Endothelin, hypertension and chronic kidney disease: new insights

Endothelin is important in the development of cardiorenal disease. This review discusses recent developments in understanding endothelin's role in hypertension and chronic kidney disease (CKD).

Endothelin-1 production is increased in hypertension and CKD. Endothelin-1 stimulates vasoconstriction, inflammation and fibrosis, thereby promoting hypertension, atherosclerosis and CKD. These effects are closely linked to angiotensin II and reactive oxygen species. In preclinical studies, endothelin receptor antagonists were effective in treating hypertension (particularly with endothelial dysfunction) and CKD. In preclinical studies, endothelin A-selective, as opposed to combined endothelin A and B, receptor blockers have generally been more efficacious. Few clinical trials have been conducted in hypertension and/or kidney disease, partly due to concerns over side effects of testicular toxicity and fluid retention. Endothelin blockade reduces blood pressure in patients with resistant hypertension, with additional beneficial metabolic effects. Endothelin antagonism improves proteinuria in CKD (diabetic or not), particularly in patients taking inhibitors of angiotensin II action.

Endothelin is a promising target in the treatment of resistant hypertension and CKD, with additional potential benefits on atherosclerosis and the metabolic syndrome. The nature and mechanisms of drug side effects require elucidation before the potential of this new class of drugs can be fully realized.