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The Vasodilatory and Cardioprotective Properties of A2A Adenosine Receptor Agonists

Glover, David Kinsey
Thesis/Dissertation; Online
Glover, David Kinsey
Linden, Joel
French, Brent
Somlyo, Avril
Beller, George Beller
Ley, Klaus
Adenosine exerts its biological effects through stimulation of 4 receptor subtypes – A 1 , A 2A , A 2B , and A 3 . Stimulation of A 2A receptors on vascular endothelium and smooth muscle cells causes vasodilatation. A 2A receptors are also present on all bone marrow-derived white cells, platelets, and T-cells and stimulation inhibits inflammation and protects tissue from inflammation-related injury. The vasodilatory and cardioprotective properties of 2 new highly potent and selective adenosine A 2A receptor agonists, ATL-193 & ATL-146e were investigated in clinically relevant animal models to assess their potential usefulness as vasodilators for pharmacologic stress perfusion imaging, and their ability to reduce post-ischemic inflammation, preserve LV contractile function, and reduce myocardial infarct size following coronary occlusion and reperfusion. ATL-193 & ATL-146e provoked maximal coronary vasodilation without causing hypotension at doses 500x lower than adenosine. An ATL-146e bolus caused a sustained coronary flow increase lasting long enough to permit myocardial perfusion imaging of a coronary stenosis. Moreover, while investigating possible drug interactions with commonly prescribed cardiac drugs, it was discovered that the calcium channel blocker verapamil markedly blunted the coronary flow increase to adenosine and ATL-146e through inhibition of K ATP channels. When low, nonvasodilatory doses of ATL-146e were tested in different models of myocardial ischemia-reperfusion injury produced by coronary occlusion and reperfusion, ATL-146e markedly reduced post-ischemic contractile dysfunction ("stunning") and significantly reduced post-ischemic inflammation and infarct size. II These potent anti-inflammatory and infarct size reducing effects were further enhanced in the presence of a phosphodiesterase type IV inhibitor, rolipram. Finally, a new radiolabeled leukotriene B 4 receptor antagonist, 99m Tc-RP517, was validated for use as a noninvasive tool for imaging neutrophil infiltration and was employed as a general marker for assessing the degree of inflammation and its response to treatment. In summary, the experimental studies described herein demonstrate that the highly selective adenosine A 2A receptor agonist compounds ATL-193 and ATL-146e may have tremendous clinical potential with both diagnostic and therapeutic applications. Further studies in humans are clearly warranted to assess their usefulness as pharmacologic stressors for myocardial perfusion imaging and as potent anti-inflammatory agents for protecting the heart from reperfusion injury following coronary revascularization. Note: Abstract extracted from PDF text
University of Virginia, Department of Molecular Physiology & Cell Biophysics, PHD (Doctor of Philosophy), 2004
Published Date
PHD (Doctor of Philosophy)
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