bibp-3226 and Hypertension

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

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Arginine; Blood Pressure; Captopril; Chlorisondamine; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Ganglionic Blockers; Hydralazine; Hypertension; Pentanoic Acids; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Neuropeptide Y; Thiazolidines; Vasodilator Agents

To study the effects of the selective neuropeptide Y (NPY) Y1 receptor antagonist BIBP 3226 in spontaneously hypertensive rats (SHR) in order to elucidate whether NPY function may be altered in the SHR and whether the NPY Y1 receptor plays a specific role in the maintenance of high blood pressure in this genetic form of hypertension.. Pithed and conscious SHR were studied after intravenous administration of 0.125-1 mg/kg BIBP 3226. The cardiovascular effects were evaluated under baseline conditions, under acute stress and after exogenous administration of 20 microg/kg NPY. The potentiating effects of NPY on pressor responses to phenylephrine and tyramine were studied in the SHR.. Intravenous administration of 0.125-1 mg/kg BIBP 3226 dose-dependently inhibited the pressor response to exogenous NPY in pithed SHR. At higher doses BIBP 3226 had an effect duration of 20-40 min. In the pithed SHR, a 0.5 mg/kg bolus injection of BIBP 3226 shifted the pressor response curve for exogenous NPY significantly to the right It also inhibited significantly the potentiating effects of NPY on pressor responses to phenylephrine and tyramine. In conscious SHR, 0.125-1 mg/kg BIBP 3226 did not reduce the basal blood pressure. In combination with a hypotensive dose of prazosin, administration of 0.5 mg/kg BIBP 3226 had no added effects lowering the basal blood pressure. A stressful stimulus, namely an air jet, caused a brief increase in blood pressure and heart rate in the conscious SHR. In this model, 0.5 mg/kg BIBP inhibited the heart rate response slightly but had no effect on the blood pressure response.. Our results demonstrate that, although the selective NPY Y1 receptor antagonist BIBP 3226 may shift the pressor response to exogenous NPY potently, it does not influence basal blood pressure significantly in the SHR.

Topics: Animals; Arginine; Blood Pressure; Electric Stimulation; Heart Rate; Hypertension; Male; Neuropeptide Y; Peripheral Nerves; Phenylephrine; Prazosin; Rats; Rats, Inbred SHR; Receptors, Neuropeptide Y; Stress, Physiological; Tyramine

The effects of a novel neuropeptide Y (NPY) Y1 receptor antagonist on resting mean blood pressure (MBP) and heart rate (HR) were observed in conscious spontaneously hypertensive rats (SHR). The interference of the antagonist with cardiovascular responses to mental stress and administration of exogenous NPY were also investigated. SHR were randomly received either the NPY Y1 receptor antagonist (BIBP 3226; n = 11) or its inactive enantiomer (BIBP 3435; n = 11) as an infusion (6 mg/kg/h for 1.5 hours). Before, during, and after the infusion, rats were first stressed with a jet of air and then given a bolus injection of exogenous NPY (2 nmol/kg). There was no statistically significant difference of resting MBP and HR between the antagonist and enantiomer groups before, during, or after infusion. The stress-induced maximum increase in HR was significantly reduced during antagonist infusion (P < 0.05). The effects of exogenous NPY on both MBP and HR were significantly attenuated by antagonist infusion (P < 0.05, respectively), and the effect lasted at least 1 hour after the end of the infusion. Plasma catecholamine levels in response to stress were not significantly different between the two groups. The results suggest that endogenous NPY Y1-receptor mechanisms may be of minor importance in short-term regulation of MBP and HR in conscious adult SHR, but may be involved in the response to mental stress.

Topics: Animals; Anti-Anxiety Agents; Arginine; Blood Pressure; Epinephrine; Heart Rate; Hypertension; Norepinephrine; Rats; Rats, Inbred SHR; Receptors, Neuropeptide Y; Stress, Psychological