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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL058807-01A1
Application #
2617020
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1998-05-01
Project End
2001-04-30
Budget Start
1998-05-01
Budget End
1999-04-30
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Marketou, Maria; Kintsurashvili, Ekaterina; Papanicolaou, Kyriakos N et al. (2010) Cardioprotective effects of a selective B(2) receptor agonist of bradykinin post-acute myocardial infarct. Am J Hypertens 23:562-8
Manolis, Athanasios J; Marketou, Maria E; Gavras, Irene et al. (2010) Cardioprotective properties of bradykinin: role of the B(2) receptor. Hypertens Res 33:772-7
Duka, Arvi; Schwartz, Faina; Duka, Irena et al. (2006) A novel gene (Cmya3) induced in the heart by angiotensin II-dependent but not salt-dependent hypertension in mice. Am J Hypertens 19:275-81
Duka, Arvi; Duka, Irena; Gao, Guohong et al. (2006) Role of bradykinin B1 and B2 receptors in normal blood pressure regulation. Am J Physiol Endocrinol Metab 291:E268-74
Ignjacev-Lazich, Ivana; Kintsurashvili, Ekaterina; Johns, Conrado et al. (2005) Angiotensin-converting enzyme regulates bradykinin receptor gene expression. Am J Physiol Heart Circ Physiol 289:H1814-20
Kintsurashvili, Ekaterina; Duka, Arvi; Ignjacev, Ivana et al. (2005) Age-related changes of bradykinin B1 and B2 receptors in rat heart. Am J Physiol Heart Circ Physiol 289:H202-5
Duka, Irena; Duka, Arvi; Kintsurashvili, Ekaterina et al. (2003) Mechanisms mediating the vasoactive effects of the B1 receptors of bradykinin. Hypertension 42:1021-5
Duka, I; Shenouda, S; Johns, C et al. (2001) Role of the B(2) receptor of bradykinin in insulin sensitivity. Hypertension 38:1355-60
Kintsurashvili, E; Duka, I; Gavras, I et al. (2001) Effects of ANG II on bradykinin receptor gene expression in cardiomyocytes and vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 281:H1778-83
Gavras, I; Gavras, H (2000) The antiarrhythmic potential of angiotensin II antagonism: experience with losartan. Am J Hypertens 13:512-7