Pharmacological evidence that metformin blocks the vasopressor responses mediated by stimulation of α1- and α2-adrenoceptors in pithed rats

Abstract

It has been reported that metformin reduces blood pressure although the mechanisms have not been described. Indeed, several mechanisms could be implicated including the interaction with α-adrenoceptors or inhibition of sympathetic outflow. Therefore, this study was designed to determine the capability of metformin to block the vasopressor responses induced by α_1/2-adrenoceptor agonists or selective electrical stimulation of sympathetic outflow. For this purpose, Wistar male rats were anesthetized, pithed and cannulated for selective preganglionic stimulation of the vasopressor sympathetic outflow or drugs administration. The effect of i.v. bolus injection of metformin (180 and 310mg/kg) or its vehicle (bidistilled water) was studied on the vasopressor responses induced by: (1) selective sympathetic stimulation (0.03-3Hz); (2) exogenous noradrenaline (0.03-3μg/kg); (3) methoxamine (1-100μg/kg); and (4) UK 14,304 (0.1-30μg/kg). The tachycardic responses to noradrenaline were also investigated in presence of metformin. The vasopressor responses induced by selective electrical stimulation of sympathetic outflow were diminished by metformin (180 and 310mg/kg) and remained unchanged in presence of vehicle. Moreover, the vasopressor responses induced by exogenous noradrenaline, methoxamine and UK 14,304 were dose-dependently inhibited by i.v. bolus injections of metformin (180 and 310mg/kg) and were not affected by vehicle. Metformin practically did not block the tachycardic responses to noradrenaline except at the dose of 3μg/kg. Taken together, these results demonstrate that metformin is capable to block vascular α_1/2-adrenoceptors but not cardiac β-adrenoceptors. Thus, this mechanism could contribute, at least in part, on the hypotensive responses induced by metformin.

Keywords: (±)-noradrenaline bitartrate (PubChem ID: 297812); 1,1-dimethyl biguanide hydrochloride (metformin) (PubChem ID: 14219); 5-Bromo-N-(2-imidazolin-2-yl)−6-quinoxalinamine, 5-Bromo-N-(4,5-dihydro-1H-imidazol-2-yl)−6-quinoxalinamine (UK 14,304, brimonidine) (PubChem ID: 2435); Blood pressure; Cardiovascular; Gallamine triethiodide (PubChem ID: 6172); Hypotension; Metformin; Methoxamine hydrochloride (PubChem ID: 6081); α(1/2)-adrenoceptors.