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The aim of the present study was to elucidate if the potentiating effect of neuropeptide Y on various vasoactive agents in vitro is (1) altered in mesenteric arteries from rats with congestive heart failure and (2) mediated by the neuropeptide Y Y1 receptor. The direct vascular effects of neuropeptide Y and its modulating effects on the contractions induced by endothelin-1-, noradrenaline-, 5-hydroxytryptamine (5-HT)-, U46619-(9,11-dideoxy-11alpha, 9alpha-epoxymethano-prostaglandin F2alpha) and ATP, and acetylcholine-induced dilatations were studied in the presence and absence of the neuropeptide Y Y1 antagonist, BIBP3226 (BIBP3226¿(R)-N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl ]-D-arginine-amide¿). Neuropeptide Y, per se, had no vasoactive effect in the arteries. The potency of endothelin-1 was significantly decreased in congestive heart failure rats. Neuropeptide Y and neuropeptide Y-(13-36) potentiated the endothelin-1-induced contraction in congestive heart failure mesenteric arteries. In 20% of the congestive heart failure rats, sarafotoxin 6c induced a contraction of 31+/-4%. Neuropeptide Y also potentiated U46619- and noradrenaline-induced contractions but not 5-HT-induced contractions in congestive heart failure arteries. In sham-operated animals neuropeptide Y potentiated noradrenaline- and 5-HT-induced contractions. These potentiations were inhibited by BIBP3226. Acetylcholine induced an equipotent relaxation in both groups which was unaffected by neuropeptide Y. In conclusion, neuropeptide Y responses are altered in congestive heart failure rats. The potentiating effect differs between vasoactive substances. Neuropeptide Y Y1 and non-neuropeptide Y1 receptors are involved.

To elucidate which neuropeptide Y receptor subtype is responsible for the neuropeptide Y-induced potentiation of the noradrenaline-evoked contraction in human omental arteries we used antisense oligodeoxynucleotide (Antisense), the new selective neuropeptide Y Y1 receptor antagonist, BIBP3226 {(R)-N2-(diphenylacetyl)-N-[(4-hydroxyphenyl) methyl]-D-arginine-amide} and the reverse transcriptase-polymerase chain reaction (RT-PCR). Neuropeptide Y significantly potentiated the noradrenaline-induced contraction in non-incubated vessels (pEC50 6.4 +/- 0.2 vs. 5.9 +/- 0.2) and in vessels incubated with 1 microM Sense oligodeoxynucleotide (Sense) (pEC50 6.0 +/- 0.1 vs. 5.6 +/- 0.2). In vessels incubated with 1 microM Antisense the potentiating effect of neuropeptide Y was completely abolished. BIBP3226 (1 microM) inhibited the neuropeptide Y-induced potentiation in human omental arteries (pEC50 5.8 +/- 0.3 vs. 6.4 +/- 0.2). Finally, messenger RNA for the neuropeptide Y Y1 receptor was detected using RT-PCR. On the basis of our results we conclude that the neuropeptide Y-induced potentiation of the noradrenaline-induced contraction is mediated by the neuropeptide Y Y1 receptor.

Neuropeptide Y (NPY) has been shown to potentiate the effects of various vasoactive agents in both in vitro and in vivo experiments. The present study was designed to investigate the potentiation effects of NPY on various vasoconstrictive agents and the influence of NPY on the dilatation effects of endothelin-1 in rats with congestive heart failure (CHF). CHF was induced by left coronary artery ligation. Sham-operated rats subjected to thoracotomy served as normal controls. Experiments in conscious rats were performed 4-6 weeks after coronary artery ligation or sham operation. The pressor responses of intravenous phenylephrine (12.5 nmol/kg), endothelin-1 (400 pmol/kg) and angiotensin II (10 ng) but not tyramine (40 micrograms) were significantly decreased in CHF rats compared with sham-operated rats (p < 0.01). In sham-operated rats, subthreshold dose of NPY (0.1 microgram/kg/min) potentiated the pressor responses of all the agonists (p < 0.05). In CHF rats, significant enhancement of mean arterial pressure (MAP) by subthreshold dose of NPY was observed with angiotensin II (p < 0.05). The MAP was enhanced by 45.4% in CHF and 40.6% in sham-operated rats respectively. NPY did not enhance the pressor responses induced by phenylephrine, endothelin-1 or tyramine in CHF rats. The initial decrease of MAP after bolus injection of endothelin-1 was observed in both CHF and sham-operated control rats, and magnitude of this response was similar in both groups. Subthreshold dose of NPY significantly reduced the vasodilatation effect of endothelin-1 in CHF (p < 0.05) but not in normal control rats. We conclude that NPY potentiates pressor effects of angiotensin II and reduces vasodilatation effects of endothelin-1 in rats with CHF. These effects of NPY may contribute to the increased vascular tone in CHF.

Previous studies have demonstrated that alpha-trinositol (D-myo-inositol-1.2.6-trisphosphate; PP56) may act as a functional neuropeptide Y (NPY) inhibitor. Because NPY is known to be a potent vasoconstrictor, the effects of alpha-trinositol on renal function, vascular responses and the potentiating effects of NPY were investigated in rats with congestive heart failure (CHF) induced by ligation of the left coronary artery. Incremental doses of alpha-trinositol were given to conscious rats (bolus 2, 4 or 10 mg/kg i.v. followed by a 15-minute infusion 20, 40 and 100 mg/kg/h, respectively). Urinary volume, sodium and potassium excretions were significantly increased in both CHF and sham-operated control animals after alpha-trinositol administration compared with saline. Diuresis and natriuresis were observed also during co-administration of alpha-trinositol with NPY but not with norepinephrine (NE). In the pithed CHF rats, threshold doses of NPY potentiated the pressor effects of endothelin-1 (ET-1) and angiotensin II (AII), but not preganglionic nerve stimulation or phenylephrine administration. Alpha-trinositol antagonized both the pressor response to NPY and the potentiation by NPY of pressor responses to effects of ET-1 and AII. Our data show that alpha-trinositol exhibis diuretic and natriuretic effects as well as vascular antagonistic effects on NPY in normal and CHF rats. These effects of alpha-trinositol may be due to an interaction with NPY mediated antidiuresis and antinatriuresis.

Since the discovery of neuropeptide Y which is co-stored and co-operate with noradrenaline (NA) in sympathetic nerve fibers, several scientific groups have searched for structures with neuropeptide Y antagonistic properties. Research has mainly focused on various peptide fragments which originate from or are related to the neuropeptide Y sequence. Some non-peptide antagonists have been proposed but they are mostly of low potency and non-selective. Our recent observations that alpha-trinositol (D-myo-inositol 1.2.6-trisphosphate) is an inhibitor of neuropeptide Y effects will hopefully lead to the development of useful non-peptide neuropeptide Y inhibitors. As a novel approach the highly selective approach of down-regulating neuropeptide Y receptors with antisense oligodeoxynucleotides is also discussed. Neuropeptide Y antagonistic agents would help us to understand the physiological role of neuropeptide Y and may serve as useful medication in circulation disorders.

The adrenergic cotransmitter neuropeptide Y (NPY) induces vascular smooth muscle contraction by occupying postsynaptic Y1 receptors and by enhancing the vasoconstriction induced by a series of other pressor agents. In particular, NPY modulates the blood pressure response to alpha-1 adrenergic agonists and angiotensin II. The inositol phosphate derivative, d-myo-inositol-1,2,6-trisphosphate (PP56), is a novel NPY antagonist which within a defined dose range selectively blocks the effects of exogenously administered NPY in vivo. In the pithed animal as well as in the freely moving Sprague-Dawley rat, an i.v. bolus administration of PP56 (2 mg/kg) followed by an infusion (20 mg/kg/hr for 30 min) inhibited the approximate 50% increase in mean arterial blood pressure induced by a continuous infusion of NPY (2 micrograms/kg/min for 10 min). Furthermore, PP56 treatment completely inhibited the enhancement induced by NPY (0.1 microgram/min for 50 min or 2 micrograms/kg/min for 10 min) of the pressor responses to preganglionic sympathetic nerve stimulation (in the pithed rat) and to i.v. bolus injections of noradrenaline (20 ng), the indirect sympathomimetic tyramine (40 micrograms) as well as to angiotensin II (10 ng). These results show that PP56, representing a new class of synthetic nonpeptide drugs, is capable of antagonizing the vascular smooth muscle contractile as well as the potentiating effects of NPY in vivo in the pithed as well as the conscious rat.

The antagonistic effects of a new inositol phosphate derivative, D-myoinositol-1,2,6-trisphosphate (PP56), on pressor responses to preganglionic sympathetic nerve stimulation and exogenously administered phenylephrine or neuropeptide Y (NPY) were investigated in vivo in the pithed rat. In this model an intravenous (i.v.) bolus administration of PP56 (1-50 mg/kg) dose dependently inhibited the increase in mean arterial blood pressure (MAP) induced by a continuous infusion of NPY (2 micrograms/kg per min for 10 min). PP56 in a dose of 5 mg/kg i.v. bolus reduced the entire NPY dose-response curve (0.4-8 microgram/kg per min 10 min infusion) without any shift to the right indicating a non-competitive interaction. Furthermore, PP56 (10-50 mg/kg i.v.) was found to inhibit the pressor response to preganglionic sympathetic nerve stimulation and i.v. bolus injection of the alpha 1-adrenoceptor agonist, phenylephrine. The dose-response curves for increasing doses of phenylephrine and incremental preganglionic sympathetic nerve stimulation were not significantly altered by a lower dose of PP56 (5 mg/kg i.v. bolus). We conclude that PP56, representing a new class of synthetic drugs, can antagonize the actions of exogenous and endogenous NPY in vivo, an action which is specific for NPY within a limited dose range.