Cardiovascular actions of chronic intracerebroventricular administration of metformin in normotensive rats.
Acute intracerebroventricular administration of the antihyperglycaemic agent metformin (0.25-1 mg) elicits sympathoinhibitory responses in spontaneously hypertensive rats. However, cardiovascular actions of chronic intracerebroventricular metformin administration are unknown. To define the dose-response relationship during chronic intracerebroventricular metformin administration, mean arterial pressure, heart rate, and locomotor activity were measured continuously by radiotelemetry in 40 normotensive rats. After a 10 day control period, an intracerebroventricular cannula was implanted and connected to an osmotic minipump which delivered metformin in the following doses: 0 [saline]. 0.01, 0.1, 1, and 10 mg/day. LD50 was 1.5 mg/day. Metformin, 1 mg/day attenuated the nocturnal, physiological increase in mean arterial pressure (-7.3 +/- 1.6% versus before metformin), produced behavioural changes and tended to increase locomotor activity. Lower doses of intracerebroventricular metformin (0.1 and 0.01 mg/day) did not affect mean arterial pressure, heart rate or locomotor activity. In conclusion, chronic intracerebroventricular administration of high dose metformin (1.0 mg/day) attenuates the nocturnal, physiological increase in mean arterial pressure. These findings are compatible with a toxic, sympathoinhibitory action of high doses of metformin intracerebroventricularly.
Andersen
D
D
Department of Pharmacology, Panum Institute, University of Copenhagen, Denmark.
Haugan
K
K
Sørensen
A M
AM
Christensen
S
S
Petersen
J S
JS
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D007276:Injections, Intraventricular; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar
D007004:Hypoglycemic Agents; D008687:Metformin