Effects of hypoxia on the pharmacological responsiveness of isolated coronary artery rings from the sheep.

1. The effects of low oxygen tension on tone and on the responsiveness to contractile and relaxant agents were examined on circumflex coronary artery rings isolated from sheep. 2. When artery rings (2-2.5 mm o.d.) were set at their optimal resting tension, introduction of hypoxia (0% O2) caused a sustained contraction which was reversible on washing with oxygenated Krebs solution. In precontracted (40 mM KCl) arteries, hypoxia caused a similar response except that it was preceded by a transient relaxation. 3. The hypoxia-induced contraction was potentiated by the combination of phentolamine (1 microM) and propranolol (1 microM), markedly reduced by verapamil (10 microM) and either abolished or reduced by indomethacin (1 microM). Indomethacin itself caused a contraction. 4. Under hypoxic conditions, the contractile effects of U46619 (a stable thromboxane analogue) and 5-hydroxytryptamine (5-HT) and the vasodilator effects of noradrenaline, iloprost (a prostacyclin mimetic) and adenosine were markedly potentiated. In contrast, vasoconstriction to potassium or acetylcholine was depressed. 5. Changing the gases from 95% O2 to 12% O2 had no significant effect on the contractile effects of U46619. However, the maximum contractile effect of U46619 was significantly enhanced by changing the gases from 12% O2 to 0% O2. 6. Rings from a smaller branch (0.6-1.3 mm o.d.) of the circumflex coronary artery of the sheep, in the presence of hypoxia, exhibited qualitatively similar changes in the responsiveness to U46619, 5-HT and adenosine to those observed in the large artery. However, the effect of potassium was potentiated rather than depressed. 7. It is concluded that hypoxia-induced contraction may involve a modified release of cyclooxygenase products and be partly dependent upon the availability of extracellular calcium. 8. The change in the responsiveness of coronary arteries, under hypoxia, to both constrictor and dilator mediators may have clinical relevance to myocardial ischaemia and angina pectoris.