The fibrinolytic system is the physiologic counterbalance to the thrombosis cascade. The generation, extent, and location of the fibrin clot are critical when hemostasis is compromised. Tissue-type plasminogen activator or t-PA is the initial protease of this pathway and is released from the vasculature in response to numerous neurohormones including acetylcholine, catecholamines, substance P, arginine vasopressin and bradykinin. Physiologic release of t-PA is deleteriously altered by modifiable cardiac risk factors such as smoking, hypertension, hyperlipidemia and obesity. Modification of these risk factors favorably alters vascular t-PA release. Our group has found that thrombin, but not bradykinin stimulates endothelial t-PA release in vitro. Furthermore, here has been recent evidence that sympathetic neurons, in addition to the endothelium, release t-PA in response to bradykinin in vivo. Taken together, these findings suggest that adventitial sympathetic neurons may play a critical role in vascular health. The central hypothesis of this proposal is that vascular innervation is a critical participant in human vascular t-PA release and overall vascular function. In order to test this hypothesis, we propose the following clinical studies. We intend measure bradykinin mediated t-PA release in the human forearm before and after blockade of systemic sympathetic outflow with the short acting central alpha-2 adrenergic antagonist dexmedetomidine. We also propose to perform intracoronary bradykinin infusions in order to measure the change in t-PA release and flow in response to bradykinin in transplant recipients and controls who are undergoing elective cardiac catheterization. Subjects will be asked return to the General Clinical Research Center to have t-PA release and flow measured in the forearm in response. In addition, elevated plasma t-PA levels and the absence of arteriolar smooth muscle t-PA predict accelerated transplant vasculopathy and graft failure in allograft recipients. As this may effect the response of bradykinin mediated t-PA release, we will compare the effects of intrabrachial and intracoronary bradykinin infusions on t-PA release in transplant recipients with and without transplant vasculopathy.

Public Health Relevance

A better understanding of the impact of sympathetic innervation on vascular function, especially with regard to fibrinolytic balance, will provide novel insights that would lead to new strategies and paradigms in the management of vascular diseases. With the overwhelming prevalence of vascular disease nationally, and worldwide, new insights and strategies have the potential translate to a tremendous public health impact.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL089400-04
Application #
8269835
Study Section
Special Emphasis Panel (ZHL1-CSR-R (O1))
Program Officer
Sarkar, Rita
Project Start
2009-08-15
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$126,808
Indirect Cost
$9,393
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Muldowney 3rd, James A S; Chen, Qingxia; Blakemore, Dana L et al. (2012) Pentoxifylline lowers plasminogen activator inhibitor 1 levels in obese individuals: a pilot study. Angiology 63:429-34