Vasorelaxation Effect of Metformin in Rat Thoracic Aorta

Abstract

Metfonnin is an oral antihyperglycemic agent used in the management of type 2 diabetes mellitus. Metforminappears to provide cardiovascular protection with intrinsicantihypertensive property. This study was to investigate the role of endothelium inmetformin-induced vasorelaxation, using rat thoracic ao1ta isolated from adult male wistarrats ( 250-300 g). The aortic segments were cut helically and incubated in 15-ml organchambers containing KrebsHenseleitsolution (KHS), pH 7.4. The medium was maintainedat 37 °C and gased continuously with 95 % 0 2 and 5 % C02. Each tissue was placed under aninitial resting tension of 1g and allowed to equilibrate for 60 min prior to the experimentalprotocol.

To determinethe metfo1min-mediated relaxation in both endothelium-intact andendothelium-denuded aortic strips, the contraction was induced by the submaximalconcentration of norepinephrine (NE, l 0-7 M), and then followed by cumulatively addition of metformin( 10-7-1.5x 10-3 M). To probe the mechanism involve in the relaxation effect ofmetformin, several compounds including methylene blue (10-5 M, an inhibitor of soluble guanylyl cyclase inhibitor), indomethacin (10-5 M, an inhibitor of cyclooxygenase), tetraethylammonium (TEA, 10-3 M, an inhibitor of calcium-sensitive potassium channels) and glibenclamide (10-5 M, an inhibitor of ATP-sensitive potassium channels) werepreincubated15 minutes prior to precontraction with NE. The relaxation response wascalculated as the percentage of NE-induced contraction.

In this study, we found that metformin caused significant vasodilation ( p<0.05), incomparison with the control group. The percentage of maximal relaxation in endotheliumintact(32.96±2.84, n= 16) was significantly higher than that of endothelium-denuded (14.93±3.07, n= 7) ( p<0.05). Moreover, Methylene blue significantly inhibited therelaxation effect of metformin in endothelium-intact segment ( p<0.05), but not inendothelium-denuded segment. However, the metfo1min-mediated relaxation was notaffected by indomethacin, TEA, and glibenclamicle.

In conclusion, metformin caused vasorelaxationof rat thoracic aorta both inendothelium dependent and endothelium independent manner. In endothelium-dependent relaxation, metfo1min may, at least in prut, exe1t its effect through the cyclic GMP pathway.