Comparative profile of vasodilation by CVT-3146, a novel A2A receptor agonist, and adenosine in conscious dogs.
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 microg/kg) or adenosine (10-250 microg/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 microg/kg and 47 +/- 7.77 microg/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.
Zhao
Gong
G
CV Therapeutics, Inc., Palo Alto, CA 94304, USA. gong.zhao@cvt.com
Linke
Axel
A
Xu
Xiaobin
X
Ochoa
Manuel
M
Belloni
Francis
F
Belardinelli
Luiz
L
Hintze
Thomas H
TH
D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects*; D003331:Coronary Vessels; D004285:Dogs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D007668:Kidney / Q000098:blood supply / Q000187:drug effects; D008638:Mesenteric Arteries / Q000187:drug effects; D058906:Purinergic P1 Receptor Agonists; D011687:Purines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D058906:Purinergic P1 Receptor Agonists; D011687:Purines; D011720:Pyrazoles; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1; D014665:Vasodilator Agents; C430916:regadenoson; D000241:Adenosine