Differences between the vasorelaxant activity of adenosine-receptor agonists on guinea-pig isolated aorta precontracted with noradrenaline or phenylephrine

The relaxant effect of adenosine and 5'-(N-ethylcarboxamido)adenosine (NECA ) against alpha-adrenoceptor-mediated contractile tone in guinea-pig isolat ed aortic rings has been examined to determine if this A(2B)-receptor-media ted relaxation was dependent upon the contracting agent, and whether the co ntractions were dependent upon intracellular or extracellular calcium. Relaxation responses were consistently greater for aortic rings pre-contrac ted with phenylephrine (3 x 10(-6) M) than for rings pre-contracted with no radrenaline (3 x 10(-6) M). Maximum inhibition by NECA was significantly gr eater for phenylephrine-contracted aortae than for noradrenaline-contracted (81.9 +/- 2.8% compared with 25.0 +/- 1.5%). These differences persisted i n the presence of beta- and alpha(2)-adrenoceptor blockade and could not, t herefore, be attributed to stimulation of these receptors by noradrenaline. The ratio of the contractions obtained before and in the presence of adeno sine or NECA was compared with the control ratio obtained before and after vehicle. Experiments were performed both in the presence of normal calcium levels and under calcium-free conditions. In normal-calcium medium, NECA in hibited phenylephrine-induced contractions (test ratio, 76.7 +/- 3.9%; cont rol ratio, 133.1 +/- 9.8%) to a greater extent than noradrenaline-induced c ontractions (108.4 +/- 4.1 and 123.4 +/- 4.9%); adenosine similarly inhibit ed phenylephrine-induced contractions more than those induced by noradrenal ine. Under calcium-free conditions, adenosine (36.7 +/- 11.9 and 110.7 +/- 26.6%) and NECA (55.2 +/- 9.1 and 87.1 +/- 14.9%) were only effective again st phenylephrine-induced contractions. This suggests that activation of the A(2B)-receptor by these agonists inhibited intracellular mobilization of c alcium for phenylephrine-induced contractions only. The effects on extracel lular calcium influx were examined for phenylephrine- and noradrenaline-ind uced contractions in normal-calcium medium but in the presence of ryanodine to prevent intracellular calcium mobilization. NECA inhibited phenylephrin e-induced contractions (77.3 +/- 12.4 and 111.4 +/- 9.3%), presumably by in terfering with influx of calcium through receptor-operated calcium channels . In contrast, NECA failed to reduce noradrenaline-induced contractions (12 1.5 +/- 10.7 and 122.4 +/- 11.6%), suggesting that the effect on noradrenal ine is predominantly via interaction with intracellular calcium. Adenosine was consistently a more effective relaxant than NECA, possibly because of a n additional intracellular component of the response. We conclude that adenosine receptor agonists inhibit phenylephrine-induced contractions of guinea-pig aorta more selectively than noradrenaline-induce d contractions. A(2B)-receptor stimulation might reveal a fundamental diffe rence between the modes of contraction elicited by these two alpha-adrenoce ptor agonists.