Project 170936

The kinins are hormone-like substances generated from blood, but also potentially from the cells that constitute the blood vessels. Two types of receptors are activated by kinins: the B2 receptors are preformed and widely distributed. The B1 receptors are not present in healthy tissues, but ther expression is completely induced under inflammatory or tissue injury conditions. Angiotensin converting enzyme (ACE) inhibitors are a widely used class of drugs used for hypertension and other cardiovascular/renal ailments that inteact with kinins, because ACE is a prominent kinin-destroying enzyme in vivo. Thus, a part of the therapeutic and/or side effects of ACE inhibitors may derive from an increased kinin concentration in tissues, vascular responses such as vasodilation and increased permeability and adaptative changes in the population of kinin receptors receptors. Objective of the project: (1) To verify whether a particular blood vessel cell type, the endothelial cell, can produce kinin precursors and process them, thus leading to the autostimulation of cell functions under ACE blockade. (2) To verify the relative importance of kinin inactivation mechanisms in human endothelial cells (ACE being one of them). (3) To establish in endothelial cell culture and in live animals (rabbits) how a widely used anti-hypertensive drug class, the ACE inhibitors, or inflammation change the kinin receptor populations (increase in the B1 type, decrease in B2 receptors). This may be related to a rare but dangerous side effect of ACE inhibitors, angioedema, because there are theoretical reasons to believe that it is linked to B1 receptor expression. Significance: The role of the B1 receptors has only been rarely addressed in the analysis of the actions of ACE inhibitors. The applicants have developed over the years many experimental approaches related to the kinin receptors an exploit an analytical platform (immunoreactive kinin determination) unique in the world.

studying DNA interstrand crosslink repair pathways to understand cancer etiology and treatment