Perivascular nerves and the endothelium contain potent vasoactive peptides such as calcitonin-gene related peptide (CGRP), neuropeptide Y (NPY) and endothelin-1 (ET-1). Because alterations of peripheral nervous function are observed in hypertension and upregulation of ET-1 can be part of the endothelial dysfunction that characterizes several diseases, these peptides might be valid pharmaco-therapeutic targets. In mesenteric resistance-sized arteries, endogenous CGRP released from sensory-motor nerves causes dilatations that are inhibited by endogenous NPY released from sympathetic nerves. This can be attributed to stimulatory and inhibitory effects of CGRP-receptors and NPY Y1-receptors, respectively, on the sarcolemmal adenylyl cyclase of the post-junctional arterial smooth muscle cells (ASMC; De Mey et al. JPET, 2008). The potent and long-lasting vasoconstrictor effects of ET-1 result from tight binding of the peptide to ASMC ETA-receptors. Antagonists and most vasodilators can not dissociate this binding and reversibly relax contractile effects initiated by ET-1. However, stimulation of ASMC CGRP-receptors by exogenous and endogenously released CGRP selectively promotes dissociation of ET-1/ETA-receptor complexes and terminates ET-1-induced vasoconstriction (Meens et al. PLoS ONE, 2010). This is observed in arteries isolated from several vascular beds and in vivo at the level of local vascular resistance and blood pressure. Because ECE and NEP are involved in the synthesis of ET-1 and in the degradation of CGRP, respectively, we tested the hypothesis that a dual NEP-/ECE-inhibitor (SOL-1) might have beneficial therapeutic effects. In young SHR rats, tissue contents of ET-1 and CGRP were increased and reduced, respectively, compared to age-matched WKY rats. Chronic treatment with SOL-1 normalized the tissue levels of the peptides and partly prevented the development of hypertension (Nelissen et al. this meeting). We conclude that crosstalk between vasoactive peptides might be a valid target for the treatment of multifactorial (cardiovascular) diseases.