Acute vasorelaxant effects of metformin and attenuation by stimulation of sympathetic agonist release

Sildenafil does not enhance but rather attenuates vasorelaxant effects of antidiabetic agents

“…sulfonylureas) and some that mimic and/or improve insulin action (the biguanide metformin and the thiazolidinediones pioglitazone and rosiglitazone) (46,47,48,49,50). Only agents of the latter type are known to exert direct vasodilatory (vasorelaxant) effects on the arterial vessel wall (17,18,19,20,21,22,23, 49, 51,52,53,54,55,56,57,58); effects now recognized as largely responsible for their antihypertensive action (49, 54,55,56,57,58). Also, the full expression of their vasorelaxant effects (at least with low, therapeutically-relevant concentrations) is delayed for a number of hours (19, 21,22,23).…”

“…However, we will employ rings from the ventral tail artery of the laboratory rat since all of our previous experiments with direct vasorelaxant properties of metformin and the thiazolidinediones were successfully performed with that particular preparation (18,19,20,21,22,23). In addition, while certainly much smaller, the rat tail artery is also more muscular and richer in adrenergic nerve endings and receptors than the aorta and, as such, more closely resembles systemic arterial resistance vessels (26,27,28).…”

“…[Eight was the largest number that our in vitro bath system and Grass recorder could accommodate on any given day]. Each ring was mounted between two tungsten wire stirrups which in our experience were strong enough not to bend during ring contractions yet thin enough not to damage the inner endothelial cell layer (18,19,20,21,22,23). Then, each ring was suspended in a 40 ml tissue bath and equilibrated for several minutes before experimentation at a resting (baseline) tension of 1000 mg in standard physiological (Krebs) buffer which was warmed to 37 °C and gassed to pH 7.4 with regulated delivery of O 2 /CO 2 .…”

“…At high concentrations, well above levels observed in plasma of diabetic patients (14,15,16), their relaxation of isolated arterial vascular tissues in vitro occurs rapidly (17,18,19,20,21). At lower, more therapeutically-relevant concentrations, the appearance of their relaxant action in vitro can be delayed for a number of hours (19, 21,22,23).…”

Metformin in Obstetric and Gynecologic Practice: A Review

“…A series of studies of metformin in normotensive and hypertensive, insulin-sensitive and insulin-resistant rats confirm that metformin tends to lower high blood pressure with minimal effect in normotensive subjects (20,(24)(25)(26)(27)(28). The majority of these laboratory studies favor a mechanism involving the sympathetic nervous system (24,26,28), possibly at a central nervous system level (26,28).…”