Analysis of the effects of graded levels of hypoxia on noradrenaline-evoked contraction in the rat iliac artery in vitro

In rings of rat iliac artery, contractions were evoked by noradrenaline (NA), the selective alpha(1) adrenoceptor agonist phenylephrine (PE), and K(+), which causes depolarisation-induced contraction. There was no evidence of alpha(2) adrenoceptor-evoked contraction. Hypoxia, induced by reducing P(O(2)) in the bath from 100 mmHg to 70, 55 or 40 mmHg, had similar effects on rings with (E+) and without (E-) endothelium. In E- rings, the NA concentration-response curve was biphasic, whereas that for PE was monophasic. Hypoxia reduced maximum contractions in response to NA and PE (NA(max) and PE(max), respectively) without affecting the concentrations that evoked 50 % of maximum contraction (EC(50)). At P(O(2)) of 70 mmHg, NA(max) of the high affinity alpha(1) receptor for NA (NA(maxh)) and PE(max) were reduced by approximately 15 %, but at P(O(2)) of 55 and 40 mmHg, NA(maxh) was severely attenuated while PE(max) fell by 45 and 75 %, respectively. Similarly, the Ca(2+) channel blocker nicardipine depressed NA(maxh) and PE(max), but P(O(2)) of 55 mmHg further reduced NA(max) and PE(max). Hypoxia also reduced contractions evoked by NA, PE or K(+) at the concentrations required to produce 80 % of the maximum contraction (EC(80)), receptor-mediated contractions being more affected. Ca(2+)-free conditions reduced the contractions evoked by NA and PE, at the EC(80), to approximately 10 % of control. The K(+) channel inhibitors glibenclamide and tetraethylammonium did not prevent hypoxia-induced depression of PE-evoked contraction. Thus, contractions evoked in iliac artery by the high affinity subtype of alpha(1) adrenoceptor for NA, which may respond to circulating levels of NA, and by the single alpha(1) adrenoceptor subtype for PE, are especially vulnerable to P(O(2)) levels less-than-or-equal 55 mmHg. We propose that this reflects hypoxia-induced inhibition of Ca(2+) influx through L-type and receptor-operated Ca(2+) channels; K(+) channel opening makes little contribution.