Pathogenesis of essential hypertension: historical paradigms and modern insights

Abstract

Since its first identification in the late 1800s, a variety of etiologies for essential hypertension have been proposed. In this paper we review the primary proposed hypotheses in the context of both the time in which they were proposed as well as the subsequent studies performed over the years. From these various insights, we propose a current paradigm to explain the renal mechanisms underlying the hypertension epidemic today. Specifically, we propose that hypertension is initiated by agents that cause systemic and intrarenal vasoconstriction. Over time intrarenal injury develops with microvascular disease, interstitial T cell and macrophage recruitment with the induction of an autoimmune response, with local angiotensin II formation and oxidant generation. These changes maintain intrarenal vasoconstriction and hypoxia with a change in local vasoconstrictor-vasodilator balance favoring sodium retention. Both genetic and congenital (nephron number) mechanisms have profound influence on this pathway. As blood pressure rises, renal ischemia is ameliorated and sodium balance restored completely (in salt-resistant) or partially (in salt-sensitive) hypertension, but at the expense of a rightward shift in the pressure natriuresis curve and persistent hypertension.

Fig. 1

The effect of the hypertensive phenotype on the pressure natriuresis curve.

Fig. 2

A pathway for the development of salt-resistant and salt-sensitive hypertension. ADMA, Asymmetric dimethyl arginine; BP, blood pressure; CSA, cyclosporin A, HTN, hypertension; K, potassium; Na, sodium; RAS, renin–angiotensin system; SNS, sympathetic nervous system.

Fig. 3

Models of salt-sensitive hypertension mediated by interstitial immune cells. BSA, bovine serum albumin; l-NAME, nitro-l-arginine methyl ester.