Metformin prevents vascular prostanoid release alterations induced by a high‐fat diet in rats

Summary Perivascular adipose tissue dysfunction induced by high‐fat feeding leads to alterations in the modulation of inflammation, contractile activity of the vascular smooth muscle and endothelial function, all risk factors in the development of hypertension. Metformin, an activator of AMP ‐activated protein kinase ( AMPK ), is currently the first‐line drug treatment for type 2 diabetes (T2 DM ) and metabolic syndrome. Besides its glucose‐lowering effect, there is an interest in actions of this drug with potential relevance in cardiovascular diseases. The high‐fat ( HF ) diet is an experimental model that resembles human metabolic syndrome. We have previously reported an altered pattern of prostanoid release in mesenteric vessels in this model. The aim of this study was to analyse the effects of metformin on mesenteric vascular bed prostanoid release, adiposity index and its relation to blood pressure in Sprague‐Dawley rats fed a HF diet for 8 and 12 weeks. Eight groups were used: control (C8, C1), HF diet ( HF 8, HF 12, 50% w/w bovine fat), metformin‐treated ( CM f8, CM f12, 500 mg/kg/day) and metformin‐treated HF diet ( HFM f8, HFM f12, both treatments). HF diet increased mesenteric vascular bed adiposity index (%, HF 8: 1.7±0.1 vs C8: 0.9±0.04 and HF 12: 1.8±0.1 vs C12: 0.8±0.1, P <.001); systolic blood pressure ( SBP , mm Hg, HF 8: 145±6 vs C8: 118±4, P <.01 and HF 12: 151±1 vs C12: 121±3, P <.001). We found a positive correlation between these two parameters. Moreover HF diet increased the release of vasoconstrictor prostanoids such as thromboxane ( TX ) B 2 (ng PR /mg of tissue, HF 8: 117±6 vs C8: 66±2 and HF 12: 123±6 vs C12: 62±5, P <.001) and prostaglandin ( PG ) F 2α (ng/mg, HF 8: 153±9 vs C8: 88±3 and HF 12: 160±11 vs C12: 83±5, P <.001). We also found that this increase in the release of vasoconstrictor prostanoids positively correlates with the elevation of SBP . In addition, HF diet increases the release of PGE 2 and decreases the prostacyclin ( PGI 2 )/ TXA 2 release ratio at 8 and 12 weeks of treatment compared to control groups. In the HFM f group, metformin treatment prevented all these increases in mesenteric vascular bed adiposity index (%, HFM f8: 1.3±0.2 vs HF 8 and HFM f12: 1.3±0.1 vs HF 12, P <.05); SBP (mm Hg, HFM f8: 127±2 vs HF 8 and HFM f12: 132±1 vs HF 12, P <.001); TXB 2 release (ng PR /mg of tissue, HFM f8: 65±12 vs HF 8, P <.05 and HFM f12: 53±3 vs HF 12, P <.001) and PGF 2 α (ng PR /mg of tissue, HFM f8: 99±13 vs HF 8, P <.01 and HFM f12: 77±8 vs HF 12, P <.001). Meanwhile metformin prevented the increment in PGE 2 release only at 12 weeks. On the other hand, metformin improved the PGI 2 /TXA 2 ratio in both periods studied. In conclusion, metformin could exert beneficial effects on adipose tissue and the vascular system by improving endothelial dysfunction induced by an imbalance of vasoactive substances in mesenteric perivascular adipose tissue in this model.