Bradykinin (BK) is a tissue hormone with vasodilatory properties, whose role in regulating systemic blood pressure or local perfusion and metabolism of certain organs is still poorly understood. Its participation in cardiovascular physiology has been explored in the past via use of selective antagonists of the B2-type BK receptors, which are believed to mediate its clinically significant actions. The development of genetically engineered mice whose B2-receptor gene has been disrupted (B2-knockouts) should permit more accurate evaluation of the role of BK. The hypothesis to be tested in this proposal is that BK, via its B2 receptor-mediated actions, tends to counteract hypertensive mechanisms and to protect the perfusion and metabolism of sensitive organs from hypertensive or ischemic tissue damage. The following Specific Aims are proposed: 1. Development of experimental hypertension of the renin-dependent (renovascular) or salt- dependent (DOC-salt, end-stage renal disease) types in B2-receptor gene knockout mice to be compared with wild type mice. 2. Development of ischemic cardiomyopathy post myocardial necrosis via: a) angiotensin II infusion and b) coronary artery ligation in mice: comparison of cardioprotective role of ACE inhibition or Ang II blockade in wild type vs B2-receptor gene knockout mice. 3. Study of insulin-mediated glucose metabolism via euglycemic insulin infusion clamp to compare glucose utilization in wild type vs B2 receptor gene knockout mice at baseline and during ACE inhibition. 4. Study of the relationship of selected local vasodilators with BK in maintaining blood pressure in B2 receptor gene knockout mice (i.e., NO, substance P, ANF) via use of their specific inhibitors. Our laboratory has had extensive experience in the past with experimental studies using rats. We have successfully adapted our methodology and equipment to the study of mice, and have acquired expertise in inducing and quantitatively monitoring cardiovascular diseases in diminutive animals.
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