The hypertensive effect of an oral adenosine analog with selectivity for the A2 receptor in the spontaneously hypertensive rat Academic Article uri icon

abstract

  • Adenosine is a potent arterial vasodilator that, because of a short duration of action and acid lability, is ineffective in the oral treatment 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 A2 receptor, which is prevalent in the vascular smooth muscle 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 in 5% DMSO and administered by gavage. Blood pressure and heart rate were 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 when the dose of Y-341 was increased from 3 to 6 and 12 mg/kg. When Y-341 was administered at 3 mg/kg/day in a single dose for 5 consecutive days, there was no significant change in the magnitude of the hypotensive response over time. Y-341 administered by gavage to normotensive Sprague 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 reduction in blood pressure thereafter. To determine the effect of Y-341 on renal function in relation to the hypotensive effect, anesthetized SHR (n = 6) were administered the drug by gavage. There was no acute effect on urine flow rate, sodium excretion, inulin clearance, or PAH clearance, as determined after 60 to 90 min. It is concluded that in the spontaneously hypertensive rat 1) Y-341 is a potent oral antihypertensive agent, 2) its hypotensive effect is not associated with tachycardia, 3) there is no tachyphylaxis over 5 days, and 4) it exerts no acute detrimental effect on renal function. These findings suggest that Y-341 is a potentially useful agent in the oral treatment of hypertension and warrants further efficacy and safety studies in the rat and in other species.

publication date

  • January 1, 1995