EFFECTS OF DIPEPTIDYL PEPTIDASE IV INHIBITION ON ARTERIAL BLOOD PRESSURE
Authors: Jackson Edwin K , Dubinion John H , Mi Zaichuan 
Published: August 2007

SUMMARYThe aim of the present study was to determine whether inhibition of dipeptidyl peptidase IV (DPP IV) elevates arterial blood pressure and whether any such effect is dependent on genetic background, the sympathetic nervous system and Y1receptors. The rationale behind this study was that: (i) neuropeptide (NP) Y1–36and peptide YY1–36(PYY1–36) are endogenous Y1receptor agonists and are metabolised by DPP IV to NPY3–36and PYY3–36, which are not Y1but rather selective Y2receptor agonists; (ii) Y1receptors mediate vasoconstriction, whereas Y2receptors have little effect on vascular tone; (iii) vaso‐constrictor effect of the Y1receptor is enhanced in spontaneously hypertensive rats (SHR) compared with normotenisve Wistar‐Kyoto (WKY) rats; and (iv) NPY1–36is released from sympathetic nerve terminals.We examined the effects of acute administration of 3‐N‐[(2S,3S)‐2‐amino‐3‐methylpentanoyl]‐1,3‐thiazolidine (P32/98; a DPP IV inhibitor) on arterial blood pressure in anaesthetized adult SHR and WKY rats in the absence and presence of either captopril, hydralazine or chlorisondamine to lower basal mean arterial blood pressure (MABP) by different mechanisms (inhibition of angiotensin‐converting enzyme, direct vasodilation and ganglionic blockade, respectively).In naïve SHR with severely elevated basal blood pressures (MABP = 176 ± 3 mmHg;n = 4), i.v. boluses (1, 3 and 10 mg/kg) of P32/98 did not affect blood pressure.When basal blood pressure was reduced by pretreatment of SHR with either captopril (30 mg/kg, i.v.; MABP = 116 ± 3 mmHg;n = 9) or hydralazine (5 mg/kg, i.p.; MABP = 84 ± 3 mmHg;n = 7), P32/98 (1, 3 and 10 mg/kg) caused significant dose‐related increases in arterial blood pressure (4 ± 2, 10 ± 2 and 12 ± 3 mmHg in the captopril‐pretreated group, respectively (P < 0.01); 5 ± 2, 8 ± 3 and 11 ± 4 mmHg in the hydralazine‐pretreated group, respectively (P < 0.01)).The increases in arterial blood pressure induced by P32/98 in captopril‐ or hydralazine‐pretreated SHR were entirely blocked by pretreatment with the selective Y1receptor antagonistN2‐(diphenylacetyl)‐N‐[(4‐hydroxyphenyl)methyl]‐d‐arginine amide (BIBP 3226; 6 mg/kg per h).When basal blood pressure was reduced in SHR by pretreatment with chlorisondamine (10 mg/kg, s.c.; MABP = 108 ± 4 mmHg;n = 7), inhibition of DPP IV with P32/98 did not affect arterial blood pressure. Basal heart rate in chlorisondamine‐treated SHR was significantly reduced compared with naïve SHR, captopril‐pretreated SHR and hydralazine‐pretreated SHR, indicating effectiveness of ganglionic blockade.Unlike the results in genetically hypertensive animals, in normotensive WKY rats pretreated with captopril (30 mg/kg, i.v.; MABP = 81 ± 4 mmHg;n = 6), or hydralazine (5 mg/kg, i.p.; MABP = 63 ± 4 mmHg;n = 4) or chlorisondamine (10 mg/kg, s.c.; MABP = 63 ± 4 mmHg;n = 5), P32/98 did not affect arterial blood pressure.We conclude that, in genetically susceptible animals, inhibition of DPP IV increases arterial blood pressure via Y1receptors when elevated blood pressure is reduced with antihypertensive drugs provided that the sympathetic nervous system is functional. The results suggest vigilance because DPP IV inhibitors are used more widely in hypertensive patients treated with antihypertensive drugs.