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

Abstract

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 g/kg) or adenosine (10 -250 g/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 ED 50 of CVT-3146 and adenosine were 0.45 Ϯ 0.07 g/kg and 47 Ϯ 7.77 g/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.Exercise is a common method of physiologic stress testing and is widely used in the diagnosis of coronary artery disease with radionuclide agents. However, for those who are unable to exercise adequately, an alternative procedure is needed. Pharmacologic stress testing with radionuclide agents is an option, which has been used for more than 20 years in the diagnosis of coronary artery disease. Two kinds of agents, coronary vasodilators (adenosine and dipyridamole) and ␤-adrenergic receptor agonists (dobutamine), are used in pharmacologic stress testing. These agents exert their actions through different mechanisms. Dobutamine increases contractility and heart rate by stimulating ␤-adrenergic receptors in the heart, thereby resulting in a significant increase in CBF. Adenosine increases CBF via direct vasodilation, and dipyridamole increases the circulating concentration of adenosine by blocking its reuptake and metabolism (Mahmarian and

Selective adenosine agonists and myocardial perfusion imaging

“…18 In another study of conscious dogs, IV regadenoson (0.1-2.5 lg/kg) or adenosine (10-250 lg/kg) caused similar dose-dependent increases in CBF and dose-dependent decreases in the late diastolic coronary resistance. 19 Regadenoson at 2.5 lg/kg caused a similar increase in maximal CBF compared to 250 lg/kg of adenosine though the increase in CBF was significantly of longer duration with regadenoson ( Figure 4). 19 Adenosine (ED50 = 47 ± 7.77 lg/kg) was 100 times less potent than regadenoson (ED50 = 0.45 ± 0.07 lg/kg).…”

“…19 Regadenoson at 2.5 lg/kg caused a similar increase in maximal CBF compared to 250 lg/kg of adenosine though the increase in CBF was significantly of longer duration with regadenoson ( Figure 4). 19 Adenosine (ED50 = 47 ± 7.77 lg/kg) was 100 times less potent than regadenoson (ED50 = 0.45 ± 0.07 lg/kg). 19 Regadenoson (2.5 lg/kg IV bolus) and adenosine (4.5-minute infusion at 280 lg/kg) were studied in anesthetized dogs.…”

The Diameter of Retinal Arterioles Is Unaffected by Intravascular Administration of the Adenosine A_2A Receptor Agonist Regadenoson in Normal Persons

“…The observed lack of effect of the adenosine analogue regadenoson on the diameter of retinal arterioles may potentially be due to a too low concentration of the compound for a vasoactive effect to have been elicited. Although the employed concentration of regadenoson can affect coronary function [8, 19], the sensitivity of retinal arterioles to the compound may be lower than that of arterioles in the systemic circulation [20]. Previous studies have shown that adenosine has affinity to a number of adenosine receptor types [21] and that the dilating effect of the compound requires functional Na-K pumps and K ATP channels [22].…”

Advances in pharmacologic agents in imaging: New A2A receptor agonists

“…In a study of conscious dogs, Zhao et al [10] measured the magnitude of vasodilation by regadenoson and adenosine in different vascular beds. The maximal increase in CBF response to the two drugs was similar, but the potency of regadenoson and adenosine was markedly different.…”