Progress 01/01/12 to 12/31/12
Outputs
OUTPUTS: The overall goal of this project was to screen potential therapeutic agents for laminitis, a devastating and painful disease that affects soft tissues of the horse's feet. Almost 15% of the horses are affected. It has enormous emotional and economic implications for both horse owners and horse industry. The exact mechanism of action of the disease is still unknow. Insulin resistance is considered one of the causes of equine laminitis. Our specific aim was to assess the effectiveness of these agents to counteract the responses of insulin resistant digital blood vessel rings (artery and veins) and compare them with the control rings (non-resistant rings). We hypothesized that insulin resistance leads to enhancement of MAP kinase pathway of insulin action leading to the production of endothelin-1. The usual relaxation of the vessel rings to insuin will be turned into a contraction during insulin resistance. Therefore, the specific aim was to pharmacologically evaluate losartan (an angiotensin antagonist) and pentoxifylline (phosphodiesterase inhibitor and TNF alpha antagonist. We used in vitro studies to monitor insulin induced responses of arterial and venous rings that were made resistant and non-resistant and preincubated with losartan or pentoxifylline. PARTICIPANTS: Changaram S. Venugopal, Earnestine Holmes, Catherin Koch and Susan Eades. This study provided oppotrunity for applying for a grant to Grayson Jockey club Research Foundation. The grant was not funded. TARGET AUDIENCES: Veterinarians in general, particularly equine practitioners. Also interested parties are equine owners, trainers, and other people in the horse industry. Pharmaceutical industry will also be interested in this study. PROJECT MODIFICATIONS: The major change we did in this study is the reduction of number of potential agents. Initially, we decided to evaluate four potential agents. They were losartan, pentoxifylline,NADPH oxidase antagonist, and an endothelin blocker. In the preliminary studies we found that NADPH oxidase antagonist and endothelin antagonist did not produced a substantial difference. So our investigation was narrowed down to two agents, losartan and pentoxifylline.
Impacts
Losartan pre-treatment of insulin resistant vessels produced to contraction to insulin. This response was more or less similar to the response of insulin-resistant vessels rings. This suggested pretreatment of losartan did not prouced a significant effect. On the contrary, pentoxifylline caused relaxation. This suggested that pentoxifylline may be beneficial in the treatment of laminitis.
Publications
- Venugopal CS, Holmes EP, Koch C, Kearney M, Eades SC. Effect of pentoxifylline and losartan on insulin-resistant equine digital vessels. Submitted to Exptl. Biology., 2013
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Progress 01/01/11 to 12/31/11
Outputs
OUTPUTS: The goal of this project was to screen potential therapeutic agents for equine laminitis. Since insulin resistance is a common condition in laminitis, we experimentally induced insulin resistance to the digital vessel rings collected from clinically healthy horses in an in vitro set up. Four potential therapeutic agents were selected for the study. They are PD 098059 (a map kinase inhibitor and an endothelin blocker), losartan (an angiotensin II antagonist), apocyanin (an NADPH oxidase inhibitor) and pentoxifylline (a phophodiesterase inhibtior and TNFa inhbitor). A group of six rings was used for each drug. Thus, there were six gruops of tissues were in the study including the control group which was not treated with any of the test agents. Both arterial and venous vessel rings were used. Treatment g PARTICIPANTS: Nothing significant to report during this reporting period. TARGET AUDIENCES: Nothing significant to report during this reporting period. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
The study showed that insulin resistance can be induced in vessel rings with in 25 minutes of exposure of the vessel to insulin. This indicates insulin resistance occur in blood vessels after a short expossure unlike the belief that chronic expossure is needed. Of the four potential agents tested, only two (pentoxifylline and losartan) are giving some promises. The other two, apocyanin and PD098059, did not show any significant effect. PD 098059 is a these two agents block the pathway of insulin resistance and/or block the active agents in the pathway.
Publications
- No publications reported this period
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