A method for determining whether hypotension caused by novel compounds in preclinical development results from histamine release

Blom, Jason D.; Yang, Po-Chang; Nicholson, Nancy S.; Case, Brenda L.; Parlow, John J.; South, Michael S.; Wegner, Craig D.

doi:10.1016/j.vascn.2003.08.002

Cited by 3 publications

(4 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In agreement with the previous studies [2,4], compound 48/80-induced mast cell degranulation resulted in a sudden drop of MAP immediately after intravenous administration (Fig. 1).…”

Section: Resultssupporting

confidence: 93%

“…Supplement 1 (2006) drop of MAP was not observed. This result was unexpected, since it has previously been reported that cromolyn pretreatment resulted in a complete inhibition of compound 48/80-induced drop of MAP [2]. This discrepancy could be explained by the different doses of compound 48/80 and cromolyn used.…”

Section: Resultsmentioning

confidence: 74%

“…Drug-induced degranulation of mast cells is an undesired effect and therefore should be avoided. One of the consequences of drug-induced mast cell degranulation is a drop of the mean arterial blood pressure (MAP) [2]. Prevention of the drop of MAP with specifi c agents, targeting either the action of released mediators from mast cells or the extent of mast cell degranulation, is a reasonable approach to clarify the mechanism of this undesired effect.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of mast cell degranulation-induced drop of blood pressure with clemastine, cromolyn and compound 48/80 pretreatment

et al. 2006

View full text Add to dashboard Cite

“…In agreement with the previous studies [2,4], compound 48/80-induced mast cell degranulation resulted in a sudden drop of MAP immediately after intravenous administration (Fig. 1).…”

Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of mast cell degranulation-induced drop of blood pressure with clemastine, cromolyn and compound 48/80 pretreatment

et al. 2006

View full text Add to dashboard Cite

“…to prevent dextran‐evoked mast cell activation (Berstad, ; Blom et al . ). The retina was imaged through the cornea and lens with an Olympus FluoView 1000 confocal scanning laser microscope equipped with a UPlanSApo 4× dry objective, 0.16 NA (Fig.…”

Section: Methodsmentioning

confidence: 97%

Purinergic control of vascular tone in the retina

Kur

Newman

2014

The Journal of Physiology

View full text Add to dashboard Cite

Key pointsr The blood supply to the CNS is controlled by the tone of arteries and arterioles. However, little is known about purinergic regulation of vascular tone in the CNS.r We have investigated purinergic control of vascular tone in the in vivo rat retina. r Reducing endogenous ATP levels by enzyme degradation and inhibiting purinergic signalling with P2X receptor antagonists decreases the tone of retinal arterioles. Raising ATP levels increases vessel tone.r Experiments using fluorocitrate to poison the metabolism of glial cells suggest glia are a source of the ATP that tonically constricts retinal vessels.r The results suggest a novel mechanism of local control of vascular tone through activation of vascular smooth muscle cell P2X receptors.Abstract Purinergic control of vascular tone in the CNS has been largely unexplored. This study examines the contribution of endogenous extracellular ATP, acting on vascular smooth muscle cells, in controlling vascular tone in the in vivo rat retina. Retinal vessels were labelled by I.V. injection of a fluorescent dye and imaged with scanning laser confocal microscopy. The diameters of primary arterioles were monitored under control conditions and following intravitreal injection of pharmacological agents. Apyrase (500 units ml −1 ), an ATP hydrolysing enzyme, dilated retinal arterioles by 40.4 ± 2.8%, while AOPCP (12.5 mM), an ecto-5 -nucleotidase inhibitor that increases extracellular ATP levels, constricted arterioles by 58.0 ± 3.8% (P < 0.001 for both), demonstrating the importance of ATP in the control of basal vascular tone. Suramin (500 μM), a broad-spectrum P2 receptor antagonist, dilated retinal arterioles by 50.9 ± 3.7% (P < 0.001). IsoPPADS (300 μM) and TNP-ATP (50 μM), more selective P2X antagonists, dilated arterioles by 41.0 ± 5.3% and 55.2 ± 6.1% respectively (P < 0.001 for both). NF023 (50 μM), a potent antagonist of P2X1 receptors, dilated retinal arterioles by 32.1 ± 2.6% (P < 0.001). A438079 (500 μM) and AZ10606120 (50 μM), P2X7 antagonists, had no effect on basal vascular tone (P = 0.99 and P = 1.00 respectively). In the ex vivo retina, the P2X1 receptor agonist α,β-methylene ATP (300 nM) evoked sustained vasoconstrictions of 18.7 ± 3.2% (P < 0.05). In vivo vitreal injection of the gliotoxin fluorocitrate (150 μM) dilated retinal vessels by 52.3 ± 1.1% (P < 0.001) and inhibited the vasodilatory response to NF023 (50 μM, 7.9 ± 2.0%; P < 0.01). These findings suggest that vascular tone in rat retinal arterioles is maintained by tonic release of ATP from the retina. ATP acts on P2X1 receptors, although contributions from other P2X and P2Y receptors cannot be ruled out. Retinal glial cells are a possible source of the vasoconstricting ATP.

show abstract

Proinflammatory and vasodilator effects of nociceptin/orphanin FQ in the rat mesenteric microcirculation are mediated by histamine

Brookes¹,

Stedman²,

Guerrini³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

]N/OFQ-NH2 (UFP-101; 60 and 150 nmol/kg iv), H1 and H2 antagonists pyrilamine (mepyramine, 1 mg/kg iv) and ranitidine (1 mg/kg iv), and mast cell stabilizer cromolyn (1 mg⅐kg Ϫ1 ⅐min Ϫ1) also abolished vasodilation and macromolecular leak to N/OFQ in vivo (P Ͻ 0.05), but did not affect hypotension. Isolated mesenteric arteries (ϳ200 m, n ϭ 25) preconstricted with U-46619 were also mounted on a pressure myograph (60 mmHg), and both intraluminally and extraluminally administered N/OFQ (10 Ϫ5 M) caused dilation, inhibited by pyrilamine in the extraluminal but not the intraluminal (control: Ϫ6.9 Ϯ 3.8%; N/OFQ: 32.6 Ϯ 8.4%; pyrilamine: 31.5 Ϯ 6.8%, n ϭ 18, P Ͻ 0.05) experiments. We conclude that, in vivo, mesenteric microvascular dilation and macromolecular leak occur via N/OFQ-NOP-mediated release of histamine from mast cells. Therefore, N/OFQ-NOP has an important role in microvascular inflammation, and this may be targeted during disease, particularly as we have proven that UFP-101 is an effective antagonist of microvascular responses in vivo.nociceptin/orphanin FQ; UFP-101; microcirculation; arteriole; nociceptin/orphanin FQ peptide receptor; ORL-1; permeability; vasodilatation; leukocyte NOCICEPTIN/ORPHANIN FQ (N/OFQ) is the endogenous ligand for the N/OFQ peptide receptor (NOP), and NOP ligands can act centrally and peripherally to modulate several biological functions, including blood pressure, heart rate, and inflammation (18,20,23,26,28,37). N/OFQ displays ϳ60% homology with the classical opioid peptides (excluding endomorphins) but lacks the NH 2

show abstract

A method for determining whether hypotension caused by novel compounds in preclinical development results from histamine release

Cited by 3 publications

References 5 publications

Inhibition of mast cell degranulation-induced drop of blood pressure with clemastine, cromolyn and compound 48/80 pretreatment

Inhibition of mast cell degranulation-induced drop of blood pressure with clemastine, cromolyn and compound 48/80 pretreatment

Purinergic control of vascular tone in the retina

Proinflammatory and vasodilator effects of nociceptin/orphanin FQ in the rat mesenteric microcirculation are mediated by histamine

Contact Info

Product

Resources

About