Identifying the second hit that explains why normotensive, insulin-resistant individuals develop elevated BP is much more elusive, at least partly because probably no more than half of patients with essential hypertension are insulin-resistant.21 However, there is information that may help explain some of the mechanistic links between insulin resistance and an increase in BP. For example, a number of relevant variables were compared in 19 healthy individuals in response to 5-day periods of high (200 mmol/d) and low (25 mmol/d) sodium diets.24 Mean changes found with a high-sodium diet were not surprising and included an increase in weight, sodium excretion, and plasma concentrations of atrial natriuretic peptide (ANP) and plasma renin activity (PRA), and a decrease in plasma aldosterone concentration. The dramatic difference in salt intake did not affect either insulin action or the insulin response to an oral glucose challenge, but there was an increase in urinary nitrate excretion on the high-salt diet of marginal statistical significance (P=.06).
Regression analysis of the whole group, however, showed that the more insulin-resistant the person, the less the natriuretic response to the high-sodium diet (−0.50, P=.04), and the greater the sodium-induced weight gain (r=0.54, P=.03). Of interest, changes in PRA, ANP, and aldosterone were not significantly related to either sodium excretion or weight gain. Finally, the only two variables significantly associated with a sodium-induced increase in mean arterial BP were weight gain (r=0.51, P<.05) and a decrease in urinary nitrate excretion (r=−0.77, P<.001). As before, there was no association between increases in BP and changes in PRA, aldosterone, or ANP. These results provide one possible explanation for what the second hit might be, at least in the case of salt-sensitive hypertension, which increases the chances of an insulin-resistant person developing essential hypertension. Specifically, the more insulin-resistant the individual, the more likely they will be to retain salt and water, with subsequent volume expansion, independent of changes in ANP, PRA, or aldosterone. Furthermore, the greater the degree of volume expansion (weight gain), the higher the sodium-induced increase in BP. Finally, since the increase in BP was inversely related to the change in urinary nitrate excretion, it can be argued that insulin-resistant individuals will be at risk for volume-related hypertension, and their ability to compensate will depend on how effective they are at increasing nitric oxide production. Consistent with this possibility is the finding that the plasma concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is increased in the subgroup of patients with essential hypertension who are also insulin-resistant.25 An impaired nitric oxide response is only one possible second hit that explains why insulin resistant individuals are at increased risk for developing hypertension, and we clearly lack the knowledge to understand why some insulin-resistant individuals become hypertensive and others do not.