As noted previously, NEFAs have been linked epidemiologically to hypertension and its genesis. NEFAs have several actions that could contribute to hypertension and help explain the link between the obesity epidemic and increasing prevalence of hypertension (37). Hypertensive patients are more likely to be overweight and obese than normoten-sive individuals. Moreover, when matched for body mass index, hypertensives are more likely to have a centralized fat pattern and a greater amount of visceral to subcutaneous abdominal fat than normotensives (38). Even within the normotensive range, abdominally obese subjects have higher blood pressures than individuals with gluteofemoral obesity, and these blood pressure differences are related to insulin resistance (39).
Subjects with abdominal obesity are not only resistant to insulin-mediated glucose disposal, but they are also resistant to insulin's NEFA lowering actions (1,2,40). Moreover, resistance to insulin's effects on fatty acids during a euglycemic clamp coincides with higher plasma NEFAs over 24 h and with a higher plasma NEFA nadir following a mixed meal (40-42). The NEFA abnormality in obese hypertensives is especially prominent. NEFAs were suppressed in upper body obese normotensives by roughly 50% and turnover by approximately one-third when plasma insulin was raised just 5 pU/mL (2). Abdominally obese hypertensives did not suppress NEFA concentration and turnover by 50% even when plasma insulin was raised ~100 pU/mL (32). NEFA concentration and turnover during the clamp correlated directly with blood pressure measured at the screening visit in these volunteers. The correlations persisted when lean normotensives were excluded and after controlling for hyperinsulinemia and insulin-mediated glucose disposal. The finding of a direct and independent relationship between NEFAs and blood pressure was confirmed in a larger group of volunteers undergoing a 15-min insulin tolerance test (1). In a subsequent study, the angiotensin-converting enzyme inhibitor enalapril significantly improved the action of insulin to suppress plasma NEFAs during a euglycemic clamp (43). The blood pressure reduction during enalapril treatment in obese hypertensive patients correlated with the improvement in insulin's capacity to suppress plasma NEFAs.
Another condition associated with hypertension and insulin resistance is familial combined hyperlipidemia (44). Patients with familial combined hyperlipidemia have plasma NEFAs of ~1.5±0.5 mM (SD) after a high-fat test meal (4). These are close to the NEFA levels that caused vasoconstriction and a pressor response in minipigs (45). Moreover, hypertriglyceridemic family members of proband cases with familial combined hyperlipidemia have a tendency to higher fasting insulin and NEFAs as well as higher systolic blood pressure than family members having normal triglycerides (4). Patients with familial combined hyperlipidemia comprise ~1-2% of the general population but ~12% of hypertensive patients, i.e., familial dyslipidemic hypertension (44). The findings that patients with familial combined hyperlipidemia have elevated plasma NEFAs (4) and are more likely to be hypertensive (44), that their affected family members have a tendency to increased NEFAs and blood pressure (4), and that elevating NEFAs raises blood pressure (45) suggest that NEFAs may link this genetic disorder and hypertension. This link is consonant with the data from the Paris Prospective Study that plasma NEFAs were positively and independently related to a new onset hypertension (8).
The link between visceral obesity and elevated blood pressures remains unknown (38,39). As noted, NEFAs have effects on multiple targets that participate in blood pressure regulation including a reduced endothelial cell nitric oxide synthase activity and endothelium-dependent vasodilation (21,23), increased endothelial cell endothelin production (24), enhanced vascular tone and reactivity (28,30), vascular and renal structural remodeling (46,47), impaired baroreflex sensitivity (48), augmented oxidative stress
(49), and elevated sympathetic to parasympathetic tone (34). The effects on impaired nitric oxide production could potentially reset renal pressure natriuresis to a higher level
(50), which is fundamentally important in sustaining high blood pressure.
Although the mechanisms by which NEFAs may change autonomic control are unknown, the visceral fat mass is active with rapid lipolysis and re-esterification of triglycerides (2). Thus, abdominally obese individuals would have increased portal delivery of NEFAs to the liver. In rats, increasing the delivery of oleic acid into the hepatic portal circulation elicits a neurogenically mediated pressor response (51). In fact, obesity-induced hypertension in rats, rabbits, and dogs has a strong neurogenic component, and several studies on obese hypertensive humans identified evidence for neurogenic hypertension (26,52-54). These observations are consistent with studies demonstrating that acute elevations of NEFAs in humans raise plasma catecholamines and increases the ratio sympathetic to parasympathetic control of the heart (34).
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