto et al, 2008), certain patients with diabetes show inadequate glycemic control with metformin monotherapy (Bailey et al, 2013). On the other hand, metformin may have pleiotropic vascular effects that are independent of its effects on glycemic control.…”

“…By use of cav-1 knockout (cav-1 2/2 ) mice, which show hyperglycemia and altered vascular reactivity (Cohen et al, 2003;Pojoga et al, 2010Pojoga et al, , 2011Asterholm et al, 2012) and metformin treatment at a dose that improved hyperglycemia in other models (Heishi et al, 2006;Matsumoto et al, 2008), we hypothesized that if the vascular changes in cav-1 deficiency states are related to hyperglycemia, then metformin improvement of hyperglycemia should be paralleled with improved vascular function. Conversely, if the vascular changes in cav-1 deficiency states are independent of hyperglycemia and metformin changes vascular outcome despite inadequate glycemic control as shown clinically in certain patients with diabetes (Bailey et al, 2013), metformin then should affect vascular function without modifying hyperglycemia.…”

Uridine adenosine tetraphosphate-induced contraction is increased in renal but not pulmonary arteries from DOCA-salt hypertensive rats

“…Exposure of RA (Fig. 1C) (43)(44)(45)(46). Indeed, Up 4 A-induced NO-dependent relaxation has been observed in rat aorta (41) and in rat perfused kidney (58).…”