Louis K. Dahl Memorial Lecture. Renal and cardiovascular mechanisms of hypertension in obesity.

Abstract

In all forms of hypertension, including human essential hypertension, pressure natriuresis is reset to higher blood pressures. Because human essential hypertension is a heterogeneous disease, it is likely that there are multiple neurohumoral and intrarenal causes of abnormal pressure natriuresis and increased blood pressure. Weight gain is recognized to be an important contributor to essential hypertension, although the mechanisms that link obesity with altered renal function and high blood pressure have not been fully elucidated. In obese dogs and humans, the shift of pressure natriuresis to higher blood pressures appears to be due mainly to increased tubular reabsorption, as glomerular filtration rate and renal plasma flow are increased compared with normal. Multiple causes of increased tubular reabsorption and hypertension in obesity have been postulated, including insulin resistance and hyperinsulinemia, activation of the sympathetic nervous and renin-angiotensin systems, and physical changes within the kidney itself. Support for the insulin L ouis K. Dahl was a true pioneer in the field of hypertension research and was widely recognized for his work that linked hypertension to altered sodium homeostasis and other environmental and genetic factors. He recognized that there is considerable heterogeneity of the blood pressure responses to changes in salt intake, depending on genetic as well as acquired factors, such as weight gain. The interplay between genetic and environmental factors in contributing to hypertension was clearly demonstrated by the development of Dahl's salt-sensitive and salt-resistant rat strains.Dan! also helped to elucidate the critical importance of altered renal function in hypertension by demonstrating with cross-transplantation studies in salt-sensitive and salt-resistant rats that the hypertension followed the kidney, transplantation of kidneys from salt-sensitive rats into salt-resistant rats caused hypertension in resistant rats, whereas transplantation of kidneys from normotensive salt-resistant rats into salt-sensitive rats prevented the usual rise in blood pressure found in salt-sensitive rats. 1 -2 These pioneering studies of Dahl pointed toward the kidney as a key link between genetic and environmental factors in regulating blood pressure.Our research has been aimed primarily at understanding the basic physiological mechanisms by which resistance-hyperinsulinemia link between obesity and hypertension has been inferred mainly from acute and epidemiologic studies showing a correlation between insulin and blood pressure. Recent studies suggest that chronic hyperinsulinemia, comparable to that found in obesity, cannot account for obesity hypertension in dogs or humans. Activation of the sympathetic nervous system may play a role in obesity-induced hypertension, and there is evidence for a role of altered intrarenal physical forces caused by histological changes within the renal medulla. The quantitative importance of each of these abnormalities in altering renal function ...

The contribution of genes, environment and of body mass to blood pressure variance in young adult males

“…Further experimental studies and multivariate genetic analysis on intermediate phenotypes are needed to clarify this issue. Enhanced orthosympathetic activity 20,21 and renal haemodynamic changes [22][23][24] have been suggested as possible intermediate phenotypes between overweight and essential hypertension. Multivariate genetic modelling is uniquely suited to jointly estimate the impact of BMI on BP against the background of the usual genetic and environmental determinants of BP.…”

Mechanisms of obesity-induced hypertension

“…Instead, the elevated heart rate seems to be the effect of decreased parasympathetic activity. 10 Inversely, modest weight reduction is able to suppress the activity of the SNS. It has been suggested, however, that an elevated efferent sympathetic activity in the peroneal nerves may not characterize all obese patients, but only those concomitantly affected by obstructive sleep apnea, an issue, which is still a matter of debate.…”

Hypertension and obesity

“…[15][16][17][18] In the Framingham Study, it was found that a 10% rise in body weight explains a 7 mm Hg rise in systolic blood pressure (SBP) in the population at large. 19 It has also been found that every kilogram excess body weight that is lost is associated with decreases of 0.33 and 0.43 mm Hg in SBP and diastolic blood pressure (DBP) respectively.…”