Inhibition of Renal Dipeptidyl Peptidase IV Enhances Peptide YY_1–36-Induced Potentiation of Angiotensin II-Mediated Renal Vasoconstriction in Spontaneously Hypertensive Rats

Abstract

Dipeptidyl peptidase IV inhibitors are a new class of antidiabetic drugs. It is urgent, therefore, to fully understand the pharmacology of these inhibitors. Although dipeptidyl peptidase IV metabolizes at least 24 endogenous substrates, the pharmacological consequences of inhibiting the metabolism of most of these substrates is unknown. Our previous results show that Y 1 receptors, but not Y 2 receptors, enhance renovascular responses to angiotensin II in kidneys from genetically susceptible animals (spontaneously hypertensive rats). Dipeptidyl peptidase IV converts peptide YY 1-36 (circulating hormone) to peptide YY 3-36 , and peptide YY 1-36 is a Y 1 -receptor agonist, whereas peptide YY 3-36 is a selective Y 2 -receptor agonist. Therefore, it is conceivable that inhibition of dipeptidyl peptidase IV in genetically susceptible kidneys may increase the ability of peptide YY 1-36 to potentiate angiotensin II-induced renal vasoconstriction. Here we demonstrate that in kidneys from spontaneously hypertensive rats 1) peptide YY 1-36 potentiates renovascular responses to angiotensin II, whereas peptide YY 3-36 has little effect, 2) 3-N-[(2S,3S)-2-amino-3-methylpentanoyl]-1,3-thiazolidine (P32/98) (dipeptidyl peptidase IV inhibitor) augments the ability of peptide YY 1-36 to enhance renovascular responses to angiotensin II, 3) dipeptidyl peptidase IV is expressed in preglomerular microvessels and glomeruli, 4) kidneys metabolize arterial PYY 1-36 to PYY 3-36 via a mechanism blocked by P32/98, and 5) preglomerular microvessels and glomeruli convert peptide YY 1-36 to peptide YY , and this conversion is inhibited by P32/98. We conclude that dipeptidyl peptidase IV is expressed in the renal microcirculation and inhibition of this ecto-enzyme causes arterial PYY 1-36 to more effectively enhance angiotensin II-induced renal vasoconstriction in genetically susceptible kidneys.Inhibitors of dipeptidyl peptidase IV (DPP IV) (an ectoenzyme also called CD26) represent a novel class of antidiabetic drugs for treatment of type 2 diabetes (Augustyns et al., 2005;Bailey, 2005;Demuth et al., 2005). Drugs in this class, such as sitagliptin (Januvia), which has recently been approved by the Food and Drug Administration, afford significant and sustained reductions in hemoglobin A1c with a low risk of hypoglycemia and little effect on body weight (Barnett, 2006). DPP IV inhibitors are efficacious both as monotherapy and in combination with other antidiabetic drugs and are effective when administered orally once daily. These characteristics of DPP IV inhibitors, along with the emerging uncertainty regarding the safety of thiazolidinediones (Nissen and Wolski, 2007), make it highly likely that DPP IV inhibitors will be extensively used in the epidemic of type 2 diabetes. Thus, there is some urgency to fully understand the pharmacology of this new class of drugs.Because DPP IV metabolizes incretin hormones, such as gastric inhibitor peptide and glucagon-like peptide-1, DPP IV inhibitors raise circulating levels of incretin hormon...

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

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