The natriuretic peptide (NP) system is a remarkably efficacious hypotensive, antihypertrophic cardiovascular hormone and receptor family. Comparative empirical research of the NP system in fish has yielded two prominent theories, the osmoregulatory and cardioprotective hypotheses. The osmoregulatory hypothesis is based largely on physiological actions and stimuli of the NP system in the eel, and implies that the NP system functions to reduce the salt burden on euryhaline teleosts following transfer from freshwater to saltwater. In contrast, the cardioprotective hypothesis is formulated from empirical evidence from the eel and trout, and contends that the NP system in fishes functions primarily to protect the heart from volume-loading cardiodilation. Results from the present studies support the cardioprotective hypothesis for the NP system in trout. Following adaptation to a freshwater high-salt diet (FW-HSD), cardiac NP transcription and pro-peptide levels were significantly elevated over levels in freshwater (FW) and saltwater (SW) adapted fish. Cardiac NP-receptors (NPRs) were also significantly elevated in FW-HSD trout as comared to FW and SW trout. Following acute volume loading cardiac NP mRNA levels were significantly elevated over control, while acute volume depletion typically resulted in a reduction of cardiac NP mRNA. Identification of extra-cardiac NP production sites in the brain and vasculature further supports a cardioprotective role for the NP system in trout. Following adaptation to FW-HSD, brain pro-BNP, NPR-A and NPR-B mRNA levels were significantly elevated over FW and SW adapted fish. Furthermore, local production of BNP and CNP in the trout vasculature supports a blood volume-sensitive response. NPR production in the efferent branchial artery (EBA) was not significantly affected by FW-HSD or SW adaptation as compared to FW, though in vitro vascular sensitivity assays for either ANP or CNP revealed EBAs from FW-HSD trout were significantly less sensitive than either FW or SW EBAs. These results show that the production of cardiac NPs and NPRs is primarily blood volume-responsive. Furthermore, NP and NPR transcription of extra-cardiac sites suggest a volume-responsive role for NPs and NPRs in the brain and vasculature. Overall, these findings in conjunction with numerous previous studies support a cardioprotective role for the NP system in trout.