Pharmacological evaluation of 1229U91, a high affinity and selective neuropeptide Y (NPY) - Y1 receptor antagonist

Hegde, Satisha; Bonhaus, Doug; Stanley, William C.; Eglen, Richard M.; Moy, T. M.; Loeb, Marcia J.; Shetty, Sanjay; Desouza, Arun H. G.; Krstenansky, John L.

doi:10.1016/1043-6618(95)87019-9

Cited by 15 publications

(22 citation statements)

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“…The receptor subtype mediating renovascular NPY effects has been characterized by selective agonists and antagonists in vitro and in vivo. Based on studies with NPY, [Leu 31 ,Pro 34 ]NPY and NPY 13-36 the renal vasoconstricting effects of NPY in the isolated perfused rat kidney are mediated by a Y 1 -like receptor [31,53,83]. This has been confirmed in studies using by the Y 1 -selective antagonists BIBP 3226 [31] and GR 231118, formerly known as 1229U91 or GW 1229 [53].…”

Section: Regulation Of Renovascular Function By Npymentioning

confidence: 89%

“…Based on studies with NPY, [Leu 31 ,Pro 34 ]NPY and NPY 13-36 the renal vasoconstricting effects of NPY in the isolated perfused rat kidney are mediated by a Y 1 -like receptor [31,53,83]. This has been confirmed in studies using by the Y 1 -selective antagonists BIBP 3226 [31] and GR 231118, formerly known as 1229U91 or GW 1229 [53]. In vivo studies using subtype-selective agonists and the Y 1 -selective antagonists, BIBP 3226 and SR 120107A, also have demonstrated that NPY-induced renal blood flow reductions are mediated via a Y 1 receptor in rats [18,19] and pigs [60,67,77].…”

Section: Regulation Of Renovascular Function By Npymentioning

confidence: 99%

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Renal effects of neuropeptide Y

Bischoff¹,

Michel²

1998

Pfl�gers Archiv European Journal of Physiology

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Neuropeptide Y (NPY) is a co-transmitter of the sympathetic nervous system including the renal nerves. The kidney expresses NPY receptors, which can also be activated by peptide YY (PYY), a circulating hormone released from gastrointestinal cells. Five subtypes of NPY receptors have been cloned, among which Y1, Y2 and Y5 appear to be involved in the regulation of renal function. NPY produces potent renal vasoconstriction in vitro in isolated interlobar arteries and in the isolated perfused kidney and in vivo upon intrarenal or systemic administration via a Y1 receptor. Nevertheless glomerular filtration rate is altered only little if at all by NPY, indicating a greater effect on the vas efferens than the vas afferens. NPY can inhibit renin release via Y1-like receptors. NPY can stimulate Na+/K+ adenosine triphosphatase (Na+/K+-ATPase) in proximal tubules via Y2 receptors and can antagonize the effects of vasopressin on isolated collecting ducts. It can also act prejunctionally to inhibit noradrenaline release via Y2 receptors. Despite the profound reductions of renal blood flow, systemic NPY infusion can cause diuresis and natriuresis; this is largely independent of pressure natriuresis mechanisms and is possibly mediated by an extrarenal Y5 receptor. Studies with the converting enzyme inhibitor ramiprilat and the bradykinin receptor antagonist icatibant indicate that bradykinin mediates, at least partly, diuretic NPY effects. NPY antagonists enhance basal renal blood flow but do not alter basal diuresis or natriuresis indicating that renovascular, but not tubular, NPY receptors may be tonically activated by endogenous NPY.

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Section: Regulation Of Renovascular Function By Npymentioning

confidence: 89%

Section: Regulation Of Renovascular Function By Npymentioning

confidence: 99%

Renal effects of neuropeptide Y

Bischoff¹,

Michel²

1998

Pfl�gers Archiv European Journal of Physiology

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“…NPY activates post-junctional Y 1 receptors to directly contract vascular smooth muscle as well as potentiate the contractile effects of both norepinephrine and ATP in a variety of in vitro preparations including the rat mesenteric bed, rat portal vein, rat and rabbit cerebral vessels, rat, dog and guinea pig coronary vessels and also in vivo in the pithed rat (Westfall et al , 1987b, Westfall et al , 1988, Westfall et al , 1990b, Wahlestedt & Reis, 1993, Grundemar & Hakanson, 1994, Zukowska-Grojec, 1995, Westfall, 2004). The development and use of specific NPY antagonists (Abounader et al , 1995, Myers et al , 1995, Leban et al , 1995, Hegde et al , 1995, Kirby et al , 1995, Malmstrom et al , 2002, Westfall, 2004) has shown that NPY is an endogenous neurotransmitter at the sympathetic neurovascular junction. NPY plays a physiological role in the regulation of vascular tone in the guinea pig vena cava and the rat mesenteric bed, and in vivo in whole pigs and the pithed rat (Malmstrom & Lundberg, 1995, Lundberg & Modin, 1995, Kennedy et al , 1997, Han et al , 1998b), as well as a pathophysiological role during stress and hypertension in both rats and humans (Erlinge et al , 1992, Michel & Rascher, 1995, Zukowska-Grojec et al , 1996, Han et al , 1998a).…”

Section: Co-transmission At the Sympathetic Neurovascular Junctionmentioning

confidence: 99%

Neuronal and non-neuronal modulation of sympathetic neurovascular transmission

et al. 2011

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Norepinephrine, neuropeptide Y and adenosine triphosphate are co-stored in, and co-released from, sympathetic nerves. Each transmitter modulates its own release as well as the release of one another; thus, anything affecting the release of one of these transmitters has consequences for all. Neurotransmission at the sympathetic neurovascular junction is also modulated by non-sympathetic mediators such as angiotensin II, serotonin, histamine, endothelin and prostaglandins through activation of specific pre-junctional receptors. In addition, nitric oxide (NO) has been identified as a modulator of sympathetic neuronal activity, both as a physiological antagonist against the vasoconstrictor actions of the sympathetic neurotransmitters, and also by directly affecting transmitter release. Here we review the modulation of sympathetic neurovascular transmission by neuronal and non-neuronal mediators with an emphasis on the actions of NO. The consequences for co-transmission are also discussed, particularly in light of hypertensive states where NO availability is diminished.

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“…The Y 1 -preferring agonist Pro 34 PYY has efficacy at the Y 4 receptor but only at high concentrations (Cox et al, 2001b). In addition GR231118, a homodimeric peptide based on the C-terminal sequence of NPY [(Ile, Glu,Pro,Dpr,Tyr,Arg,Leu,Arg,Try-NH 2 )-2-cyclic(2,4Ј),(2Ј,4)-diamide, also known as 1229U91] was originally identified as a competitive Y 1 receptor antagonist with low Y 2 affinity (Daniels et al, 1995;Hegde et al, 1995), but this dimeric nonapeptide also has Y 4 affinity and efficacy (Matthews et al, 1997;Parker et al, 1998;Schober et al, 1998Schober et al, , 2000. The recent generation of Y 4 knockout ( Ϫ/Ϫ ) mice provides the only current alternative to explore the loss of specific function associated with obesity (Sainsbury et al, 2002), cardiac function (Smith-White et al, 2002), and water intake (Wultsch et al, 2006).…”

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confidence: 99%