RT Journal Article
SR Electronic
T1 Effects of Adrenergic, Cholinergic and Ganglionic Blockade on Acute Depressor Responses to Metformin in Spontaneously Hypertensive Rats
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 618
OP 623
VO 281
IS 2
A1 Martin S. Muntzel
A1 Ayat Abe
A1 Jørgen S. Petersen
YR 1997
UL http://jpet.aspetjournals.org/content/281/2/618.abstract
AB Metformin lowers blood pressure in humans and in experimental animal models. To determine the mechanism of acute metformin-induced hypotension, we measured changes in mean arterial pressure (MAP) and heart rate (HR) during metformin alone (0, 10, 50, 100 mg/kg i.v.;n = 10) and during concomitant alphaadrenergic (phentolamine, 5 mg/kg; n = 5),beta adrenergic (propranolol, 3 mg/kg;n = 6), muscarinic (atropine, 200 μg/kg;n = 7), ganglionic (hexamethonium, 30 mg/kg;n = 11), nitric oxide synthase (NG-methyl-l-arginine acetate salt, 15 mg/kg;n = 9) and combination ganglionic plusalpha adrenergic plus beta adrenergic (n = 6) blockade in spontaneously hypertensive rats (SHR). Responses to metformin alone were also assessed in normotensive Wistar-Kyoto rats (n = 6). In SHRs, metformin elicited depressor responses accompanied by tachycardia (100 mg/kg; ΔMAP, −26 ± 3 mm Hg; ΔHR, +49 ± 12 bpm). Depressor responses in Wistar-Kyoto rats were significantly attenuated (100 mg/kg; ΔMAP, −9 ± 4 mm Hg; P < .01). Hypotensive actions of metformin in SHRs were abolished and reversed into pressor responses by hexamethonium (100 mg/kg; ΔMAP, +24 ± 6 mm Hg), phentolamine (100 mg/kg; ΔMAP, +62 ± 10 mm Hg) and by combination ganglionic plus adrenergic (100 mg/kg; ΔMAP, +62 ± 10 mm Hg) blockade. Neither propranolol, atropine nor NG-methyl-l-arginine acetate salt affected hypotensive responses to metformin. We conclude that acute intravenous metformin administration decreases MAP by causing withdrawal of sympathetic activity. The increase in MAP uncovered by hexamethonium and phentolamine suggests that the original depressor response to metformin is buffered by mechanisms unrelated to the autonomic nervous system. The American Society for Pharmacology and Experimental Therapeutics