Understanding the mechanisms of angiotensin II signaling involved in hypertension and its long-term sequelae: insights from Bartter's and Gitelman's syndromes, human models of endogenous angiotensin II signaling antagonism.

Angiotensin II (Ang II) plays a key role in hypertension, renal and cardiovascular pathophysiology via intracellular pathways that involve the activation of a multiplicity of signaling mechanisms. Although experimental and genetic animal models have been developed and used to explore Ang II signaling's role in hypertension, a complete understanding of the processes mediating Ang II signaling in hypertension in humans remains elusive. One impediment is that these animal models do not exhibit all the traits of human hypertension, making it impossible to extrapolate from them to humans. To overcome this issue, we have used patients with Bartter's and Gitelman's syndromes, a human model of endogenously blunted and blocked Ang II signaling that presents a constellation of clinical findings which manifest themselves as the opposite of hypertension. This article reviews the aspects of the pathophysiology of human hypertension and its short and long term sequelae, and uses the results of our studies in Bartter's and Gitelman's syndromes along with those of others to gain better insight and understanding of the role of Ang II signaling in these processes.