Sitagliptin augments angiotensin II‐induced renal vasoconstriction in kidneys from rats with metabolic syndrome

Abstract

SUMMARY Dipeptidyl peptidase IV (DPPIV) inhibitors enhance renovascular responses to angiotensin II (Ang) in spontaneously hypertensive rats (SHR) but not Wistar-Kyoto rats. Because DPPIV inhibitors are often used in the metabolic syndrome, it is important to determine whether in this setting DPPIV inhibition enhances renovascular responses to Ang. Six-week-old Lean-ZSF1 rats (harbor SHR genes; do not have the metabolic syndrome; n=11) and Obese-ZSF1 rats (harbor SHR genes; express the metabolic syndrome; n=10) were obtained from Charles River (Wilmington, MA). At 7 weeks of age, compared to Lean-ZSF1, Obese-ZSF1 demonstrated significant (p<0.05) increases in body weight (262±8 versus 310±13 g), plasma glucose (112±4 versus 153±9 mg/dl), hemoglobin A1c (4.7±0.1 versus 5.8±0.4 %), urinary glucose excretion (0.02±0.003 versus 6.70±1.80 g/kg body weight/24 hours) and urinary protein excretion (100±7 versus 313±77 mg/kg body weight/24 hours). Mean blood pressure was high (133±7 mmHg) in both strains. At 8 weeks of age, kidneys were isolated and perfused. In Lean-ZSF1, renovascular responses (changes in perfusion pressure) to physiological levels of Ang (0.1 nmol/L) were 3.4±1.3 (n=5) and 18.2±5.9 (n=6) mmHg in untreated versus sitagliptin-treated (1 µmol/L) kidneys, respectively. In Obese-ZSF1, renovascular responses to Ang were 5.5±1.3 (n=4) and 17.8±8.2 (n=6) mmHg in untreated versus sitagliptin-treated kidneys, respectively. Analysis of variance revealed a significant (p=0.0367) effect of sitagliptin on renovascular responses to Ang that was strain independent. Conclusion: Sitagliptin enhances renovascular responses to Ang in rats harboring SHR genes, and this effect persists in rats with diabetic nephropathy and the metabolic syndrome.

The Effects of Dipeptidyl Peptidase-4 Inhibition on Microvascular Diabetes Complications

“…They showed that inhibition of DPP-4 prevents the catabolism of NPY(1-36) and thereby increases the effects of NPY(1-36) released from renal sympathetic nerves on Y1 receptors, thus leading to an enhancement of the renovascular effects of AT-II (85). Along this line, Tofovic et al (84) showed that sitagliptin enhances renovascular responses to AT-II in SHR rats; they also demonstrated that this effect persists in rats with diabetic nephropathy and metabolic syndrome. Kirino et al (86) assessed renal function in F344/DuCrlCrlj rats, a substrain of the inbred Fischer 344 strain lacking DPP-4 enzyme activity.…”

“…The relationship between DPP-4 activity and kidney function is complex, and available studies frequently report conflicting results. Tofovic et al (84) were among the first to underline this complexity, also in the light of the pleiotropic effect of DPP-4. They showed that inhibition of DPP-4 prevents the catabolism of NPY(1-36) and thereby increases the effects of NPY(1-36) released from renal sympathetic nerves on Y1 receptors, thus leading to an enhancement of the renovascular effects of AT-II (85).…”

Angiotensin-Converting Enzyme Inhibitor Use and Major Cardiovascular Outcomes in Type 2 Diabetes Mellitus Treated With the Dipeptidyl Peptidase 4 Inhibitor Alogliptin

“…This finding is consistent with animal data showing that DPP-4 inhibitors reduce BP when given alone but not when coadministered with an ACE inhibitor. 1,6 Additionally, DPP-4 inhibition with vildagliptin 14 potentiates endothelium-dependent vasodilation in response to acetylcholine, whereas others have reported that sitagliptin and alogliptin attenuated endothelial function based on changes in flow-mediated vasodilation in patients with type 2 diabetes mellitus. 15 These vascular findings have been implicated as a potential mechanism for augmented sympathetic activity that could have played a role in the increase in HF hospitalizations in the SAVOR TIMI 53 trial.…”

“…5 In addition, experimental data show that DPP-4 inhibition may enhance renal angiotensin II effects in a spontaneously hypertensive rat model. 6 Furthermore, activation of the sympathetic nervous system through substance P may be more likely in the presence of higher dose ACE inhibition and DPP-4 inhibition. 3 For example, the impact of coadministration of a high-dose ACE inhibitor and a DPP-4 inhibitor includes increases in blood pressure (BP) and heart rate in short-term, controlled clinical pharmacology studies.…”

Incretin-based therapy: renal effects

“…В модели L-NAME-индуцированной (L-NAME -N,ω-нитро-L-аргинина метиловый эфир) гипертензивной нефропатии у крыс ситаглиптин увеличивал содержание eNO-синтазы в по-чечной ткани [46]. Вместе с тем, ситаглиптин усиливал вазоконстриктивное действие ангиотензина II на почеч-ные сосуды в экспериментах на крысах линий Lean-ZSF1 и Obes-ZSF1 со спонтанной АГ [47]. В эксперименте на изолированной почке крыс линии SRH, предрасполо-женных к АГ, описано усиление реноваскулярного эф-фекта ангиотензина II под воздействием ситаглиптина; данный эффект был связан с ингибированием деграда-ции нейропептида Y в симпатических нервах почек [48].…”