Tachycardia caused by A2A adenosine receptor agonists is mediated by direct sympathoexcitation in awake rats.
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 microg/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 microg/kg) of regadenoson at which there was no appreciable decrease in MAP. Pretreatment with 30 microg/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 beta-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 microg/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.
Dhalla
Arvinder K
AK
Department of Pharmacology, CV Therapeutics, Palo Alto, CA 94304, USA. arvinder.dhalla@cvt.com
Wong
Mei-Yee
MY
Wang
Wei-Qun
WQ
Biaggioni
Italo
I
Belardinelli
Luiz
L
D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009638:Norepinephrine / Q000097:blood; D011687:Purines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology*; D013610:Tachycardia / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D013997:Time Factors; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D011687:Purines; D011720:Pyrazoles; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; C430916:regadenoson; D009638:Norepinephrine