The lord of the ring: Mandatory role of the kidney in drug therapy of hypertension

Strong evidence supports the idea that total peripheral resistance (TPR) is increased in all forms of human and experimental hypertension. Although the etiological participation of TPR in the origin and long-term maintenance of hypertension has been extensively debated, it now seems clear that the renal, nonadaptive, infinite gain-working, pressure-sensitive natriuresis and diuresis is the main mechanism of blood pressure control in the long term. The tissue, cellular, biochemical, and genetic sensors and executors of this process have not been fully identified yet, but the role of the renal medulla has gained growing attention as the physiopathological scenario in which the key regulatory elements reside. Specifically, the functionality of the renomedullary vasculature seems to be highly responsible for blood pressure control. The vasculature of the renal medulla becomes a new and more specific target for the therapeutic intervention of hypertension. Recent data on the effect of baroreceptor-controlled renal sympathetic activity on the long-term regulation of blood pressure are integrated. The renomedullary effects of the main antihypertensive drugs are discussed, and new perspectives for the therapeutic intervention of hypertension are outlined. Comparison of the genetic program of the renal medulla before and after the development of hypertension in spontaneously hypertensive and experimentally induced animal models might provide a mechanism for identifying the key genes that become activated or suppressed in the development of high blood pressure. These genes, their encoded proteins, or other elements related to their signalling and genetic pathways might serve as new and more specific targets for the pharmacological treatment of abnormally elevated blood pressure. Besides, proteins specifically located to the luminal side of the renomedullary vascular endothelium may serve as potential targets for site-directed drug and gene therapy.