Arterial heparin deposition: role of diffusion, convection, and extravascular space

Abstract

Transvascular transport has been studied with atherogenic, tracer, and inert compounds such as low-density lipoprotein, horseradish peroxidase, and albumin, respectively. Few studies used vasoactive compounds, and virtually all studies examined entry from the lumen and not from the perivascular space. We compared several mechanisms that govern arterial heparin deposition after administration to the perivascular and endovascular aspects of the calf carotid artery in vitro and the rabbit iliac artery in vivo. In the absence of transmural hydrostatic pressure gradients, heparin deposition following endovascular administration was unaffected by deendothelialization and was indistinguishable from perivascular delivery. Deposition in the former was enhanced by the addition of a pressure gradient and to a greater extent in denuded arteries, indicating that convection influences transport but is dampened by the endothelium. Neither the endothelium nor the adventitia pose significant resistances to heparin. Deposition in vivo was greater following endovascular hydrogel release than perivascular application from similar devices to native or denuded arteries. The loss of drug to extra-arterial microvessels exceeded the loss of drug to the lumen flow. These findings are essential for describing vascular pharmacokinetics and for implementing local pharmacotherapies.

Mechanism of controlled release kinetics from medical devices

“…Moreover, the eventual biological response is greatly influenced by diffusive and convective forces that govern drug transport, penetration, distribution and retention in the arterial wall Lovich et al, 1998), which are dependent on drug content and elution kinetics. Drug properties (mainly hydrophobicity), arterial architecture and local pharmacology exert their own influence on drug release from devices and drug uptake at the stentartery interface (Hwang et al, 2003, Lovich et al, 2001).…”

Specific binding to intracellular proteins determines arterial transport properties for rapamycin and paclitaxel

“…Heparin regulates virtually every aspect of the vascular response to injury (16). Yet heparin is so soluble and diffusible that it simply cannot stay in the artery for more than a few minutes after release and has no effect on intimal hyperplasia when eluted from a stent (4,17,18).…”

Some Things Just Have to Be Done In Vivo

“…34 There may be two pools of LpL, one displayed on luminal GPIHBP1 and one deep within adipose tissue and striated muscle. 34 Both pools might be eventually accessible to heparin, which has been reported to readily pass through arterial endothelium, 35 but only the pool adherent to GPIHBP1 would be accessible to emulsions and able to hydrolyze lipoprotein triglyceride. On the other hand, because heparin inhibits transendothelial transport of LpL in vitro, 19 heparin that reaches the tissue pool of LpL might strand it there, rather than facilitating its release into plasma.…”