Abstract
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.
Footnotes
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Send reprint requests to: Martin S. Muntzel, Ph, D., Lehman College, Department of Biological Sciences, 250 Bedford Park Boulevard West, Bronx, NY 10468-1589.
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↵1 This work was supported by a grant from the Professional Staff Congress of the City University of New York (P.S.C.-C.U.N.Y.) and by grants from the Danish Research Council for Health Sciences, the Danish Diabetes Association, Fonden til Lægevidenskabens Fremme, Eva and Robert Voss Hansen Foundation and the Ruth Kønig-Petersen’s Foundation.
- Abbreviations:
- BP
- blood pressure
- HR
- heart rate
- MAP
- mean arterial pressure
- SHR
- spontaneously hypertensive rat
- WKY
- Wistar-Kyoto rat
- l-NMMA
- NG-methyl-l-arginine acetate salt
- Received June 3, 1996.
- Accepted January 6, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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