Vasoconstriction to endothelin-1 in the goat middle cerebral artery after transient global cerebral ischemia

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 Ca²⁺ in endothelin-1-induced contractions and the ability of the Ca²⁺ entry blocker, nicardipine, to counteract them after ischemia were also assessed. Concentration-response curves to endothelin-1 (10⁻¹²–3×10⁻⁸ 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 pEC₅₀ (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_max) 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_max value was again significantly reduced (<i>P</i><.01). When arteries obtained from goats 7 days after 20 minutes of ischemia were incubated in Ca²⁺-free medium or nicardipine (10⁻¹⁰ and 10⁻⁸ mol/L), the concentration-response curve to endothelin-1 was significantly inhibited (<i>P</i><.01) both in terms of pEC₅₀ and of E_max. 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 Ca²⁺ channels in Ca²⁺ 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.