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.