Effects of dipeptidyl peptidase iv inhibition on arterial blood pressure.
1. The 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 Y(1) receptors. The rationale behind this study was that: (i) neuropeptide (NP) Y(1-36) and peptide YY(1-36) (PYY(1-36)) are endogenous Y(1) receptor agonists and are metabolised by DPP IV to NPY(3-36) and PYY(3-36), which are not Y(1) but rather selective Y(2) receptor agonists; (ii) Y(1) receptors mediate vasoconstriction, whereas Y(2) receptors have little effect on vascular tone; (iii) vaso-constrictor effect of the Y(1) receptor is enhanced in spontaneously hypertensive rats (SHR) compared with normotensive Wistar-Kyoto (WKY) rats; and (iv) NPY(1-36) is released from sympathetic nerve terminals. 2. 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). 3. 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. 4. 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)). 5. The increases in arterial blood pressure induced by P32/98 in captopril- or hydralazine-pretreated SHR were entirely blocked by pretreatment with the selective Y(1) receptor antagonist N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl]-d-arginine amide (BIBP 3226; 6 mg/kg per h). 6. 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. 7. 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. 8. We conclude that, in genetically susceptible animals, inhibition of DPP IV increases arterial blood pressure via Y(1) receptors 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.
Jackson
Edwin K
EK
Center for Clinical Pharmacology, Department of Pharmacology, University of Pittsburgh School of Medicine, 100 Technology Drive, Suite 450, Pittsburgh, PA 15219-3130, USA. edj@pitt.edu
Dubinion
John H
JH
Mi
Zaichuan
Z
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D002216:Captopril / Q000494:pharmacology; D002714:Chlorisondamine / Q000494:pharmacology; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005730:Ganglionic Blockers / Q000494:pharmacology; D006830:Hydralazine / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D010421:Pentanoic Acids / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017476:Receptors, Neuropeptide Y / Q000187:drug effects* / Q000378:metabolism; D053778:Thiazolidines / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; C092926:BIBP 3226; D054873:Dipeptidyl-Peptidase IV Inhibitors; D005730:Ganglionic Blockers; C453900:P32-98 compound; D010421:Pentanoic Acids; D017476:Receptors, Neuropeptide Y; D053778:Thiazolidines; D014665:Vasodilator Agents; C097212:neuropeptide Y-Y1 receptor; D006830:Hydralazine; D001120:Arginine; D002216:Captopril; D018819:Dipeptidyl Peptidase 4; D002714:Chlorisondamine