Combinated effect of vildagliptin and valsartan on the treatment of heart failure in rats

Author(s)

Daniel Francisco de Arruda Junior

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD)
• Defense date: 2019-08-30

Examining board members

Adriana Castello Costa Girardi; Fabiana de Sant'Anna Evangelista; Paulo Caleb Júnior de Lima Santos

• Advisor: Adriana Castello Costa Girardi

Abstract

Inhibition of dipeptidyl peptidase IV (DPPIV), an enzyme responsible for the degradation of glucagon-like incretin peptide-1 (GLP-1), represents an effective and safe therapy for patients with type 2 diabetes mellitus. However, due to the multiple actions of GLP-1, besides its other endogenous substrates, the effect of inhibition of DPPIV activity can go far beyond the glycemic benefit, promoting cardio, vaso and renoprotective actions. In this context, data previously published by our laboratory demonstrate that in heart failure (HF) not associated with diabetes there is an increase in the activity and abundance of DPPIV in plasma and cardiac endothelium, suggesting that this peptidase plays an important role in the pathophysiology of HF. Consistent with this idea, we demonstrated that the inhibition of DPPIV significantly attenuates cardiac dysfunction in rats submitted to myocardial injury through radiofrequency ablation. This improvement includes decreased left ventricular end-diastolic pressure, increased systolic performance, and decreased cardiac stiffness. The central role of the renin-angiotensin system in the pathophysiology of HF is well established. Angiotensin II is a potent vasoconstrictor and important mediator of renal retention of sodium and water in renal tubules. In addition, angiotensin II potentiates the neural release of catecholamines, is arrhythmogenic, promotes vascular hyperplasia and pathological myocardial hypertrophy, as well as stimulates the death of cardiomyocytes. As a consequence, angiotensin II receptor antagonism is one of the bases of HF treatment. In view of the foregoing, this study aimed to test the hypothesis that the association between a DPPIV inhibitor and an angiotensin II receptor antagonist promotes synergistic therapeutic effects when administered to rats with congestive heart failure. For this, Wistar rats weighing ± 250g were submitted to left ventricular radiofrequency ablation for induction of heart failure (HF) or sham surgery (Sham). Six weeks after surgery the rats were divided into 5 groups and treated orally (gavage) for four weeks: 1) Sham + Vehicle (water); 2) HF + Vehicle (water); 3) HF + Valsartan (30mg / kg / day); 4) HF + Vildagliptin (120mg / kg / day); 5) HF + Assoc (120 mg / kg / day Vildagliptin + 30 mg / kg / day Valsartan). Vehicle-treated HF rats showed elevated total plasma BNP, pulmonary congestion, cardiac hypertrophy and increased collagen deposition in the remaining myocardium when compared to the Sham group. On the other hand, both valsartan or vildagliptin monotherapy and combined treatment significantly reduced circulating levels of BNP. In addition, all treatments were effective in reducing pulmonary congestion, cardiac hypertrophy and interstitial fibrosis compared to the HF group. The HF + Vehicle group had higher activity and abundance of DPPIV in plasma and heart compared to Sham rats. Interestingly, we found that plasma and heart DPPIV activity was lower not only in HF rats receiving vildagliptin but also in those receiving valsartan monotherapy compared to vehicle treated HF rats. Additionally, we report that the DPPIV inhibitor vildagliptin reduces the concentration of cardiac angiotensin II, whereas the valsartan AT1 receptor antagonist is able to reduce the activity of DPPIV in the plasma and heart of rats with HF. Taken together, these data suggest that there is no additive cardioprotective effect of the administration of DPPIV inhibitor and AT1 receptor antagonist in rats with HF quite possibly due to a possible overlap of cardioprotective pathways activated by these drugs (AU)

• FAPESP's process: 14/17135-9 - Posttranscriptional and posttranslational regulation of the enzyme dypeptidil peptidase IV in heart failure
• Grantee: Daniel Francisco de Arruda Junior
• Support Opportunities: Scholarships in Brazil - Doctorate