AVE3085, an enhancer of endothelial nitric oxide synthase, restores endothelial function and reduces blood pressure in spontaneously hypertensive rats.

Abstract

BACKGROUND AND PURPOSE:

Nitric oxide (NO) plays an important role in endothelial function, and impaired NO production is involved in hypertension. Therefore, compounds that regulate endothelial NO synthase (eNOS) may be of therapeutic benefit. A novel, low molecular weight compound AVE3085 is a recently developed compound with the ability to enhance eNOS transcription. The present study investigated the effects of AVE3085 in endothelial dysfunction associated with hypertension.

EXPERIMENTAL APPROACH:

Spontaneously hypertensive rats (SHRs) were treated with AVE 3085 (10 mg·kg·day(-1) , orally) for 4 weeks. Isometric force measurement was performed on rings of isolated aortae in organ baths. Protein expression of eNOS, phosphorylated-eNOS and nitrotyrosine in the aortae were examined by Western blotting. mRNA for eNOS in rat aortae were examined by reverse-transcriptase polymerase chain reaction (RT-PCR).

KEY RESULTS:

AVE3085 greatly improved endothelium-dependent relaxations in the aortae of SHRs. This functional change was accompanied by up-regulated expression of eNOS protein and mRNA, enhanced eNOS phosphorylation and decreased formation of nitrotyrosine. Furthermore, AVE3085 treatment reduced the blood pressure in SHR without affecting that of hypertensive eNOS(-/-) mice.

CONCLUSIONS AND IMPLICATIONS:

The eNOS-transcription enhancer AVE3085 restored impaired endothelial function in a hypertensive model. The present study provides a solid basis for the potential development of eNOS-targeting drugs to restore down-regulated eNOS, as a new strategy in hypertension.

• Authors: Qin Yang, Hong-Mei Xue, Wing-Tak Wong, Xiao-Yu Tian, Yu Huang, Stephen K W Tsui, Patrick Ks Ng, Paulus Wohlfart, Huige Li, Ning Xia, Silke Tobias, Malcolm John Underwood, Guo-Wei He
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 163 Issue 5 Pg. 1078-85 (Jul 2011) ISSN: 1476-5381 [Electronic] England
• PMID: 21385179 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Chemical References

• 2,2-difluorobenzo(1,3)dioxole-5-carboxylic acid indan-2-ylamide
• Antihypertensive Agents
• Benzodioxoles
• Indans
• Nitric Oxide Synthase Type III
• Nos3 protein, rat

Topics

• Administration, Oral
• Animals
• Antihypertensive Agents (administration & dosage, pharmacology, therapeutic use)
• Aorta, Thoracic (cytology, drug effects, enzymology)
• Benzodioxoles (administration & dosage, pharmacology, therapeutic use)
• Blood Pressure (drug effects)
• Blotting, Western
• Dose-Response Relationship, Drug
• Endothelial Cells (drug effects, enzymology)
• Endothelium, Vascular (drug effects, physiology)
• Hypertension (drug therapy, enzymology, physiopathology)
• Indans (administration & dosage, pharmacology, therapeutic use)
• Male
• Nitric Oxide Synthase Type III (genetics, metabolism)
• Rats
• Rats, Inbred SHR
• Rats, Inbred WKY
• Reverse Transcriptase Polymerase Chain Reaction