Endothelin as a natriuretic hormone: the case for a paracrine action mediated by nitric oxide

Time for primary review 26 days. There is a widely held view that function of the kidney is the key to understanding human essential hypertension. Indeed, all of the currently recognised human monogenic causes of hypertension reflect abnormalities in the genes that determine ion transport in the distal portion of the nephron [1]. It is also recognised that permanent elevation of blood pressure in experimental models of hypertension, and both primary and secondary hypertension in man, requires the shifting of the natriuretic response curve of the kidney towards higher pressures [2]. However, the mechanism underlying pressure-natriuresis, and its resetting in hypertension, remains poorly understood. In this review we have analysed experiments indicating a role for endothelin (ET)-1 as a key natriuretic hormone and propose a new and testable hypothesis for a paracrine action of ET-1 through NO that accommodates the existing experimental findings.ET-1 is a 21 amino acid peptide, synthesised mainly by endothelial cells (ECs) and produced from an inactive precursor peptide by several rounds of specific proteolysis. The last step is performed by endothelin converting enzyme (ECE), which releases ET-1 from big ET-1. ET-1 acts in an autocrine and paracrine fashion on two subtypes of ET receptors, termed the ETA (ETAR) and ETB receptors (ETBR). Both ETAR and ETBR are located on vascular smooth muscle cells and binding of ET-1 to these receptors results in sustained vasoconstriction. ETBR are also present on ECs where their activation results in the production of NO and dilator prostanoids, and subsequent vasodilatation. The ET system is now known to play an important role in the regulation of vascular tone and blood pressure [3,4].However, the role of ET-1 produced and secreted in the kidney may be independent of the systemic vascular effects. Analysis of different tissues found the highest … *Corresponding author. Tel.: +44-131-651-11-94; fax: +44-131-650-65-27 Yuri.Kotelevtsev{at}ed.ac.uk