Sitagliptin augments angiotensin II-induced renal vasoconstriction in kidneys from rats with metabolic syndrome.
1. Dipeptidyl peptidase (DPP) IV inhibitors enhance renovascular responses to angiotensin (Ang) II in spontaneously hypertensive rats (SHR), but not Wistar-Kyoto rats. Because DPPIV inhibitors are often used in metabolic syndrome, it is important to determine whether DPPIV inhibition in this setting enhances renovascular responses to AngII. 2. Six-week-old Lean-ZSF1 rats (harbouring SHR genes, but without metabolic syndrome; n = 11) and Obese-ZSF1 rats (harbouring SHR genes and expressing metabolic syndrome; n = 10) were provided food and water ad libitum, and metabolic parameters and renovascular responses to AngII were assessed when the animals were 7 and 8 weeks of age, respectively. 3. At 7 weeks of age, compared with Lean-ZSF1, Obese-ZSF1 demonstrated significant (P < 0.05) increases in bodyweight (262 +/- 8 vs 310 +/- 13 g), plasma glucose (112 +/- 4 vs 153 +/- 9 mg/dL), haemoglobin A1c (4.7 +/- 0.1 vs 5.8 +/- 0.4%), urinary glucose excretion (0.021 +/- 0.003 vs 6.70 +/- 1.80 g/kg bodyweight per 24 h) and urinary protein excretion (100 +/- 7 vs 313 +/- 77 mg/kg bodyweight per 24 h). Mean blood pressure was high (133 +/- 7 mmHg) in both strains. 4. At 8 weeks of age, kidneys were isolated and perfused. In Lean-ZSF1 rats, renovascular responses (i.e. changes in perfusion pressure) to physiological levels of AngII (0.1 nmol/L) were 3.4 +/- 1.3 and 18.2 +/- 5.9 mmHg in untreated (n = 5) and 1 micromol/L sitagliptin-treated (n = 6) kidneys, respectively. In Obese-ZSF1 rats, renovascular responses to AngII were 5.5 +/- 1.3 and 17.8 +/- 8.2 mmHg in untreated (n = 4) and sitagliptin-treated (n = 6) kidneys, respectively. Analysis of variance revealed a significant (P = 0.0367) effect of sitagliptin on renovascular responses to AngII that was independent of strain. 5. In conclusion, sitagliptin enhances renovascular responses to AngII in rats harbouring SHR genes and this effect persists in rats with diabetic nephropathy and metabolic syndrome.
Tofovic
David S
DS
Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15219, USA.
Bilan
Victor P
VP
Jackson
Edwin K
EK
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D003928:Diabetic Nephropathies / Q000188:drug therapy; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D006442:Glycated Hemoglobin / Q000032:analysis; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects*; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000235:genetics; D011507:Proteinuria / Q000188:drug therapy; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012079:Renal Circulation / Q000187:drug effects; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects* / Q000235:genetics; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000804:Angiotensin II; D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006442:Glycated Hemoglobin; D011719:Pyrazines; D000068900:Sitagliptin Phosphate; D014230:Triazoles; D014662:Vasoconstrictor Agents