ANTIHYPERTENSIVE EFFECTS OF 2-OCTYNYLADENOSINE (YT-146), A SELECTIVE ADENOSINE A(2) RECEPTOR AGONIST, IN DAHL SALT-SENSITIVE RATS

The antihypertensive effects of a novel adenosine A(2) receptor agonis t, 2-octynyl adenosine (YT-146), were evaluated in Dahl salt-sensitive rats. After rats were fed a high-salt (8% NaCl) diet for 2 or 3 weeks , they received oral YT-146 (0.1 or 1.0 mg/kg) or vehicle as a single dose (acute study) or once daily for 10 days (chronic study). In the a cute study, tail-cuff blood pressure (BP) and pulse rate (PR) were mea sured before and 3, 6, and 24 h after administration, and blood sample s were collected 3 h after administration. In the chronic study, BP an d PR were measured 3 and 24 h after administration and urine was colle cted for 24 h on day 9. blood samples were also collected 3 h after ad ministration on day 10. BP was significantly lowered by 1.0 mg/kg of Y T-146 in either the acute study (from 184 +/- 3 to 152 +/- 5 mm Hg, P < .01) or the chronic study (from 226 +/- 4 to 201 +/- 2 mm Hg, P < .0 1), while an increase in PR was not observed (acute study: from 382 +/ - 8 to 366 +/- 3 beats/min; chronic study: from 420 +/- 8 to 411 +/- 8 beats/min). YT-146 had no effect on plasma renin activity (PRA), plas ma aldosterone, vasopressin (ADH), and atrial natriuretic peptide (ANP ) in the acute study. In the chronic study, neither PRA, plasma ADH co ncentration, urinary volume, urinary excretion of Na and K, nor creati nine clearance were affected, although plasma ANP concentration was si gnificantly lowered (176 +/- 35 v 73 +/- 20 pmol/ mL, P < .05) by 1.0 mg/kg of YT-146, compared with vehicle-treated rats. These data indica te that orally administered YT-146 shows antihypertensive effects with out reflex tachycardia and has no remarkable effect on renal function in an animal model of hypertension.