Potency and in vitro tolerance of organic nitrates: partially denitrated metabolites contribute to the tolerance-devoid activity of pentaerythrityl tetranitrate.

Potency and in vitro tolerance of organic nitrates: partially denitrated metabolites contribute to the tolerance-devoid activity of pentaerythrityl tetranitrate. Research Abstract Details 

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Potency and in vitro tolerance of organic nitrates: partially denitrated metabolites contribute to the tolerance-devoid activity of pentaerythrityl tetranitrate. Abstract Text:

Andreas Koenig,Kathrin Lange,Joerg Konter,Andreas Daiber,Dirk Stalleicken,Erika Glusa,Jochen Lehmann,

Neither therapeutic dosage of nitrovasodilators nor the development of tolerance correlates with nitrate groups in these molecules. Clinically, low dosages of glyceryl trinitrate (GTN) develop tolerance, but 100-fold higher dosages of pentaerythrityl tetranitrate (PETN) do not. Vasorelaxation was studied on prostaglandian F2alpha (PGF2alpha)-precontracted porcine pulmonary arteries in organ bath procedure. In vitro tolerance was induced by incubating the arteries with different nitrate concentrations and thereafter concentration-response curves were repeated. Furthermore, 14 mg/kg PETN were daily administered to rats by gavage; PETN and metabolites were measured in feces and blood. In vitro, the vasodilator potencies increased from mononitrates to tetranitrates (pD2: 4.14 to 8.18); PETN was the most potent vasodilator. In vitro tolerance was found with PETN and trinitrates but not with dinitrates and mononitrates. Thus, in vitro tolerance correlated with the in vitro potency of nitrates but not with the vasodilator potency of NO donors in general, because S-nitroso-N-aectyl-D-penicillamine and N-phenylpiperazin-NONOate were more potent than GTN but did not induce tolerance. After feeding of rats with PETN, pentaerythrityl dinitrate (PEdiN) and mononitrate (PEmonoN) but neither PETN nor PEtriN (both detected in feces) were found in the blood. The missing systemic bioavailability of PETN and PEtriN may explain the discrepancy between in vitro and in vivo findings. We conclude that the partially denitrated metabolites PEdiN and PEmonoN contribute to the moderate and tolerance-devoid clinical activity of PETN.

Potency and in vitro tolerance of organic nitrates: partially denitrated metabolites contribute to the tolerance-devoid activity of pentaerythrityl tetranitrate. Publishing Authors By Initials

A Koenig,K Lange,J Konter,A Daiber,D Stalleicken,E Glusa,J Lehmann,

For similar chemical actions and uses: pharmacologic actions: therapeutic uses: cardiovascular agents: vasodilator agents research abstracts see: chemical actions and uses: pharmacologic actions: therapeutic uses: cardiovascular agents: vasodilator agents research

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Potency and in vitro tolerance of organic nitrates: partially denitrated metabolites contribute to the tolerance-devoid activity of pentaerythrityl tetranitrate. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Journal of cardiovascular pharmacology

VOLUME: 50

Page Numbers: 68-74

Journal Abbreviation: J. Cardiovasc. Pharmacol.

ISSN: 0160-2446

DAY: 3

MONTH: Jul

YEAR: 2007

Potency and in vitro tolerance of organic nitrates: partially denitrated metabolites contribute to the tolerance-devoid activity of pentaerythrityl tetranitrate. Information

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LANGUAGE: eng

NlmUniqueID: 7902492

Potency and in vitro tolerance of organic nitrates: partially denitrated metabolites contribute to the tolerance-devoid activity of pentaerythrityl tetranitrate. Keywords Mesh Terms:

KEYWORDS: Vasodilator Agents

MESH TERMS: pharmacology

Chemical & Substance for Abstract: Potency and in vitro tolerance of organic nitrates: partially denitrated metabolites contribute to the tolerance-devoid activity of pentaerythrityl tetranitrate. Information

Substance Name: Pentaerythritol Tetranitrate

Registry Number: 78-11-5

Grant and Affiliation Information for Potency and in vitro tolerance of organic nitrates: partially denitrated metabolites contribute to the tolerance-devoid activity of pentaerythrityl tetranitrate.

AFFILIATION: Institut für Pharmazie, Friedrich-Schiller-Universität Jena, Jena, Germany.

Country: United States

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MEDLINETA: J Cardiovasc Pharmacol

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