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Titolo:
Bolus intravenous injection of phosphorothioate oligonucleotides causes hypotension by acting as alpha(1)-adrenergic receptor antagonists
Autore:
Iversen, PL; Cornish, KG; Iversen, LJ; Mata, JE; Bylund, DB;
Indirizzi:
Univ Nebraska, Coll Med, Dept Pharmacol, Omaha, NE 68198 USA Univ Nebraska Omaha NE USA 68198 Med, Dept Pharmacol, Omaha, NE 68198 USA Univ Nebraska, Coll Med, Dept Physiol, Omaha, NE 68198 USA Univ Nebraska Omaha NE USA 68198 l Med, Dept Physiol, Omaha, NE 68198 USA
Titolo Testata:
TOXICOLOGY AND APPLIED PHARMACOLOGY
fascicolo: 3, volume: 160, anno: 1999,
pagine: 289 - 296
SICI:
0041-008X(19991101)160:3<289:BIIOPO>2.0.ZU;2-T
Fonte:
ISI
Lingua:
ENG
Soggetto:
IN-VIVO; ANTISENSE OLIGONUCLEOTIDES; CYNOMOLGUS MONKEYS; OLIGODEOXYNUCLEOTIDE PHOSPHOROTHIOATE; NONANTISENSE MECHANISM; NEOINTIMAL FORMATION; NUDE-MICE; CELL-LINE; C-MYB; INHIBITION;
Keywords:
phosphorothioate; oligodeoxynucleotide; hypotension; alpha(1)-adrenergic receptor;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
51
Recensione:
Indirizzi per estratti:
Indirizzo: Iversen, PL AVI BioPharma, 4575 SW Res Way,Suite 200, Corvallis, OR 97333 USA AVI BioPharma 4575 SW Res Way,Suite 200 Corvallis OR USA 97333
Citazione:
P.L. Iversen et al., "Bolus intravenous injection of phosphorothioate oligonucleotides causes hypotension by acting as alpha(1)-adrenergic receptor antagonists", TOX APPL PH, 160(3), 1999, pp. 289-296

Abstract

Bolus intravenous injections of phosphorothioate oligonucleotides (PS-ODN)into primates cause profound hypotension, which has been attributed to complement activation, the biochemical pathway leading to acute inflammatory response. Because the hypotension was not accompanied by peripheral or pulmonary edema and epinephrine was not effective, but administration of 200 mi Ringer's lactate was effective, we examined the possibility that the 15-base PS-ODN interferes with sympathetic tone. We administered doses ranging from 3.3 to 10 mg/kg of a 15-base PS-ODN as a 30-60 s iv bolus into the rightatrium of conscious Macaca mulatta. Blood pressure fell to 27 mm Hg following a 5.0 mg/kg dose, but no hypotension was observed after a 3.3 mg/kg dose; 10 mg/kg was lethal. Adrenergic receptor binding was evaluated in radioligand binding assays using rat cerebral cortex membranes with radiolabeled prazosin. The 15-base PS-ODN competes with prazosin for the alpha(1)-adrenergic receptor with an IC50 of 14 mu M, which favors binding over serum albumin (K-d = 37 to 48 mu M) Admiring serum albumin with 5.0 mg/kg 15-base PS-ODN prior to injection prevented hypotension, suggesting that unbound PS-ODN interferes with sympathetic tone before binding to plasma proteins. Interactions of the 15-base PS-ODN with the alpha(1)-adrenergic receptor in vivowere confirmed by a decreased response to phenylephrine. Reducing the length from 15 to 9 or 5 bases abolished alpha(1)-adrenergic receptor binding in vitro and bolus infusion of 5.0 mg/kg of 9-base PS-ODN no longer producedhypotension. In conclusion, the 15-base PS-ODN shows cooperative binding to the alpha(1)-adrenergic receptor, which produces cardiovascular effects that are oligomer length, dose, and formulation dependent, (C) 1999 AcademicPress.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/09/20 alle ore 15:22:47