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Cardiovascular Research 1999 43(1):237-247; doi:10.1016/S0008-6363(99)00051-6
© 1999 by European Society of Cardiology
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Copyright © 1999, European Society of Cardiology

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

Jacob D. Peuler*

Department of Pharmacology, Midwestern University, Downers Grove, IL, USA

* Corresponding author. Tel.: +1-630-515-6068; fax: +1-630-971-6414 jpeule{at}midwestern.edu

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 β- 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 β-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 pressor response to iv metformin after GB ({Delta}MAP, 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 β-receptor-mediated pressor action likely due to a direct metformin-induced release of NE from postganglionic sympathetic nerve endings.

KEYWORDS Experimental; Regulatory systems; Pharmacology; Autonomic nervous system; Blood pressure; Diabetes; Hypertension; Vasoconstriction/dilation


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