Binding of endothelin-1 (ET-1) to ETA-receptors promotes hypertension and can be terminated selectively by calcitonin gene-related peptide (CGRP). Endothelin converting enzyme (ECE) and neutral endopeptidase (NEP) are involved in ET-1 synthesis and in ET-1-and CGRP-degradation. Hypotheses: (1) ET-1 and CGRP contribute to the development of hypertension and (2) chronic ECE/NEP inhibition during this period lowers ET-1 levels and blood pressure (BP). The content of ET-1 and CGRP was determined by radioimmuno assay in the heart and kidney of male Spontaneously Hypertensive Rats (SHR) of 6, 8 and 12 weeks of age and age-matched Wistar Kyoto (WKY) rats. Also 4 week old male SHR and WKY rats were treated for 4 weeks with the novel ECE/NEP inhibitor SOL-1. At 8 weeks BP was determined intra-arterially. ET-1 content was significantly elevated in cardiac and renal tissue of 8 and 12 week old SHR compared to age-matched WKY. An age-dependent increase in cardiac CGRP content was observed only in WKY. In SHR, SOL-1 treatment significantly reduced BP and lowered cardiac and renal ET-1 content while CGRP content was significantly increased. The effect of chronic ECE/NEP inhibition on BP and on ET-1 and CGRP levels supports our hypothesis that ET-1 and CGRP are involved in the development of hypertension in SHR.