Proinflammatory effects of angiotensin II and endothelin: targets for progression of cardiovascular and renal diseases.

Angiotensin II and endothelin-1 can both be regulated by nuclear factor-kappaB. They are to varying degrees also capable of activating nuclear factor-kappaB and increasing the expression of nuclear factor-kappaB dependent genes. Angiotensin II related vascular effects are in part mediated by endothelin-1. Nitric oxide synthase inhibition facilitates angiotensin II related effects, which can be inhibited both by angiotensin II type 1 receptor blockers and by endothelin system inhibitors. This supports the notion that a combined therapeutic strategy of inhibiting angiotensin II and endothelin-1 generation or blocking their effects at the receptor level would be superior to either strategy alone. Animal studies are encouraging but not without conflicting results. Angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers have a superb track record in experimental animal models and in a host of clinical studies. Selective and nonselective blockers of the endothelin-1 receptors are important research tools and are also undergoing clinical trials. Inhibitors of the endothelin converting enzyme have been developed. The recent elucidation of the endothelin converting enzyme's physical structure should facilitate the development of still more novel compounds to inhibit endothelin-1 generation.