Adenosine preconditions against endothelin-induced constriction of coronary arterioles

Myocardial hypoperfusion is accompanied by concomitant increases in adenosine and endothelin-1 (ET-1) production, but the vasodilatory effect of adenosine prevails over that of ET-1. Therefore, we hypothesized that adenosine-induced or ischemic preconditioning reduces the vasoconstrictive effect of ET-1. Coronary arteriolar diameter in vivo was measured using fluorescence microangiography in anesthetized open-thorax dogs. ET-1 (5 ng·kg^-1·min^-1 administered intracoronary, n = 10) induced progressive constriction over 45 min [25 ± 6% (SE)]. The constriction was blocked by preconditioning with adenosine (25 μg·kg^-1·min^-1 administered intracoronary) for 20 min and 10 min of washout (n = 10) or attenuated by ischemic preconditioning (four 5-min periods of ischemia, 9 ± 5% at 45 min). To investigate the receptor involved in this process, coronary arterioles (50-150 μm) were isolated and pressurized at 60 mmHg in vitro. The ET-1 dose-response curve (1 pM-5 nM) was rightward shifted after preconditioning with adenosine (1 μM) for 20 min and 10 min of washout (n = 11). Blockade of A₂ receptors [8-(3-chlorostyryl)caffeine, 1 μM, n = 9] but not A₁ receptors (8-cyclopentyl-1,3-dipropylxanthine, 100 nM, n = 7) prevented this shift. These results suggest that adenosine confers a vascular preconditioning effect, mediated via the A₂ receptor, against endothelin-induced constriction. This effect may offer a new protective function of adenosine in preventing excessive coronary constriction.