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.
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.
| 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 |
| Benge, Cassandra D; Muldowney 3rd, James A S (2012) The pharmacokinetics and pharmacodynamics of valsartan in the post-myocardial infarction population. Expert Opin Drug Metab Toxicol 8:1469-82 |
