Abstract
We have examined the effects of global ischemia and subsequent reperfusion on the reactivity of goat middle cerebral artery to endothelin-1. The participation of extracellular Ca<sup>2+</sup> in endothelin-1-induced contractions and the ability of the Ca<sup>2+</sup> entry blocker, nicardipine, to counteract them after ischemia were also assessed. Concentration-response curves to endothelin-1 (10<sup>−12</sup>–3×10<sup>−8</sup> mol/L) obtained in arteries from goats subjected to either 5 or 10 minutes of ischemia and 7-day reperfusion did not significantly differ from curves obtained in arteries from sham-operated goats. Concentration-response curves to endothelin-1 in arteries from goats subjected to 20 minutes of ischemia and 7-day reperfusion, however, showed significantly higher pEC<sub>50</sub> (negative logarithm to base 10 of the concentration of endothelin-1 producing 50 of the maximal effects) value (<i>P</i><.01) than in arteries from sham-operated goats. The effect of 20 minutes of ischemia was assessed at various reperfusion times. The maximal effects (E<sub>max</sub>) values of the concentration-response curves to endothelin-1 were significantly reduced (<i>P</i><.01) 1 and 3 days after ischemia when compared with sham-operated animals. The concentration-response curve to endothelin-1 was displaced to the left 7 days after the ischemia. Two weeks after the ischemia, the E<sub>max</sub> value was again significantly reduced (<i>P</i><.01). When arteries obtained from goats 7 days after 20 minutes of ischemia were incubated in Ca<sup>2+</sup>-free medium or nicardipine (10<sup>−10</sup> and 10<sup>−8</sup> mol/L), the concentration-response curve to endothelin-1 was significantly inhibited (<i>P</i><.01) both in terms of pEC<sub>50</sub> and of E<sub>max</sub>. In conclusion, there was an increase in the endothelin-1 potency 1 week after 20 minutes of ischemia. At this time, the involvement of dihydropyridine-sensitive L-type Ca<sup>2+</sup> channels in Ca<sup>2+</sup> entry induced by endothelin-1 to develop contraction is reduced when compared with normal arteries. We suggest that the increased reactivity to endothelin-1 could have pathophysiological relevance, and the reduced effect of nicardipine could have therapeutical relevance in cerebral ischemia.
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