Context: The aim of this article was to review the existing data on the interactions between insulin, insulin resistance and endothelin, and how those contribute to the development of hypertension in insulin-resistant states.

Evidence Acquisition: A literature search of MEDLINE database was performed to identify English-language articles published during the last 20 yr. Search terms used were "endothelin", "insulin" "insulin resistance", "hyperinsulinemia" in combination with "blood pressure" and "hypertension". Reference lists of retrieved articles were also evaluated for relevant information.

Evidence Synthesis: Several mechanisms connect insulin resistance and compensatory hyperinsulinemia with blood pressure elevation in the context of the metabolic syndrome, i.e. sodium retention, sympathetic activation and impairment of endothelial nitric oxide production. Accumulating evidence suggest that activation of the endothelin system seems to be another important, yet less discussed, mechanism. In vitro studies have shown that insulin stimulates both endothelin-1 production and action on the vascular wall. In vivo, high levels of insulin result in increase in circulating endothelin-1 in healthy individuals and this effect is also seen in insulin-resistant subjects, a relationship not observed with nitric oxide production. Moreover, endothelin receptor antagonism effectively reduces blood pressure in animal models of insulin resistance and hypertension. On the other hand, elevation of endothelin-1 levels can further increase insulin resistance, forming possibly a deleterious circle.

Conclusions: Endothelin-1 may play a crucial role in the pathogenesis of hypertension in insulin-resistant states. Future research should examine the potential of endothelin receptor antagonism to help blood pressure control in patients with insulin resistance.