Endothelin-converting Enzyme Activity in Human Cerebral Circulation

Abstract

An increased level of endothelin (ET)-1 seems to be involved in the development of augmented cerebrovascular resistance in different pathological conditions, most notably vasospasm after subarachnoid hemorrhage. Therefore, interfering with the ET synthesis or ET receptor blockade may be a promising approach in the treatment of cerebral vasospasm after subarachnoid hemorrhage. Although the receptors mediating the effects of ET-1 human cerebrovasculature are well characterized, data concerning the functionally relevant ET-converting enzyme (ECE) activity are scarce. ECE activity was determined in organ bath studies by the use of intraoperatively harvested human pial arteries. The level of ECE activity was analyzed by comparing the shift in the concentration effect curves obtained for ET-1 and its precursor, big ET-1. In addition, the presence of ECE-1alpha immunoreactivity was studied in human cerebral tissue. ECE-1alpha immunoreactivity was found, although not consistently, in human cerebral arteries and was restricted to the endothelium. In isolated pial arterial segments, ET-1 and big ET-1 induced concentration-related contractions with mean pD(2) values of 9.25 +/- 0.34 and 7.13 +/- 0.17, respectively, yielding a 123-fold shift of big ET-1 versus mature ET-1. Preincubation with phosphoramidon (10(-4) mol/L) resulted in a small yet significant inhibition of the contraction induced by big ET-1. The results of our study indicate the presence of functional ECE activity and ECE-1alpha immunoreactivity in human cerebral arteries. Furthermore, the data suggest the presence of ECE-like activity that differs from that of ECE-1alpha.