Sitagliptin Augments Sympathetic Enhancement of the Renovascular Effects of Angiotensin II in Genetic Hypertension

Abstract

Abstract-DipeptidylIn this regard, there are 2 endogenous agonists of Y 1 Rs that would be presented to the kidney microcirculation, ie, peptide YY 1-36 (PYY ) and neuropeptide Y 1-36 (NPY 1-36 ). Both are pancreatic polypeptide-fold peptides. A fatty meal releases PYY 1-36 into the systemic circulation from endocrine L-cells in the small bowel, colon, and rectum producing physiologically active levels of PYY in plasma that are 500% to 1000% above basal circulating levels, 2-8 and this circulating PYY 1-36 would be delivered promptly to the renal microcirculation via the blood stream (humoral Y 1 R-agonist input to kidney microcirculation). Renal sympathetic nerves release NPY 1-36 in response to central nervous system-mediated activation of the renal sympathetic nerves (neural Y 1 Ragonist input to kidney microcirculation), resulting in high local levels of NPY 1-36 in sympathetically-innervated renal microvessels during renal sympathetic activation. 9 Because both PYY 1-36 and NPY 1-36 are potent Y 1 R agonists, 10,11 physiological processes that increase PYY 1-36 release from the gut, NPY 1-36 release from renal sympathetic nerves, or both simultaneously would activate Y 1 Rs in the renal microcirculation, which in genetically-susceptible kidneys would enhance Ang II-induced renal vasoconstriction.

Endogenous adenosine contributes to renal sympathetic neurotransmission via postjunctional A1receptor-mediated coincident signaling

“…RSNS was accomplished by placing a platinum bipolar electrode around the renal artery close to the kidney and connecting the electrode to a Grass stimulator (model SD9E; Grass Instruments, Quincy, MA) as previously described by us (35). The tissues around the electrode were kept moist with Tyrode's solution and the stimulation parameters were biphasic pulses, 1-ms pulse duration; 35 V at indicated frequencies.…”

Is the Use of DPP-4 Inhibitors Associated With an Increased Risk for Heart Failure? Lessons From EXAMINE, SAVOR-TIMI 53, and TECOS

“…The mechanisms underlying this interaction are unclear but might relate to altered degradation of the peptide substance P or neuropeptide Y related to DPP-4 inhibition, ultimately leading to sympathetically mediated vasoconstriction. In addition, Jackson and Mi (47) showed that in a renal perfusion model, enhancement of angiotensin-IImediated constrictor responses, owing to increases of neuropeptide Y, could be exacerbated by sitagliptin and blocked if sitagliptin were given together with a neuropeptide Y inhibitor, again suggesting enhanced vasoconstriction.…”

Incretin-based therapy: renal effects

“…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].…”