Adenosine preconditions against endothelin-induced constriction of coronary arterioles

Myocardial hypoperfusion is accompanied by concomitant increases in adenosi ne and endothelin-1 (ET-1) production, but the vasodilatory effect of adeno sine 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 w ith adenosine (25 mug.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 rec eptor involved in this process, coronary arterioles (50-150 mum) were isola ted 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 muM) f or 20 min and 10 min of washout (n = 11). Blockade of A(2) receptors [8-(3- chlorostyryl) caffeine, 1 muM, n = 9] but not A(1) receptors (8-cyclopentyl -1,3-dipropylxanthine, 100 nM, n = 7) prevented this shift. These results s uggest that adenosine confers a vascular preconditioning effect, mediated v ia the A(2) receptor, against endothelin-induced constriction. This effect may offer a new protective function of adenosine in preventing excessive co ronary constriction.