Vasodysfunction That Involves Renal Vasodysfunction, Not Abnormally Increased Renal Retention of Sodium, Accounts for the Initiation of Salt-Induced Hypertension

Abstract

Prevailing theory holds that abnormally large increases in renal salt retention and cardiac output are early pathophysiologic events mediating initiation of most instances of salt-induced hypertension. This theory has come under increasing scrutiny because it is based on studies that lack measurements of sodium balance and cardiac output obtained during initiation of salt-loading in proper normal controls, i.e., salt-resistant subjects with normal blood pressure. Here we make the case for a “vasodysfunction” theory for initiation of salt-induced hypertension: In response to an increase in salt intake, a subnormal decrease in total peripheral resistance that involves a subnormal decrease in renal vascular resistance, in the absence of abnormally large increases in sodium retention and cardiac output, is the hemodynamic abnormality that usually mediates initiation of salt-induced increases in blood pressure (BP). It is the failure to normally decrease vascular resistance in response to salt loading that enables a normal increase of cardiac output to initiate the salt-induced increase in blood pressure. This theory is based on the results of properly controlled studies which consistently demonstrate that in salt-sensitive subjects, salt-loading initiates increased BP through a hemodynamic mechanism that: 1) does not usually involve early increases in sodium retention and cardiac output greater than those which occur with salt-loading in normal controls, and 2) usually involves an early failure to decrease vascular resistance to the same extent as that observed during salt-loading in normal controls. Multiple mechanisms including disturbances in nitric oxide and sympathetic nervous system activity likely underlie this subnormal vasodilatory response to salt that usually precedes and initiates salt-induced hypertension.

An alternative hypothesis to the widely held view that renal excretion of sodium accounts for resistance to salt-induced hypertension

“…2 However, the dissociation of salt-induced changes in blood pressure from salt-induced changes in blood volume could be explained by alterations in vascular resistance that may not necessarily depend on alterations in renal or extra-renal sodium handling. 19, 57 Normal salt-resistant subjects, acutely 20–34, 41, 42, 45, 46 and chronically, 27, 40, 47, 49, 50 can sustain large salt-induced increases in sodium balance, blood volume, and cardiac output without increases in blood pressure because they vasodilate and substantially reduce vascular resistance in response to high salt diets. 19, 24, 25, 41, 45, 46, 49, 50 Thus, in normal individuals, resistance to the pressor effects of acute or chronic increases in salt intake is not usually due to an ability to rapidly excrete a salt load and prevent substantial increases in sodium balance, blood volume, and cardiac output.…”

“…19, 57 Normal salt-resistant subjects, acutely 20–34, 41, 42, 45, 46 and chronically, 27, 40, 47, 49, 50 can sustain large salt-induced increases in sodium balance, blood volume, and cardiac output without increases in blood pressure because they vasodilate and substantially reduce vascular resistance in response to high salt diets. 19, 24, 25, 41, 45, 46, 49, 50 Thus, in normal individuals, resistance to the pressor effects of acute or chronic increases in salt intake is not usually due to an ability to rapidly excrete a salt load and prevent substantial increases in sodium balance, blood volume, and cardiac output. 19 Rather, it may be due to reductions in systemic vascular resistance in response to acute and chronic salt-loading 19, 24, 25, 41, 45, 46, 49, 50 mediated largely, or only by, reductions in renal vascular resistance.…”

“…Recently, we noted 19 that the results of acute salt-loading studies in normotensive salt-resistant subjects seem to be at odds with the widely-held view that normal subjects are usually salt-resistant because they excrete a salt load rapidly 9 and undergo very little blood volume expansion. 1 Here we systematically review the results of studies that investigate whether normal subjects are usually resistant to the pressor effects of either acute or chronic salt loading because they rapidly excrete the excess salt and their blood volume is hardly altered.…”

Logical Issues With the Pressure Natriuresis Theory of Chronic Hypertension

“…The theory holds that abnormal pressure natriuresis causes sustained salt-induced hypertension by causing abnormal increases in CO that are too small to be detected. 9,13,14,28 These observations add to growing concerns 15,27,[31][32][33][34][35][36][37] about the pressure natriuresis theory of chronic hypertension. Accordingly, we anticipate that this theory, advanced through the pioneering efforts of Arthur Guyton and others, 4,5,13,[38][39][40][41][42] will eventually be replaced by testable theories about the abnormalities that initiate hypertension and cause it to be sustained.…”

“…26 Importantly, and in direct opposition to these statements, at no time during the initiation or maintenance of salt-induced hypertension has it been found that CO is greater in salt-loaded salt-sensitive subjects than in saltloaded normal controls. 27 To address this fact, the proponents of the pressure natriuresis theory contend that the abnormal increases in CO are too small to detect. 9,13,14,28 For example, it is stated that: "The long-term elevation in cardiac output is so slight that usual methods for measuring cardiac output are not adequate to prove that it is indeed elevated."…”