THE HYPOTENSIVE EFFECT OF AN ORAL ADENOSINE ANALOG WITH SELECTIVITY FOR THE A(2) RECEPTOR IN THE SPONTANEOUSLY HYPERTENSIVE RAT

Adenosine is a potent arterial vasodilator that, because of a short du ration of action and acid lability, is ineffective in the oral treatme nt of hypertension. Y-341 is a synthetic adenosine analog that is acid stable and has a prolonged duration of action. It is highly selective for the A(2) receptor, which is prevalent in the vascular smooth musc le and mediates vasodilation. To determine the efficacy of Y-341 as an antihypertensive agent, the effect of Y-341 on arterial pressure was studied in spontaneously hypertensive rats (SHR) in the awake state, 3 to 4 days after arterial cannulation. Y-341 (3 mg/kg) was dissolved i n 5% DMSO and administered by gavage. Blood pressure and heart rate we re monitored continuously at predetermined intervals. Fifteen minutes after administration, Y-341 reduced MAP from 180 +/- 4 to 126 +/- 2 mm Hg (n = 9, P < .001). There was no significant change in heart rate. The hypotensive effect was sustained over 8 h. Vehicle (n = 5) had no effect on blood pressure. The hypotensive effect was dose dependent wh en the dose of Y-341 was increased from 3 to 6 and 12 mg/kg. When Y-34 1 was administered at 3 mg/kg/day in a single dose for 5 consecutive d ays, there was no significant change in the magnitude of the hypotensi ve response over time. Y-341 administered by gavage to normotensive Sp rague Dawley rats decreased MAP from 133 +/- 5 mm Hg to a nadir of 117 +/- 4 mm Hg (n = 5, P < .01) after 45 to 60 min, with no further redu ction in blood pressure thereafter. To determine the effect of Y-341 o n renal function in relation to the hypotensive effect, anesthetized S HR (n = 6) were administered the drug by gavage. There was no acute ef fect on urine flow rate, sodium excretion, inulin clearance, or PAH cl earance, as determined after 60 to 90 min. It is concluded that in the spontaneously hypertensive rat 1) Y-341 is a potent oral antihyperten sive agent, 2) its hypotensive effect is not associated with tachycard ia, 3) there is no tachyphylaxis over 5 days, and 4) it exerts no acut e detrimental effect on renal function. These findings suggest that Y- 341 is a potentially useful agent in the oral treatment of hypertensio n and warrants further efficacy and safety studies in the rat and in o ther species.