The role of the kidney in the pathogenesis of hypertension : 3 Time for a neo - Guytonian paradigm or a paradigm shift ?

24 The ‘Guytonian paradigm’ places the direct effect of arterial pressure, on renal excretion of salt and 25 water, at the center of long-term control of blood pressure and thus the pathogenesis of 26 hypertension. It originated in the sixties and remains influential within the field of hypertension 27 research. However, the concept of one central long-term feedback loop, through which arterial 28 pressure is maintained by its influence on renal function, has been questioned. Furthermore, some 29 concepts in the paradigm are undermined by experimental observations. For example, volume 30 retention and increased cardiac output induced by high salt intake do not necessarily lead to 31 increased arterial pressure. Indeed, in multiple models of salt-sensitive hypertension the major 32 abnormality appears to be failure of the vasodilator response to increased cardiac output, seen in 33 salt-resistant animals, rather than an increase in cardiac output itself. There is also evidence that 34 renal control of extracellular fluid volume is driven chiefly by volume-dependent neurohumoral 35 control mechanisms rather than through direct or indirect effects of changes in arterial pressure, 36 compatible with the concept that renal sodium excretion is controlled by parallel actions of different 37 feedback systems, including hormones, reflexes, and renal arterial pressure. Moreover, we still do 38 not fully understand the sequence of events underlying the phenomenon of ‘whole body 39 autoregulation’. Thus, the events by which volume retention may develop to hypertension 40 characterized by increased peripheral resistance remain enigmatic. Finally, by definition, animal 41 models of hypertension are not ‘essential hypertension’; progress in our understanding of essential 42 hypertension depends on new results on system functions in patients. 43 44 Abstract word count = 254 45 46