Goat cerebrovascular reactivity to ADP after ischemia-reperfusion. Role of nitric oxide, prostanoids and reactive oxygen species

To analyze the cerebrovascular effects of ischemia-reperfusion, cerebrovascular reactivity to ADP was studied after inducing 60-min occlusion followed by 60-min reperfusion of the left middle cerebral artery (MCA) in anesthetized goats. In 12 goats, at the end of reperfusion, left MCA resistance was decreased by 19%, and reactive hyperemia to 5- and 10-s occlusions as well as the cerebral vasodilatation to ADP (0.03-0.3 μg) but not to sodium nitroprusside (0.3-3 μg) was decreased. In 28 animals, killed at the end of reperfusion, segments 3-mm long were obtained from the left (ischemic) and right (control) MCA, prepared for isometric tension recording, and precontracted with the thromboxane A2 analogue U46619. The relaxation to ADP (10− 8 to 10− 5 M) but not to sodium nitroprusside (10− 8 to 10− 4 M) was lower in ischemic arteries. l-NAME (inhibitor of nitric oxide synthesis, 10− 4 M), charybdotoxin (10− 7 M) + apamin (10− 6 M) (blockers of KCa), or catalase (1000 U/ml) reduced the relaxation to ADP only in control arteries. Charybdotoxin + apamin further augmented the l-NAME-induced reduction in the relaxation to ADP in control arteries. The inhibitor of cyclooxygenase meclofenamate (10− 5 M) increased the relaxation to ADP only in ischemic arteries. The superoxide dismutase mimetic tiron (10− 2 M) increased the ADP-induced relaxation only in ischemic arteries. Therefore, it is suggested that ischemia-reperfusion produces cerebrovascular endothelial dysfunction, which may be associated with decreased nitric oxide bioavailability, decreased release of an EDHF, and increased production of vasoconstrictor prostanoids. All these alterations may be related in part with an increased production of superoxide anion.