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CARDIOVASCULAR

Tachycardia Caused by A_2A Adenosine Receptor Agonists Is Mediated by Direct Sympathoexcitation in Awake Rats

Department of Pharmacology, CV Therapeutics, Palo Alto, California (A.K.D., M.-Y.W., W.-Q.W., L.B.); and Department of Medicine, Vanderbilt University, Nashville, Tennessee (I.B.)

Adenosine-induced tachycardia is suggested to be mediated via A_2A receptors; however, the exact mechanism for this effect remains to be understood. The present study was carried out using regadenoson, a selective A_2A adenosine receptor agonist, to determine the role of the A_2A receptor subtype in adenosine-induced tachycardia. Regadenoson (0.3-50 µg/kg) given as a rapid i.v. bolus to awake rats caused a dose-dependent increase in heart rate (HR). Mean arterial pressure (MAP) increased at lower doses, whereas at higher doses, there was a decrease in MAP. The increase in HR was evident at the lowest dose (0.3 µg/kg) of regadenoson at which there was no appreciable decrease in MAP. Pretreatment with 30 µg/kg ZM 241385 [4-(2-[7-amino-2-(2-furyl)-[1,2,4]-triazolo-[2,3-a]-[1,3,5]-triazin-5-ylamino]ethyl)phenol], an A_2A receptor antagonist, attenuated the decrease in MAP and the increase in HR caused by regadenoson. Pretreatment with metoprolol (1 mg/kg), a -blocker, attenuated the increase in HR but had no effect on the hypotension caused by regadenoson. In the presence of hexamethonium (10 mg/kg), a ganglionic blocker, the tachycardia was completely prevented even though MAP was further reduced. Regadenoson treatment (10 µg/kg) significantly (p < 0.05) increased plasma norepinephrine levels almost 2-fold above baseline. The dissociation of HR and MAP effects by dose, time, and pharmacological interventions provides evidence that tachycardia caused by regadenoson is independent of the decrease in MAP and may not entirely be baroreflex-mediated, suggesting that regadenoson may cause a direct stimulation of the sympathetic nervous system via activation of A_2A adenosine receptors.

Address correspondence to: Dr. Arvinder K. Dhalla, CV Therapeutics, 1651 Page Mill Road, Palo Alto, CA 94304. E-mail: arvinder.dhalla{at}cvt.com

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