Author

Ryan Morrison

Date of Award

2006

Degree Name

Biomedical Sciences

College

Joan C. Edwards School of Medicine

Type of Degree

Ph.D.

Document Type

Dissertation

First Advisor

William McCumbee

Second Advisor

Todd Green

Third Advisor

Elsa Mangiarua

Fourth Advisor

Monica Valentovic

Fifth Advisor

Gary Wright

Abstract

Hypertension is a serious health problem that affects approximately 1 in 4 American adults. Most cases are diagnosed as essential hypertension, meaning that the exact cause is unknown. In most patients, however, excess weight is a major contributory factor to the development of essential hypertension. The role of obesity in promoting hypertension is now well documented and has become the foundation for an entire field of research known alternately as obesity-hypertension, obesity-induced hypertension, or obesity-associated hypertension. In this field, rapid advances are being made in our understanding of how obesity and hypertension are linked. A plethora of related risk factors, mediators, and pathways have now been identified and described through the use of a variety of animal models. Nonetheless, the relationships between these factors and the extents to which they promote obesity-hypertension are often poorly understood. Unscrambling the various cardiovascular and metabolic determinants of obesity- hypertension remains a persistent problem because both obesity and hypertension typically exhibit polygenic etiologies and diet-dependent dynamics in humans. The judicious use of appropriate animal models promises to be an important tool in this quest. In addition, animal models are vital platforms for designing and evaluating approaches to the treatment of obesity-hypertension. One model of particular interest is the obese Zucker rat, which develops extreme obesity but only develops slight, if any, hypertension. The primary objective of the research in this dissertation was to determine whether obese rats were more sensitive to experimental conditions known to induce hypertension than age- and gender-matched lean controls. Lean and obese Zucker rats were subjected to two experimental protocols that are known to induce hypertension in other rodent strains: (1) the administration of deoxycorticosterone-acetate and salt to uninephrectomized rats and (2) feeding rats a moderately high fat, salt-supplemented (MHF-SS) diet. In each case, the obese Zucker rat was found to be more susceptible to the development of hypertension. A second goal of this research was to ascertain a possible mechanism through which the MHF-SS diet might induce hypertension in obese Zucker rats. In this regard, dysfunction of the nitric oxide system, particularly in the kidney, was implicated in the pathogenesis of the MHF-SS diet in obese Zucker rats. In conclusion, this research suggests that the obese Zucker rat is labile with regard to blood pressure and that renal nitric oxide dysfunction may promote hypertension when obese Zucker rats are fed a moderately high fat, high salt diet.

Subject(s)

Obesity -- Research.

Hypertension -- Research.

Animal models in research.