Opposing adrenergic actions of intravenous metformin on arterial pressure in female spontaneously hypertensive rats

Objective: Intravenous (iv) injection of the antidiabetic drug metformin rapidly lowers mean arterial pressure (MAP) in spontaneously hypertensive rats (SHR). However, if autonomic ganglia or alpha-adrenoceptors are first blocked then metformin rapidly raises MAP in SHR. This study was conducted to further characterize the adrenergic mechanisms of these opposing iv actions of the drug, Methods: Conscious, undisturbed female SHR with indwelling vascular catheters were used to measure acute effects of iv metformin (100 mg/kg; before and after sustained ganglionic blockade, GB, with chlorisondamine, 5 mg/kg) on: (1) circulating levels of catecholamines, (2) MAP after pharmacologic modulation of beta- as well as alpha-adrenoceptors and (3) all the above in the absence as well as presence of the adrenal medulla. Results: Plasma norepinephrine (NE) and epinephrine (E) levels (pg/ml) were rapidly increased by iv metformin (8 SHR, p<0.05) both before GB (Delta NE = +146 +/- 41; Delta E = +119 +/- 31) and after GB (Delta NE = +79 +/- 24; Delta E = +120 +/- 32). Similar increases in plasma NE (though not E) were seen in SHR without adrenal medullae. Blockade of beta-adrenoceptors with propranolol (pro; 3 mg/kg, 8 SHR) enhanced the rapid depressor response to iv metformin before GB (Delta MAP, mmHg: -38 +/- 4 with pro vs -17 +/- 3 without pro; p<0.05) and attenuated the rapid presser response to iv metformin after GB (Delta MPAP, mmHg: +8 +/- 3 with pro vs +30 +/- 4 without pro; p<0.05). Results were similar in SHR without adrenal medullae. Finally, if baseline MAP under GB was raised back to hypertensive levels with iv infusion of either NE or phenylephrine then iv metformin did not raise but rather reduced MAP in SHR. Conclusion(s): The acute depressor action of iv metformin in female SHR (1) is most likely due to a direct vasodilator action which includes inhibition of alpha-receptor-mediated vasoconstriction and (2) is buffered by an acute beta-receptor-mediated presser action likely due to a direct metformin-induced release of NE from postganglionic sympathetic nerve endings. (C) 1999 Elsevier Science B.V. All rights reserved.