The long term-objective is to help unravel the genetic complexities of essential hypertension. Pre-planned mutations in genes likely to be important in the etiology of essential hypertension and in the homeostasis of blood pressure, blood volume and sodium balance will be generated by gene targeting in animals having an otherwise constant genetic background. Centering initially on two peptide hormone systems with opposing effects, genes will be modified that control the supply of or the response to the peptides. There are five specific aims: (i) Angiotensin II (ANG II), an octapeptide with potent vasoconstrictive and salt-retaining effects, is coded as the amino-terminus of a large precursor, angiotensinogen. The first specific aim is to modify the gene for angiotensinogen so that: a) it makes no product; b) the portion coding for ANG II is altered, but the rest is unchanged. (ii) The second specific aim is to inactivate the gene coding for the type 1 receptor of ANG II, which is expressed in vascular smooth muscle cells, kidneys and adrenals. (iii) Atrial natriuretic factor (ANF) is a potent salt-eliminating and smooth muscle relaxing peptide; its 28 amino acids are coded as the carboxy terminus of a large precursor (proANF). The third specific aim is to modify the gene for proANF so that: a) it makes no product; b) the portion coding for ANF is altered but the rest is unchanged. (iv) The fourth specific aim is to study the phenotypes generated by the planned mutations: a) singly; and b) in combinations. (v) The fifth specific aim is to study the responses of the mutant animals to manipulations that disturb circulatory homeostasis, including: a) non-invasive procedures (e.g. changes in salt intake; pharmacological agents); b) procedures that normally lead to hypertension (e.g. renal artery clipping; 5/6 renal ablation).
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