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Chronic reserpine pretreatment has been shown to produce postjunctional beta-adrenergic supersensitivity in cardiac tissue. The present investigation was undertaken to determine whether chronic reserpine administration also alters the heart's sensitivity to muscarinic cholinoceptor agonists. The direct and indirect (antiadrenergic) negative inotropic effects of muscarinic agonists were examined in isolated rat left atria at various times after initiation of reserpine pretreatment (1.0 mg.kg-1 x day-1 for 7 days). Supersensitivity to the positive inotropic effects of isoproterenol was demonstrated at 1, 2, and 3 wk after initiation of treatment. Concentration-response curves were then obtained for the muscarinic agonist carbachol and the adenosine A1 receptor agonist (-)-N6-(2-phenylisopropyl)-adenosine (PIA) in reducing the inotropic response to isoproterenol (3.16 microM). The potency of carbachol was increased by approximately 2.0-fold at 1, 2, and 3 wk. Also, sensitivity to the direct negative inotropic effects of carbachol was increased 1.7-fold at 1 wk but not at 2 and 3 wk. At 1 wk, reserpine pretreatment did not alter either the direct or the indirect negative inotropic effects of PIA. These results show that postjunctional beta-adrenergic supersensitivity produced by chronic reserpine pretreatment is accompanied by a reciprocal increase in sensitivity of isolated rat left atria to the negative inotropic effects of muscarinic agonists.

T-cell lymphoma invasion and metastasis-inducing factor (Tiam)1 is an established proto-oncogene that drives cancer cell migration and metastasis. The correlation between Tiam1 integrity and patient survival, epithelial-mesenchymal transition, and angiogenesis, render it as an important prognostic factor in multiple human malignancies. Tiam1 is a guanine nucleotide exchange factor (GEF) that facilitates the activation of the small GTPase Rac1, thereby controlling cytoskeletal organization, cell polarity, motility, and invasion. In light of the clinical relevance of Tiam1 signaling, we investigated the utility of small molecule inhibitors that target Tiam1 as a therapeutic intervention strategy. We used an in silico computational approach to screen 10 million compounds for candidate drugs that bind to a select patch on Tiam1's surface. We then identified 13 compounds that inhibit the migration of Tiam1-expressing A549 cells without affecting overall viability. Our studies open the door for a new targeted therapy approach in Tiam1-relevant cancers. Citation Format: Claire Fritz, Michaela Stamper, Stephen Valentino, Lynn Ulatowski, Meghana Gupta, Varsha Thakur, Stacey Chung, Nick DeHann, Christian Laggner, Danny Manor. Potential small-molecule inhibitors of the Tiam1 oncogene product [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2271.

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