Paula M. Oliver, Ph.D.

Dissertation research performed under the guidence of Dr. Nobuyo N. Maeda

ABSTRACT
    Essential hypertension is a multifactoral disease in which arterial pressures are persistently high without identifiable cause. Although environmental factors are important in disease susceptibility, hypertension can occur when mutations are introduced into genes which regulate blood pressure or sodium homeostasis. Natriuretic peptide receptor A (NPRA) is a cell membrane associated protein which binds both atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). When activated, it initiates events leading to lowering of blood pressure through elevating intracellular cGMP levels. To study the role of this receptor in essential hypertension, I produced animals with 0 to 4 copies of the NPRA gene (Npra in mouse). In F1 generation male animals, tail cuff pressures decreased as Npra copy number increased with 1 copy animals exhibiting blood pressures an average of 9 mmHg above wild type controls, and 3 copy animals averaging 4.5 mmHg below 2 copy controls on normal salt diet, suggesting a salt insensitive form of hypertension. When placed on high salt diet, one copy animals exhibited further elevations of blood pressure (by two tailed T test, P = 0.032), suggesting these animals also show a salt sensitive form of hypertension. In F2 animals, the affect of Npra copy number on blood pressure in males is augmented by high concentrations of dietary sodium whereas this effect is not observed in females. Elevated heart weights were observed in both male and female animals lacking Npra, although this hypertrophy was more severe in males. Moreover, males exhibited a high rate of mortality and death of these animals appeared to be due to complications of heart disease. The severity of the hypertrophy in male mice lacking Npra and the increased incidence of fibrotic scarring in this group could lead to initiation of arrythmia or congestive heart failure and could account for the increased rate of mortality. These animals should provide a valuable tool for studying the role of Npra in initiation of blood pressure changes, and development of left ventricular hypertrophy as well as provide a model for determining the role of cardiac hypertrophy in mortality.