Name: PHABLO WENDELL COSTALONGA OLIVEIRA
Publication date: 18/05/2018
Advisor:
Name |
Role |
|---|---|
| NAZARE SOUZA BISSOLI | Advisor * |
| ROGER LYRIO DOS SANTOS | Co-advisor * |
Examining board:
| Name |
Role |
|---|---|
| MARCELO PERIM BALDO | External Examiner * |
| NAZARE SOUZA BISSOLI | Advisor * |
| ROGER LYRIO DOS SANTOS | Co advisor * |
| SONIA ALVES GOUVEA | Internal Examiner * |
| SUELY GOMES DE FIGUEIREDO | Internal Examiner * |
Summary: Introduction: Metformin and omega-3 very long chain polyunsaturated fatty acids (VLC-PUFA; ≥ C20) have been shown beneficial effects on cardiovascular system in humans and animal models. However, little is known about its effects no mesenteric vascular dysfunction, autonomic imbalance and baroreflex dysfunction related to hypertension.
Aims: We aimed to evaluate the chronic effects of metformin and omega-3 VLCPUFA on vascular dysfunction and cardiac autonomic impairment related to hypertension in spontaneously hypertensive rats (SHR). Methods: Twelve-week-old male Wistar and SHR rats were divided into 4 groups according to the treatment: WN (Wistar Normotensive); SC (SHR with Control treatment [vehicle/water]); SM (SHR treated with Metformin 300 mg/kg/day) and SO (SHR treated with Omega-3: concentrated omega-3 fish oil 300 mg/kg/day
[33 % EPA, 22 % DHA]), treated by gavage for 30 days. After catheter implantation in femoral artery and vein, the induced baroreflex sensitivity was tested in response to vasoactive drugs, phenylephrine and sodium nitroprusside, and cardiac autonomic control was evaluated using pharmacological blockades, atropine to test parasympathetic activity and atenolol to test sympathetic activity. Spontaneous
baroreflex was also evaluated in basal condition. Norepinephrine vasoconstriction responses were evaluated in mesenteric vascular bed in an ex vivo system, in presence and absence of pharmacological inhibitors: LNAME and indomethacin. Plasmatic levels of inflammatory cytokine TNFα were evaluated by ELISA. Cardiac oxidant and antioxidant proteins were evaluated by Western blot analyses.
Results: None of the treatments was able to reduce blood pressure in hypertensive animals. Heart rate was reduced in SM WHEREas the mean of the SO group was numerically lower than that of SC, but without statistical difference. The parasympathetic cardiac control was lower in SC WHEREas the means of SM and SO groups were numerically higher than that of SC, but without statistical difference. The sympathetic control was higher in SC group and metformin, but not omega-3,
reduced it to WN values. Baroreflex function was lower in SC in all analysis and metformin promoted a partial improvement. On the other hand, omega-3 promoted baroreflex enhancement only when induced by sodium nitroprusside. Mesenteric vascular reactivity to noradrenaline was greater in SC than in WN and both the treatments promoted an attenuation of its response. This difference between the
groups was shown to be related to the prostanoids pathway, since L-NAME increased the response in all groups in a similar way and indomethacin greatly reduced the response in hypertensive animals, approaching the values of the treated groups (SO and SM) to the untreated group values (SC). Both treatments reduced TNFα and metformin decreased NOX2 levels that were increased in SC.
Conclusions: Metformin and omega-3 VLC-PUFA have potential to improve autonomic and vascular parameters that are found impaired in hypertension, even without promoting blood pressure lowering, which seems to be related to effects on inflammation and oxidative stress. These findings open up new perspectives for future of metformin and omega-3 use in hypertension.
