The vascular wall is an important endocrine and paracrine organ. Biologically active substances released or present within the wall modulate the properties of the constituent cells. Glandular kallikrein (a kinin- generating enzyme) and its mRNA are present in arteries and veins. Kinins release endothelium-derived factors, which are potent vasodilators and inhibit the growth of vascular smooth muscle cells (VSMC). In addition, they release tissue plasminogen activator (tPA) from endothelial cells and thereby induce fibrinolysis. Our general hypothesis is that the kallikrein-kinin system is an integral component of the vascular wall and is functionally involved in vascular homeostasis. We postulate that vascular kallikrein releases kinins which act at or near their site of formation, contributing to regulation of vascular tone, fibrinolysis and growth.
Our specific aims are:
Aim I : 1) To elucidate the factors regulating kallikrein content and release from arteries and veins; 2) To determine whether kinins are released from vascular tissue; 3) To identify the kininases present in vascular tissue.
Aim II : 1) To determine whether kinin-stimulated release of tPA is mediated by changes in EDRF, and 2) to determine whether increasing endogenous kinins after administration of kininase inhibitors increases plasma fibrinolytic activity.
Aim I V: To determine whether blocking kinins abolishes part of the antiproliferative effect of angiotensin-converting enzyme inhibitors (CEI) following balloon endothelial denudation;
Aim V : To determine whether the vascular kallikrein-kinin system is altered in renovascular, volume-dependent and genetic hypertension. We will measure vascular kallikrein content, kallikrein mRNA and kallikrein release in 2 kidney/1-clip Goldblatt hypertension, DOCA-salt rats and both prehypertensive and hypertensive SHR. These studies will determine whether the vascular kallikrein-kinin system contributes to the regulation of circulatory homeostasis.
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