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CARDIOVASCULAR

Comparative Profile of Vasodilation by CVT-3146, a Novel A_2A Receptor Agonist, and Adenosine in Conscious Dogs

CV Therapeutics, Inc., Palo Alto, California (G.Z., L.B.); and Department of Physiology, New York Medical College, Valhalla, New York (A.L., X.X., M.O., F.B., T.H.H.)

The purpose of this study was to determine the magnitude of vasodilation by CVT-3146 in different vascular beds and to compare it with that by adenosine in conscious dogs. Intravenous bolus injections of CVT-3146 (0.1–2.5 µg/kg) or adenosine (10–250 µg/kg) caused a dose-dependent increase in the coronary blood flow (CBF) and a dose-dependent decrease in the late diastolic coronary resistance. Although the maximal increase in CBF response to the two drugs was not significantly different, the ED₅₀ of CVT-3146 and adenosine were 0.45 ± 0.07 µg/kg and 47 ± 7.77 µg/kg, respectively. The highest dose of CVT-3146 caused a much longer coronary vasodilation than the highest dose of adenosine. There were no significant differences in increases in cardiac output induced by higher doses of CVT-3146 or adenosine. Most importantly, CVT-3146 resulted in a smaller decrease in total peripheral resistance (TPR) compared to that seen with adenosine. In addition, CVT-3146 yielded a smaller increase in the lower body flow (LBF) than adenosine. Adenosine also caused dose-dependent renal vasoconstriction, whereas CVT-3146 did not affect the renal blood flow. The administration of CVT-3146 or adenosine caused a dose-dependent vasodilation in the mesentery, which was not significantly different from each other. In summary, CVT-3146 is a 100-fold more potent coronary vasodilator than adenosine. CVT-3146 causes smaller decreases in TPR and smaller increases in LBF than those induced by adenosine, indicating that it is more selective for coronary than peripheral vasodilation. Furthermore, CVT-3146 did not cause renal vasoconstriction. These features make CVT-3146 a better candidate for pharmacologic stress testing.

Address correspondence to: Dr. Gong Zhao, CV Therapeutics, Inc., 3172 Porter Drive, Palo Alto, CA 94304. E-mail: gong.zhao{at}cvt.com