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Vol. 285, Issue 1, 9-15, April 1998

Cardiovascular Pharmacology of the A2A Adenosine Receptor Antagonist, SCH 58261, in the Rat

Angela Monopoli, Carlo Casati, Gianluca Lozza, Angelo Forlani and Ennio Ongini

Schering-Plough Research Institute, San Raffaele Science Park, I-20132, Milan, Italy

We characterized the in vivo cardiovascular profile of SCH 58261, 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c] pyrimidine, a selective A2A adenosine receptor antagonist, in conscious, freely moving rats by use of the telemetry system. In normotensive rats, SCH 58261, at 10 mg/kg i.p., significantly (P < .05) inhibited hypotension and tachycardia induced by the A2A receptor agonist 2-hexynyl-5'-N-ethylcarboxamidoadenosine (0.01 mg/kg i.p.), but not the bradycardic effect caused by the A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (0.03 mg/kg i.p.). SCH 58261, when administered alone, at 0.1 and 1 mg/kg i.p., did not induce significant hemodynamic changes, but at 10 mg/kg i.p., it slightly increased both systolic blood pressure (SBP) and diastolic blood pressure (DBP) (+19 ± 3 and +16 ± 2 mm Hg, respectively; P < .01) and heart rate (HR) (+85 ± 5 beats/min; P < .01). These effects were inhibited by adrenergic blockade with propranolol (30 mg/kg i.p.) and phentolamine (10 mg/kg i.p.): -5 ± 3 mm Hg on DBP and -12 ± 11 beats/min on HR (P < .01). In spontaneously hypertensive rats, SCH 58261, at 3 and 10 mg/kg i.p., increased weakly both SBP (+19 ± 5 mm Hg and +25 ± 4 mm Hg) and DBP (+14 ± 4 mm Hg and +23 ± 4 mm Hg) vs. vehicle (P < .01) and HR (+45 ± 17 and +64 ± 18 beats/min vs. vehicle, respectively; P < .01). The data indicate that SCH 58261 retains A2A selective receptor antagonist properties in vivo. Its effect on cardiovascular sympathetic outflow further suggests that endogenous adenosine exerts a tonic vascular regulation through A2A receptors. Therefore, SCH 58261 can be a useful pharmacological tool for clarifying A2A-mediated cardiovascular actions of adenosine.

0022-3565/98/2851-0009$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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