Mechanisms of Obesity-Induced Hypertension
The mechanisms of obesity-induced hypertension are multifactorial and complex. Many animal models have been used to study the renal, cardiovascular, and neurohumoral contributions to hypertension in obesity. Unfortunately, these models do not closely mimic human obesity hypertension. Like most forms of hypertension, obesity hypertension is associated with an increase in sodium reabsorption, increased extracellular fluid, and a shift in pressure natriuresis. Factors that may contribute to altered natriuresis in obesity hypertension include hyperinsulinemia, activation of the renin-angiotensin system, activation of the sympathetic nervous system, or altered intrarenal forces.
Obesity hypertension is associated with increases in cardiac output, heart rate, and intravascular volume, yet the total peripheral resistance remains near normal. Alterations in regional blood flow to the kidneys, heart, skeletal muscle, and gastrointestinal tract have been observed in human obese subjects and contribute to the increased cardiac output. The mechanisms causing these alterations in hemodynamics are not fully understood.
Hyperinsulinemia as a consequence of insulin resistance is associated with obesity and has been suggested to raise blood pressure by increasing sodium reabsorption directly, by enhancing sympathetic activity, or by increasing responsiveness to angiotensin II in the secretion of aldosterone. Evidence for this mechanism comes from epidemiologic studies showing a correlation between blood pressure and diabetes mellitus and from experiments employing acute infusion of insulin. However, long-term infusion of insulin in dogs fed a high-fat diet does not result in increased sodium retention and hypertension. An association between obesity and disturbance of insulin metabolism is well established, but the relationship between hyperinsulinemia/insulin resistance and its long-term effect on blood pressure is unclear and currently debated.[16,19,20]
Obesity hypertension is associated with activation of the renin-angiotensin system. High renin levels are found in obese humans and in dogs fed a high-fat diet, even with concomitant sodium retention and excess extracellular volume. Enhancement of renin-angiotensin activity may be secondary to increased sympathetic tone. Alternatively, intrarenal forces related to structural changes in the renal medulla may alter the renin-angiotensin axis, resulting in increased tubular sodium reabsorption.
There is sufficient evidence that sympathetic tone is enhanced in obesity. Plasma norepinephrine increases with raised caloric intake and decreases with caloric restriction. Measurements of muscle sympathetic nerve activity are increased in obesity. The role of sympathetic activity in the maintenance of obesity hypertension has also been demonstrated by pharmacologic blockade of - and -adrenergic receptors in obese and lean hypertensive animals and humans.
The mediators that link sympathetic activity and obesity hypertension remain unclear. The identification of leptin, a hormonal peptide product of the "obese gene" is secreted by adipocytes and has been shown to affect sympathetic nerve traffic and may, therefore, play a role in increasing sodium absorption, mean arterial pressure, and heart rate in obesity hypertension. Further research is ongoing to determine the role of leptin in obesity and may provide pharmacologic options for the management of obesity hypertension.
© 2002 Le Jacq Communications, Inc.
Cite this: Therapeutic Considerations in the Treatment of Obesity Hypertension - Medscape - May 01, 2002.